HK1100562B

HK1100562B - Process for preparing amine platinum complexes

Info

Publication number: HK1100562B
Application number: HK07108382.2A
Authority: HK
Inventors: E．S．Y．翁; C．M．贾恩多米尼可
Original assignee: 阿诺麦德股份有限公司
Priority date: 1999-04-13
Filing date: 2007-08-01
Publication date: 2011-08-26

Description

Process for preparing amine platinum complexes

The present application is a divisional application of chinese patent application 200610009318.1 entitled "method for preparing amine platinum complexes".

Cross reference to related applications

This application claims priority from provisional U.S. patent application serial No. 60/128939, filed on month 4, 1999, which is incorporated herein by reference in its entirety.

Technical Field

The invention relates to the field of platinum drugs. In particular, the present invention relates to an improved process for the preparation of platinum complexes having the general formula (Ia) or (Ib):

wherein L and L 'may be the same or different if L' is NH₃L may not be NH₃(ii) a L and L ' are each an amine or substituted amine coordinated to the Pt atom through a nitrogen atom, are heterocyclic amines or heterocyclic aromatic amines, or they are represented by NRR ' R ' where R, R ' or R ' is independently selected from: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, nonaromatic or heterocyclic aromatic groups, L is preferably a substituted amine, the substituent of which sterically hinders the access of the Pt atom to the DNA chain of a cell, preferably a tumor cell; a may be the same or different and is a halogen or a leaving group, such as a hydroxyl, alkoxide, carboxylate, and may also be the same or different or form a bidentate ligand carboxylate, phosphonocarboxylate, bisphosphonate or sulphate; y is halogen, hydroxy, carboxylate, carbamate or carbonate.

Background

Us patent nos. 4329299 and 5665771 describe platinum compounds and their use against tumors. Both of these patents disclose compositions comprising cis- [ PtA₂(L′)(L)]And c, t, c- [ PtA₂Y₂(L′)(L)]Wherein A is a leaving group such as halogen, hydroxyl or carboxylate, L is an amine coordinated through a nitrogen atom, and L' is ammonium or a substituted amine. Methods for preparing these compounds are disclosed in patents well known in the art [ Hydes, p.c., U.S. patent No. 4329299 (1982); murrer, b.a., U.S. patent No. 5665771 (1997); braddock, p.d., Connors, t.a.; jones, m., Khokhar, a.r.; melzak, d.h., Tobe, m.l., chem.biol.interactions, 1975, 11, 145-161; and Giandomenico, c.m.; abrams, m.j.; murrer, b.a.; vollano, j.f.; rheinheimer, m.i.; wyer, s.b.; boscard, g.e.; higgins (iii), j.d., inorg. chem., 1995, 34, 1015-. FIG. 1 shows cis- [ PtCl ]₂(NH₃)(L)]And c, t, c- [ PtCl₂(OH)₂(NH₃)(L)]The process is illustrated for example. With readily available and commonly used K₂[PtCl₄]As starting material, cis- [ PtCl₂(NH₃)(L)]The synthesis of (2) involves four steps, c, t, c- [ PtCl₂Y₂(NH₃)(L)]The synthesis of (2) requires five steps. These complexes are synthesized in low overall yields using methods well known in the art. Slave K disclosed in U.S. Pat. No. 4329299₂[PtCl₂]The overall yield was less than 8% and reported in U.S. Pat. No. 5665771 and the literature (Khokhar et al and Giandomenico et al) as 20-30%. The overall yield is low because many stages are involved in the synthesis process and because [ PtCl ]₂(NH₃)₂]Conversion to [ PtCl₃(NH₃)]^-There are difficulties and low yields, which require the use of expensive Pt catalysts. From [ PtCl₂(NH₃)₂]To K [ PtCl ]₃(NH₃)]Nor is the synthesis of K [ PtCl ] not particularly stable, in a large range₃(NH₃)]Consistent quality of the synthesis is also difficult to obtain. The above process also requires silver and iodide ions (iodide ion), producing silver and iodide contaminated waste.

U.S. Pat. No. 4533502 and British patent No. 2137198A disclose a process for preparing [ PtX [ ]₂(L)(L′)]Wherein L and L 'are ligands bound by amine nitrogen, and L ≠ L' [ Rochon, f.d., Kong, p. -c., british patent GB 2137198A (1984) and Rochon, f.d., Kong, p. -c., U.S. patent No. 4533502 (1985) ]. This method is well known in the art and details of the synthetic method have been published (Courtot, P.; Rumin, R.; Peron, A.; Girault, J.P.J., Organomet)allic chem., 1978, 145, 343-; kong, P. -C., Can.J.chem., 1986, 64, 1894-. FIG. 2 with [ PtCl ]₂(L)(L′)]The process is illustrated for the sake of example. With K₂[PtCl₄]As a starting material, the processes disclosed in us patent No. 4533502 and british patent No. GB 2137198a involve 4 steps and 3 separations of intermediates. [ PtLI ] for oligomer intermediates₂]_xWherein X is 2-4; a variety of oligomers are possible. No disclosure is made in this patent from K₂[PtCl₄]The overall yield obtained. Silver and iodide ions are used in the process and corresponding silver and iodide contaminated waste is produced.

[PtCl₃L]^-Represents an intermediate product of the invention, wherein L is an amine and not NH₃. Has been reported to be derived from diluted K₂[PtCl₄]Preparation of [ PtCl ] in Dimethylformamide (DMF) solution₃L]^-(Rochon, F.D., Kong, P. -C., Can, J.Chem., 1978, 56, 441-. Preparation of [ PtCl ] in non-DMF or aqueous solutions, or with amines other than pyridine and its derivatives has not been reported₃L]^-. K [ PtCl ] in DMF reported in literature₃L]The synthesis temperature of (a) is from 65 ℃ to 80 ℃ and, depending on the pyridine derivative, the isolated product yields are from 40% to 90%. [ PtCl ] in DMF₃L]^-Can produce reactive or unstable Pt DMF complexes that can interfere with subsequent reactions or decompose to insoluble black Pt impurities. For example, in Can.J.chem., 1978, 56, 441 (see also Chemical abstracts V.89 (7.1978), abstract No. 35686), Rochon et al report that K [ PtCl ] is present₃(2, 6-lutidine)]Insoluble black impurities precipitate when dissolved in aqueous solution. It has also been reported that in K [ PtCl ]₃(4-methylpyridine)]And K [ PtCl ]₃(pyridine)]In the separation process of (A) to obtain a catalyst containing [ PtCl₂(DMF) (pyridine derivative)]And other impurities. [ PtCl ]₂(DMF)L]Examples of the complexesReports have been made (Kong, P. -C., Rochon, F.D., Can.J.Chem., 1979, 57, 682-684; Rochon, F.D., Kong, P. -C., Melanson, R., Can.J.Chem., 1980, 58, 97-101; and Rochon, F.D., Melanson, R., Doyon, M., Butler, I.S., Inorg.Chem., 1994, 33, 4485-4493).

Chemical abstracts, v.126 (4 months 1997), abstract 194433 and inorg. chem. (1997), 36: 854-861 discloses the use of [ Pt (C-C)₆H₁₁NH₂)]As a starting material, Pt [ (NH) is formed₃)(c-C₆H₁₁NH₂)]Cl₂(FIG. 2). However, this reaction involves the formation of a Pt-A-Pt bond with NH after the formation of an intermediate with the same substituents₃Cleavage of the group.

Chemical abstracts, v.108 (month 6 1998), abstract 215224 and inorg. chim. acta (1988), 143: 81-7 discloses [ Pt (Cl)₄]^2-Conversion to [ Pt (Cl) ]₃NH₃]^1-However, there is no disclosure of adding a substituted cyclic amine to the intermediate.

Citation of the above documents is not intended as an admission that any of the above documents is pertinent prior art. The statement as to the date of these documents or the contents thereof is based on the information available to the applicant and does not constitute any admission by the applicant as to the correctness of the dates or contents of these documents, all documents referred to in this application being incorporated by reference in their entirety. In particular, this application claims priority from U.S. provisional patent application serial No. 60/128939, filed on 13/4/1999, and which is incorporated by reference herein in its entirety.

Disclosure of Invention

The invention provides a method for preparing a cisplatin complex with a general formula Ia or Ib,

the method comprises the following steps:

a) let [ PtA₄]^2-Or salts thereof, with L in a solvent to form [ PtA₃(L)]^-；

b) Let [ PtA₃(L)]^-Reacting with L' in a second solvent to form cis- [ PtA₂(L′)(L)]；

c) In the case where the cisplatin complex is of formula Ib and Y is hydroxy or halogen, reacting the cis- [ PtA ] formed in step b)₂(L′)(L)]And H₂O₂Reacting to form c, t, c- [ PtA [ ]₂Y₂(L′)(L)](ii) a And

d) in the case where the cisplatin complex is of formula Ib and Y is a carboxylate, carbamate or carbonate, first, the cis- [ PtA ] formed in step b) is reacted according to step c)₂(L′)(L)]And H₂O₂Reaction of [ PtA ]₂(L′)(L)]Form [ PtA₂(OH)₂(L′)(L)]Followed by the reaction of [ PtA₂(OH)₂(L′)(L)]Reaction with acylating agents to form [ PtA₂Y₂(L′)(L)]；

Wherein L and L ' are different and are each an amine or substituted amine coordinated to the Pt atom through a nitrogen atom, is a heterocyclic or heteroaromatic amine, or is represented by NNR ' R ", wherein R, R ' and R" are independently selected from the group consisting of: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, non-aromatic or aromatic heterocyclic groups; with the proviso that only L' may be NH₃And at least one of L and L' is a substituted heterocyclic or heteroaromatic amine;

wherein A, which may be the same or different, is a halide or non-halide leaving group.

The invention also provides a method for preparing the cis-platinum complex with the general formula Ia 'or Ib',

the method comprises the following steps:

d) in the case where the cisplatin complex is of formula Ib and Y is a carboxylate, carbamate or carbonate, first, according to step c), the cis- [ PtA2 (L') (L) formed in step b) is reacted]And H₂O₂Reaction of [ PtA ]₂(L′)(L)]Form [ PtA₂(OH)₂(L′)(L)]Followed by the reaction of [ PtA₂(OH)₂(L′)(L)]Reaction with acylating agents to form [ PtA₂Y₂(L′)(L)]；

e) Converting a to a ', wherein a' is a different halide or non-halide leaving group;

wherein L and L ', which may be the same or different, are each an amine or a substituted amine, provided only L ' may be wherein L and L ' are different, are each an amine or a substituted amine coordinated to the Pt atom through a nitrogen atom, are heterocyclic or heteroaromatic amines, or are represented by NNR ' R ' wherein R, R ' and R ' are independently selected from: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, non-aromatic or aromatic heterocyclic groups; with the proviso that only L' may be present]To be NH₃And at least one of L and LIs a substituted heterocyclic or heteroaromatic amine;

The invention also provides a cisplatin complex of formula Ib:

wherein L is

L' is NH₃A is Cl and OH, and Y is OH. "

The invention describes a process for the preparation of a platinum compound, preferably a platinum tetrahalide such as [ PtCl ], directly from a cheap and readily available platinum starting material₄]^2-Or [ PtBr ]₄]^2-More efficient and economical preparation of cis- [ PtA₂(L′)(L)](formula Ia) and c, t, c- [ PtA)₂Y₂(L′)(L)]A method of forming a Pt complex of the form (formula Ib).

Wherein L and L 'may be the same or different, and L' may be NH₃L may not be NH₃(ii) a L and L ' are each an amine or substituted amine coordinated to the Pt atom through a nitrogen atom, are heterocyclic or heteroaromatic amines, or they are represented by NRR ' R ' where R, R ' or R ' are independently selected from: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, non-aromatic or aromatic heterocyclic group, L is preferably a substituted amine, the substituent of which sterically hinders the access of the Pt atom to the DNA chain of a cell, preferably a tumor cell; a may be the same or different and is a halogen or a leaving group, such as a hydroxyl, alkoxide, carboxylate, and may also be the same or different or form a bidentate ligand carboxylate, phosphonocarboxylate, bisphosphonate or sulphate; y is halogen, hydroxy, carboxyA compound, a carbamate, or a carbonate.

In one embodiment, the process of the present invention is preferably used to prepare compounds of formula Ia.

The terminology used herein is based on the meanings recognized in the art and will be clearly understood by those of ordinary skill in the art from the present disclosure. For the sake of clarity, the terms may also have specific meanings, such that their use in the text will be clear. For example, a ligand is an ion or molecule that is attached to and believed to bind to a metal atom or ion. Monodentate refers to a site that has a covalent or coordinate bond with a metal. Bidentate refers to a position having two sites that can form a covalent or coordinate bond with a metal. Preferably, the L and L' amines of the present invention form monodentate coordination with Pt via the nitrogen atom. Also, "steric hindrance" is used according to a usual usage in the art. Thus, "sterically hindered amine" refers to an amine component that, due to its size or volume, hinders or interferes with the rotation or other function or performance of any other component of the Pt complexes disclosed herein. The process of the present invention is preferably used to prepare the compounds described in U.S. Pat. No. 5665771 (especially sterically hindered amines derived from formula Ia of this patent), which is incorporated herein by reference in its entirety, and in particular the definitions of the substituents disclosed therein are incorporated herein by reference. When it is contemplated that both L and L' are heterocyclic or heteroaromatic amines attached to the nitrogen, the term "substituted" as used herein refers to a substituent group independently selected from: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, non-aromatic or aromatic heterocyclic groups; preferably, L is a substituted amine, whereby the substituent sterically hinders access of the Pt atom to the DNA strand of the cell, preferably the tumor cell. Examples of such substituted L or L' include, but are not limited to: alkylamines which may include methylamine, dimethylamine, tributylamine, diisopropylamine; aromatic amines which may include aniline, toluidine, aminonaphthalene, and aminoanthracene; heterocyclic amines that may include piperidine, piperazine, and pyrrolidine; and heterocyclic aromatic amines which may include pyridine, pyrazole, imidazole, oxazole, isoxazole; pyrimidines and pyrazines. Other substituents will be desirable to those of ordinary skill in the art who will readily understand that other substituents may also be used in the present invention in a manner consistent with the presently disclosed methods.

More specifically, for example, in the case of substituted cyclic amines, the substituent may be a lower alkyl or lower alkoxy group of 1 to 4 carbon atoms (specifically methyl or methoxy), a halogen (specifically chlorine and bromine), or an aryl group (specifically phenyl). The substituents may themselves be substituted with lower alkyl or halogen. The term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms. The cyclic amine may carry other substituents near the coordinating nitrogen atom or present on the ring. Other substituents include electron withdrawing substituents or electron donating substituents such as nitro and alkoxy (e.g., methoxy). If the cyclic amine is a fused ring system, the rings to which it is fused are aromatic rings in the 2-and 3-positions of the cyclic amine, although additional substituents may be present, but are not required. It is also contemplated to use the present invention to prepare the trans isomer. In a preferred embodiment, the present invention is used to prepare the cis isomer.

For purposes of illustrating the invention, a compound of formula [ PtCl ]₄]^2-Synthesis of cis- [ PtCl₂(NH₃)(L)]And c, t, c- [ PtCl₂(OH)₂(NH₃)(L)]For example. Cis- [ PtBr ] of the same class₂(NH₃)(L)]And c, t, c- [ PtBr₂(OH)₂(NH₃)(L)]Can also be substituted by [ PtBr ] in the same manner₄]^2-And (4) preparing.

For cis- [ PtCl₂(NH₃)(L)]The improved process involves 2 steps, the first step is the reaction of [ PtCl ] in an aprotic solvent₄]^2-Is converted into [ PtCl ] or into a concentrate₃L]^-. The second step is to react [ PtCl ] in ammonium hydroxide solution₃L]^-Is converted into cis- [ PtCl₂(NH₃)(L)]. The improved process has fewer synthetic steps and fewer isolated products, requires less volume of ecologically hazardous solvents, produces less gold than synthetic processes currently used in the artBelonging to the polluted waste, cis- [ PtCl ]₂(NH₃)(L)]The total yield of (A) is higher. The method also does not use silver and iodide ions and does not produce waste polluted by silver and iodide. All steps of the method are stable and reproducible, and can consistently produce products of the same quality.

The first step of the improvement is to react [ PtCl ] in a first solvent under appropriate conditions₄]^2-Reaction with amine L to give [ ptCl₃L]^-. The most readily available [ PtCl ] is generally used₄]^2-The potassium salt of (1). However, [ PtCl ]₄]^2-Other salts of (4) can also be used. Suitable conditions refer to reaction conditions that facilitate and drive the performance of the chemical reactions disclosed and claimed. In particular, the conditions provided by the present invention include, but are not limited to: temperature, pH, concentration of reactants, degree of agitation, mesh size of reactants, and other conditions that facilitate the performance of the disclosed chemical reaction. However, other suitable conditions are those familiar to the skilled artisan that result from the disclosed chemical reactions. To help K₂[PtCl₄]Dissolving, preferably using finely ground K₂[PtCl₄]And (3) powder. Preferably, K is₂[PtCl₄]Is no greater than about 240 μ M. More preferably, K is₂[PtCl₄]Is no greater than about 100 μ M. In the reaction, 1-1.3 equivalents of amine and 1 equivalent of K₂[PtCl₄]And (4) reacting. More preferably, 1 to 1.2 equivalents of amine are used. Most preferably, 1.05 to 1.15 equivalents of amine to 1 equivalent of K are used₂[PtCl₄]And (4) reacting. The use of high equivalents of amine increases the rate of reaction, but also increases the formation of by-products, reducing the yield of the reaction. In addition, the amine L is added gradually in small portions to the reaction mixture over a period of time. Preferably, the amine is introduced in equal amounts of more than two parts, more preferably in equal amounts of more than 4 parts.

The reaction can be carried out at a temperature of 30-100 deg.C, but more preferably the reaction temperature is 40-70 deg.C, most preferably 50-65 deg.C. Generally, the higher the reaction temperature, [ PtCl ]₄]^2-The greater the reaction rate with the amine. However, high reaction temperatures can increase the formation of by-products or allow the formation of reactive and unstable Pt impurities. Reaction temperatures of not less than about 60 ℃ in a solvent capable of coordinating with the metal atom (e.g., DMF) may promote the formation of Pt solvent complexes that may decompose or interfere with the next step in the process.

The reaction is carried out in an aprotic solvent. Preferably, the solvent contains less than about 25% water, and preferably less than about 10% water. More preferably, the water content is less than 3%. The reaction can be carried out in aprotic solvents such as acetone, chloroform, dichloromethane, dimethylacetamide, dimethylformamide, N-methylpyrrolidone and tetrahydrofuran. N-methylpyrrolidone is the most preferred solvent.

The first reaction step is carried out in a ratio of less than 15ml solvent per 1mmol platinum. In a preferred embodiment of the invention, the ratio of solvent (ml) to Pt (mmol) used is 3-6: 1. However, in a more preferred embodiment of the invention, the ratio of solvent to Pt in the first reaction step is 1-2: 1.

[ PtCl ] has been described in the literature₃L]^-Synthesis in DMF, wherein L is pyridine or a derivative thereof (Rochon, f.d., Kong, p. -c., can.j.chem., 1978, 56, 441-. For K [ PtCl ]₃(L)]By the synthesis of K [ PtCl ]₃(2-methylpyridine)]The disclosed methods are compared to illustrative examples. In the published method, K [ PtCl ]₃(2-methylpyridine)]The separation of (2) requires two steps, in each of which the solvent is evaporated under reduced pressure. Evaporation of DMF under reduced pressure required heating to 40 ℃. In a wide range of industrial syntheses, evaporation of the solvent under reduced pressure, especially requiring heating, is an expensive and time consuming process. In our preferred method, K [ PtCl ]₃(2-methylpyridine)]Without the need to evaporate the solvent, nor to transfer material from one solvent to another. The invention disclosesThe process is more efficient and it is better suited for the large-scale industrial preparation of the compound. Two methods for producing K [ PtCl ]₃(2-methylpyridine)]Has comparable yield and quality. K [ PtCl ] prepared using methods well known in the art and using the methods disclosed herein₃(2-methylpyridine)]The infrared spectrum and NMR spectrum data of (a) are shown in fig. 4 and 5. The invention clarifies [ PtCl₃L]^-Synthesis in other solvents such as acetone, chloroform, dichloromethane and N-methylpyrrolidone.

The coordination of solvent molecules with Pt causes the formation of reactive or unstable Pt species, which presents problems for the process described in the present invention. Among the published methods (Rochon, F.D., Kong, P. -C., Can.J.Chem., 1978, 56, 441-445) [ PtCl ] has been reported₃(pyridine derivatives)]In the synthesis of [ PtCl₂(DMF) (pyridine derivative)]And other impurities. In the present invention, we disclose a temperature range in which undesirable species such as [ PtCl ] are present₂(DMF) (pyridine derivative)]Is minimized. The formation of a black precipitate during product isolation indicates the presence of reactive Pt impurities. With K [ PtCl ]₃(2-methylpyridine)]Synthesis in dimethylformamide as an example, no insoluble black precipitate was observed when the synthesis temperature was below 60 ℃. In our best method, the temperature used in the first step reaction is about 50-65 ℃. However, impurities such as [ PtCl ] in unwanted species or reaction products₂(DMF) (pyridine derivative)]Any temperature at which formation of (c) is minimized (< 10%) or eliminated is within the contemplation of the present invention.

In aqueous ammonium hydroxide solution [ PtCl ]₃L]^-Conversion to [ PtCl₂(NH₃)L]Step 2 of the present invention is illustrated. Step 2 is [ PtCl ]₃L]^-With NH₃Reaction in another solvent to give [ PtCl₂(NH₃)L]. In ammonium hydroxide solution at about 30-60 deg.C [ PtCl ]₂(NH₃)L]And (4) synthesizing. More preferably, the reaction temperature is 35-55 deg.C, most preferably 40-50 deg.C. In general, theThe high reaction temperature shortens the reaction time but also promotes the formation of Pt-polyamino/amine by-products. The formation of large amounts of by-products reduces the yield of the reaction.

The pH of the reaction is approximately 7-14. The pH is preferably 7 to 12, more preferably 8 to 10. Running the reaction at a pH greater than 10 again results in low yields due to the increased Pt polyamine by-product.

The reaction concentration was 1 g of K [ PtCl ]₃L]3-10ml of solvent. 1 g of K [ PtCl ]₃L]Perferably 1 g of K [ PtCl ] in 4-8ml of solvent₃L]Most preferably 5-7ml of solvent. Unexpectedly, the reaction at high concentrations is effective to produce high yields of product. The reaction can be carried out at a more dilute concentration, but the yield of the reaction is low due to the formation of by-products. Larger volumes of solvent and more dilute concentrations also require the disposal of larger volumes of ecologically undesirable solvents and waste. Preferably, the reaction is carried out strictly in aqueous solution. However, a combination of organic and aqueous solvents may also be used. The second solvent may contain 0.1N to 6N chloride. In particular, the present invention provides that the second reaction step 1b) is carried out at a ratio of solvent (ml) to platinum (mmol) of not more than about 5: 1. NH when the second step of the process is carried out₃The ratio to Pt is in the range of about 3 to 7, preferably 4 to 6, and most preferably 4.5 to 5.5. The second reaction step 1b) provided by the present invention is carried out with a molar ratio of free radicals L' to Pt of about 3: 1 to 1: 1. Excess NH₃Reaction time is reduced but also the formation of Pt-polyamino/amine by-products is increased.

From cis- [ PtA₂(NH₃)(L)]Initially, it can be via cis- [ PtA₂(NH₃)(L)]The suspension is reacted with hydrogen peroxide to obtain c, t, c- [ PtA [ ]₂(OH)₂(NH₃)(L)]. Other compounds of formula c, t, c- [ PtA ] prepared using methods well known in the art₂Y₂(NH₃)(L)]The Pt (IV) complex of (a) may be formed from c, t, c- [ PtA [ ]₂(OH)₂(NH₃)(L)]Wherein Y is halogen, hydroxy, carboxylate, carbamate or carbonate, and both Y areNot hydroxyl at the same time.

For the description of cis- [ PtCl₂(NH₃)(L)]And c, t, c- [ PtCl₂(OH)₂(NH₃)(L)]Examples of the preparation of (A) can also be applied to the formula cis- [ PtA₂(L)(L′)]And c, t, c- [ PtA₂Y₂(L)(L′)]Wherein L and L 'may be the same or different, and L' may be NH₃L may not be NH₃(ii) a L and L ' are each an amine or substituted amine coordinated to the Pt atom through a nitrogen atom, are heterocyclic or heterocyclic aromatic amines, or are represented by NRR ' R ' wherein R, R ' or R ' are independently selected from: hydrogen, substituted or unsubstituted straight, branched or cyclic aliphatic, aryl, non-aromatic or aromatic heterocyclic group, L is preferably a substituted amine, the substituent of which sterically hinders the access of the Pt atom to the DNA chain of a cell, preferably a tumor cell; a may be the same or different and is a halogen or a leaving group, such as a hydroxyl, alkoxide, carboxylate, or form a bidentate ligand carboxylate, phosphonocarboxylate, bisphosphonate or sulphate; y is halogen, hydroxy, carboxylate, carbamate or carbonate.

For complexes of Ia or Ib, methods for converting ligand A to a different leaving group (e.g., halide, hydroxy, alkoxide, or monodentate carboxylate, or bidentate phosphonyl carboxylate, or bidentate phosphonate, or bidentate sulfate) are well known in the art. Examples of these transformations are described in equations 1 and 2. It is envisaged that many other permutations and combinations of leaving group transformations will produce useful complexes. The disclosed methods for the preparation of intermediates would be useful for the preparation of all of these compounds.

Equation 1. Process for the preparation of complexes of formula Ia, where the two leaving groups A are halides and are different.

Intermediate Ia without isolation of intermediate of the invention

Equation 2. conversion of two ligands a (where a is the halide of the new compound that can be formed and both a's are the same and can form a bidentate carboxylate).

Having generally described this invention, the same will be more readily understood through the following examples, which are intended as illustrative and not limiting, unless specified.

Drawings

FIG. 1 illustrates the reaction of K [ PtCl ]₃(NH₃)]Synthesis of cis- [ PtCl₂(NH₃))L)]And c, t, c- [ PtX [ ]₂Y₂(NH₃)(L)]。

FIG. 2 illustrates the process [ PtI ]₂(L)]_xOligomer Synthesis [ PtCl₂(L)L′]。

FIG. 3 illustrates the synthesis of [ PtA ] by the process of the invention₂(L′)(L)]。

FIG. 4 illustrates [ PtCl ] prepared by the disclosed method₂(NH₃) (2-methylpyridine)]Infrared spectrum and NMR spectrum data. FIG. 4A. PtCl prepared by the method disclosed in the present invention₂(NH₃) + (2-methylpyridine)]Infrared spectrum of (D). FIG. 4B [ PtCl ] prepared by the method disclosed in the present invention₂(NH₃) (2-methylpyridine)]Is/are as follows¹⁹⁵PtNMR spectrum. FIG. 4C [ PtCl ] prepared by the method disclosed in the present invention₂(NH₃) (2-methylpyridine)]Is/are as follows¹HNMR spectroscopy.

FIG. 5 illustrates [ PtCl ] prepared by a method well known in the art, illustrated in FIG. 1₂(NH₃) (2-methylpyridine)]Infrared spectrum and NMR spectrum data. FIG. 5A. PtCl prepared by a method well known in the art as illustrated in FIG. 1₂(NH₃) (2-methylpyridine)]Infrared spectrum of (D). FIG. 5B [ PtCl ] prepared by a method well known in the art as illustrated in FIG. 1₂(NH₃) (2-methylpyridine)]Is/are as follows¹⁹⁵Pt NMR spectroscopic data. FIG. 5C [ PtCl ] prepared by a method well known in the art as illustrated in FIG. 1₂(NH₃) (2-methylpyridine)]Is/are as follows¹H NMR spectroscopic data.

Detailed Description

In the examples set forth below, use¹H NMR and¹⁹⁵pt NMR spectroscopy, elemental analysis and HPLC analysis of the compounds. In DMF-d⁷Recording NMR spectra with a Bruker Avance 300 instrument (¹H and¹⁹⁵pt NMR) and compared to spectra of reference compounds synthesized using techniques well known in the art. Elemental analysis (% C,% H,% N) was performed using a Perkinelmer 2400 or Carlo Erba 1108 analyzer. The% Cl content was determined by titration with silver nitrate. The compounds described in the examples below were analysed using two HPLC methods (anionic and cationic HPLC methods). For the anionic HPLC method, K [ PtCl ]₃(2-methylpyridine)]And [ PtCl ]₂(NH₃) (2-methylpyridine)]The retention times of (a) and (b) were 21.9 minutes and 4.2 minutes, respectively. For the cationic process, [ PtCl ]₂(NH₃) (2-methylpyridine)]The retention time of (a) was 3 minutes. HPLC retention times of the synthesized compounds were compared to retention times of references prepared by methods well known in the art. The operating conditions for the anionic and cationic HPLC methods were as follows:

cationic HPLC method:

column: Hichrom-RPB, 5 μm, 100mm × 4.6mm, 100 angstroms, series number HIRPB3374

Moving phase：A：0.02M H₃PO₄(99.99%, Aldrich34524-5), 5mM hexanesulfonic acid (Sigma 39789), pH adjusted to 2.7 with concentrated NaOH

B; methanol (Fisher HPLC grade)

Gradient: 0 min 95% A5% B

6 min 95% A5% B

20 min 50% A50% B

25 min 50% A50% B

25.01 min 95% A5% B

Total operating time: 35.01 minutes

Flow rate: 1.0 ml/min

Temperature: 25 deg.C

A detector: DAD @267nm

An injector: 10 μ l

Anionic HPLC method:

column: Hichrom-RPB C₈/C₁₈5 μm, 100 mm. times.4.6 mm, 100 angstroms, series number HIRPB3265

Mobile phase: a: 0.02M H₃PO₄(99.999%, Aldrich45228-9), 5mM tetrabutylammonium hydrogen sulfate (Sigma39683-4), pH adjusted to 2.5 with concentrated NaOH

B: methanol (Fisher HPLC grade)

Gradient: 0 min 95% A5% B

5 min 95% A5% B

22 min 65% A35% B

23 min 50% A50% B

28 min 50% A50% B

30 min 95% A5% B

Total operating time: 40 minutes

Flow rate: 1.0 ml/min

Temperature: 35C

A detector: DAD @230nm

An injector: 15 μ l

Examples 1-9 illustrate step 1 of the process.

Example 1) K [ PtCl₃(2-methylpyridine)]Synthesis in N-methylpyrrolidone

Mixing K with mortar and pestle₂[PtCl₄]Ground to a very fine powder. A25 mL round bottom flask was charged with 3.5047 g (8.443mmol) K₂[PtCl₄]Then 6-7 ml of anhydrous NMP was added. 0.8648 g (9.286mmol) of 2-methylpyridine were added to 3-4ml of NMP and divided into 5 equal portions. A first aliquot of 2-methylpyridine was added to the Pt mixture. The mixture was completely immersed in an oil bath at 60 ℃ and stirred at 1200 rpm. The remaining 2-picoline aliquots were added separately at 30-35 minute intervals, with the rate of 2-picoline addition being 20% every 30-35 minutes. After the last portion was added, the reaction was allowed to proceed for an additional 50-60 minutes. The reaction solution was finally orange. The reaction solution was allowed to cool to ambient temperature. 100mL of methylene chloride was added to the reaction at ambient temperature. Addition of dichloromethane causes K [ PtCl ]₃(2-methylpyridine)]And KCl precipitation. The precipitate was collected by vacuum filtration using a frit filter and washed with dichloromethane (3X 5mL) followed by diethyl ether (3X 5 mL). TrueThe precipitate was dried in air at ambient temperature for 16-24 hours and weighed. Yield 3.8440 g (86.8%). C₆H₇N₁Cl₃KPt·1.2K₁Cl₁Calculated (found): c, 13.74 (13.54); h, 1.35 (1.39); n, 2.67 (2.59); cl, 28.51 (28.32).¹HNMR(300MHz，DMF-d⁶): 9.12(d, 1 pyridine H); 7.90(t, 1 pyridine H); 7.61(d, 1 pyridine H); 7.40(t, 1 pyridine H); 3.40(s, 3 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and K [ PtCl ] prepared by methods well known in the art₃(2-methylpyridine)]Is/are as follows¹⁹⁵The Pt NMR spectra were consistent. HPLC (anionic HPLC method): the retention time is consistent with that of the reference.

Example 2) K [ PtCl₃(2, 6-lutidine)]Synthesis in N-methylpyrrolidone

Mixing K with mortar and pestle₂[PtCl₄]Ground to a very fine powder. In a 15mL round bottom flask was added 1.9427 g (4.68mmol) of K₂[PtCl₄]Then 4ml of anhydrous NMP was added. 0.5501 g (5.13mmol) of 2, 6-lutidine were added to 3-4ml of NMP and divided into 5 equal portions. The first aliquot of 2-methylpyridine was added to the Pt mixture. The mixture was completely immersed in an oil bath at 60 ℃ and stirred at 1200 rpm. The remaining aliquots were added separately at intervals of 30-35 minutes. 2-methylpyridine was added at a rate of 20% addition every 30-35 minutes. The total reaction time was 24 hours. The reaction solution was finally orange. The reaction solution was allowed to cool to ambient temperature. 200mL of methylene chloride was added to the reaction at ambient temperature. Addition of dichloromethane leads to K [ PtCl ]₃(2-methylpyridine)]And KCl precipitation. The precipitate was collected by vacuum filtration through a frit filter, washed 3 times with 5mL of dichloromethane followed by diethyl ether (3X 5 mL). The precipitate was dried in vacuo at ambient temperature for 16-24 hours and weighed. Yield 2.1415 g (84.7%). C₇H₉N₁Cl₃KPt·1.24K₁Cl₁Calculated (found): c, 15.57 (15.40); h, 1.68 (1.72); n, 2.59 (2.60); cl (27.83 (27.70).¹H NMR(300MHz，DMF-d⁶): 7.6(t, 1 pyridine H); 7.28(d, 2 pyridine H); 3.51(s, 3 methyl H); 3.43(s, 3 methyl H).

Example 3) K [ PtCl ] at 50 ℃₃(2-methylpyridine)]Synthesis in dimethylformamide

Mixing K with mortar and pestle₂[PtCl₄]Ground to a very fine powder. In a 25mL round bottom flask was added 2.6461 g (6.375mmol) K₂[PtCl₄]Then 6mL of anhydrous DMF was added. To the Pt solution was added 0.6233 g (6.693mmol) of 2-methylpyridine. The reaction was carried out in an oil bath at 50 ℃ for about 120 minutes. The reaction solution was finally orange. The reaction solution was allowed to cool to ambient temperature. 100mL of chloroform was added to the reaction at ambient temperature. Addition of chloroform results in K [ PtCl ]₃(2, 6-lutidine)]And KCl precipitation. The precipitate was collected by vacuum filtration through a frit filter, washed 3 times with 5mL portions of methylene chloride, followed by 3 times with diethyl ether. 5mL each time. The precipitate was dried under vacuum at ambient temperature for 16-24 hours and then weighed. Yield 2.8565 g (84%). C₇H₉N₁Cl₃KPt·1.3K₁Cl₁Calculated (found): c, 13.58 (13.65); h, 1.33 (1.31); n, 2.67 (2.64); cl (28.73 (28.78).¹H NMR(300MHz，DMF-d⁶): 9.12(d, 1 pyridine H); 7.90(t, 1 pyridine H); 7.61(d, 1 pyridine H); 7.40(t, 1 pyridine H); 3.40(s, 3 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and K [ PtCl ] prepared by methods well known in the art₃(2-methylpyridine)]Is/are as follows¹⁹⁵The Pt NMR spectra were consistent. HPLC (anionic HPLC method): the retention time is consistent with that of the reference.

Example 4) K [ PtCl ] at 50 ℃₃(2, 6-lutidine)]Synthesis in dimethylformamide

Mixing K with mortar and pestle₂[PtCl₄]Ground to a very fine powder. In a 15mL round bottom flask was added 1.0900 g (2.62mmol) K₂[PtCl₄]Then 2-3mL of anhydrous DMF was added. 0.3078 g was added to 1-2ml of DMF(2.87mmol) of 2, 6-lutidine and divided into 5 equal portions. The first aliquot of 2-methylpyridine was added to the Pt mixture. The mixture was completely immersed in an oil bath at 50 ℃ and stirred at 1200 rpm. The remaining aliquots were added separately at intervals of 30-35 minutes. 2-methylpyridine was added at a rate of 20% addition every 30-35 minutes. The total reaction time was 72 hours. The reaction was finally orange. The reaction solution was cooled to ambient temperature and filtered. 100mL of methylene chloride was added to the reaction at ambient temperature. Addition of dichloromethane leads to K [ PtCl ]₃(2, 6-lutidine)]And (4) precipitating. The precipitate was collected by vacuum filtration through a frit filter, washed 3 times with 5mL of dichloromethane followed by diethyl ether (3X 5 mL). The precipitate was dried in vacuo at ambient temperature for 16-24 hours and weighed. Yield 0.6815 g (53.1%). C₇H₉N₁Cl₃KPt·0.1K₂[PtCl₄]Calculated (found): c, 17.19 (17.20); h, 1.85 (1.90); n, 2.86 (2.935); cl, 24.64 (24.61).¹H NMR(300MHz，DMF-d⁶): 7.6(t, 1 pyridine H); 7.28(d, 2 pyridine H); 3.51(s, 3 methyl H); 3.43(s, 3 methyl H).

Example 5) in acetone, dichloromethane or chloroform [ PtCl ]₃(2-methylpyridine)]^-Synthesis of (2)

A25 mL round bottom flask was charged with 1.0040 g (2.419mmol) K₂[PtCl₄]And 1mL of acetone. 0.67 g (2.4mmol) of tetrabutylammonium chloride are dissolved in 2mL of acetone and then added to K₂[PtCl₄]In solution. 0.2783 g (2.988mmol) of 2-methylpyridine were dissolved in 2mL of acetone and added to the Pt solution. The reaction temperature was maintained at 60 ℃. K₂[PtCl₄]Slowly dissolve to be soluble [ PtCl ] within 1 hour₄]^2-Tetrabutylammonium salt of (1). The reaction solution was stirred at 50 ℃ for 16 hours. The reaction solution was filtered to remove KCl and acetone was removed under reduced pressure to give an orange oil, [ PtCl ]₃(2-methylpyridine)]^-。¹H NMR(300MHz，DMF-d⁶): 9.0(d, 1 pyridine H); 7.8(t, 1 pyridine H); 7.45(d, 1 pyridine H); 7.25(t, 1 pyridine H)(ii) a 3.20(s, 3 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): consistent with the reference.

Preparation of [ PtCl ] using chloroform or dichloromethane as solvent in the same manner₃(2-methylpyridine)]^-。¹HNMR: consistent with the reference.

For separating [ PtCl₃(2-methylpyridine)]^1-The orange oil was dissolved in 2mL of methanol. Addition of potassium acetate in methanol results in K [ PtCl ]₃(2-methylpyridine)]And (4) precipitating. The precipitate was dried under vacuum at ambient temperature for 16-24 hours and then weighed. Yield 0.5762 g (55%).

Example 6) Synthesis of [ PtCl ] from tetrabutylammonium Tetrachloroplatinate in acetone₃(tributylamine)]^-

0.2715 g (0.33mmol) of tetrabutylammonium tetrachloroplatinate were dissolved in acetone. To the Pt solution was added 0.1323 g (0.7135mmol) of tributylamine. The reaction solution was heated at 60 ℃ overnight. The reaction solution was filtered to remove KCl and acetone under reduced pressure to give an orange oil, the corresponding [ PtCl ]₃(tributylamine)]-the product.¹⁹⁵Pt NMR(300MHz，DMF-d⁶): consistent with the reference. For separating [ PtCl₃(tributylamine)]^2-The orange oil was dissolved in 2mL of methanol. Adding potassium acetate in methanol to make K [ PtCl ]₃(tributylamine)]And (4) precipitating. The precipitate was dried under vacuum at ambient temperature for 16-24 hours and then weighed. Yield 0.1577 g (64%).

Example 7) Synthesis of K [ PtCl ] in N-methylpyrrolidinone (NMP)₃(2, 5-dimethylpyrazine)]

Mixing K with mortar and pestle₂PtCl₄Ground to a very fine powder. In a 10mL round bottom flask was added 1.0724 g (2.58mmol) K₂PtCl₄And about 5mL of NMP. The reaction vessel was stirred at a rate of about 700rpm and immersed in an oil bath at 65 ℃. 0.3196 g (2.96mmol) of 2, 5-dimethylpyrazine and about 1mL of NMP were mixedAnd (6) mixing. Approximately 4 equal parts of 2, 5-dimethylpyrazine were added to the reaction mixture at 30 minute intervals. After the addition of the last aliquot, the reaction was allowed to proceed for an additional 60 minutes and then cooled to ambient temperature. 150mL of methylene chloride was added to the reaction mixture. The addition of dichloromethane caused precipitation of the product. The precipitate was collected by vacuum filtration using a frit filter, washed 3 times with 30mL of dichloromethane followed by diethyl ether (3X 10 mL). The precipitate was dried under vacuum at ambient temperature for 16 hours and then weighed. Yield 1.0507 g (66.3%). C₆H₈N₂Cl₃Calculated KPt · 2.2KCl (found): c, 11.73 (11.50); h, 1.31 (1.50); n, 4.56 (4.27); cl, 30.14 (29.86).¹HNMR(300Mhz，DMF-d⁷): 9.11(s, 1 pyrazine H); 8.68(s, 1 pyrazine H); 3.31(s, 3 methyl H); 2.68(s, 3 methyl H).

Example 8) Synthesis of K [ PtCl3(4, 6-dimethylpyrimidine) ]in NMP

Mixing K with mortar and pestle₂PtCl₄Ground to a very fine powder. In a 15mL round bottom flask was added 0.5277 g (1.27mmol) K₂PtCl₄And about 3mL of NMP. The reaction vessel was stirred vigorously while it was immersed in an oil bath at 65 ℃. 0.1549 g (1.43mmol) of 4, 6-dimethylpyrimidine were mixed with about 1mL of NMP. Approximately 4 equal parts of 4, 6-dimethylpyrimidine were added to the reaction mixture at 30 minute intervals. After the addition of the last aliquot, the reaction was allowed to proceed for an additional 60 minutes and then cooled to ambient temperature. The reaction was quenched with about 80mL of dichloromethane. This resulted in the precipitation of solids. The precipitate was collected by vacuum filtration using a frit filter, washed 3 times with 30mL of dichloromethane followed by diethyl ether (3X 10 mL). The precipitate was dried under vacuum at ambient temperature for 16 hours and then weighed. Yield 0.4353 g (76.3%).¹H NMR(300Mhz，DMF-d⁷): 9.58(s, 1 pyrimidine H); 7.65(s, 1 pyrimidine H); 3.32(s, 3 methyl H); 2.65(s, 3 methyl H).

Example 9) Synthesis of [ PtCl ] from tetrabutylammonium Tetrachloroplatinate in acetone₃(diisopropylamine)]^-

A25 mL round bottom flask was charged with 0.7961 grams (0.9687mmol) of tetrabutylammonium tetrachloroplatinate and 8mL of acetone. 0.1699 g (1.679mmol) of diisopropylamine were dissolved in 2mL of acetone and added to the Pt solution. The reaction was immersed in an oil bath at 60 ℃ and stirred for 60 hours. By passing¹⁹⁵Pt NMR spectra confirmed red [ PtCl ]₄]^-Conversion to orange [ PtCl₃(diisopropylamine)]^-. The [ PtCl ] can be used directly without isolation of its potassium or tetrabutylammonium salt₃(diisopropylamine)]^-To prepare [ PtCl₂(NH₃) (diisopropylamine)]。¹⁹⁵Pt NMR(300MHz，DMF-d⁷): and [ PtCl ] prepared by methods well known in the art₃(diisopropylamine)]^-Is/are as follows¹⁹⁵The Pt NMR spectra were consistent.

Examples 10-18 illustrate step 2 of the process

Example 10) in aqueous solution [ PtCl₂(NH₃) (2-methylpyridine)]Synthesis of (2)

A25 mL round bottom flask was charged with 6.819 g (12.50mmol) of K [ PtCl ]₃(2-methylpyridine)]1.5KCl and 10ml of 2.5N KCl solution. 8.2688(63.12mmol) of ammonium acetate trihydrate was dissolved in 25mL of 2.5N ammonium hydroxide and the solution was added to the stirred Pt mixture. The total volume of the reaction was approximately 35 mL. In the dark, the orange mixture was immersed in a 45 ℃ oil bath and stirred at > 1000 rpm. The orange mixture gradually turned into a yellow mixture. The yellow precipitate was collected by vacuum filtration through a frit filter, washed 2 times with 5mL portions of water, followed by acetone (3X 5 mL). The precipitate was dried under vacuum at ambient temperature for 16-24 hours and then weighed. Yield 3.8996 g (83%). C₆H₁₀N₂Cl₂Calculated Pt (found): c, 19.16 (19.25); h, 2.68 (2.72); n, 7.45 (7.43); cl, 18.85 (18.81).¹H NMR(300MHz，DMF-d⁶): 9.19(d, 1 pyridine H); 8.03(t, 1 pyridine H); 7.15(d, 1 pyridine H); 7.51(t, 1 pyridine H); 4.39(bs，3 NH₃H) of (e); 3.34(s, H of 3 methyl).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and [ PtCl ] prepared by methods well known in the art₂(NH₃) (2-methylpyridine)]Is/are as follows¹⁹⁵The Pt NMR spectra were consistent. HPLC (cationic HPLC method): the retention time is consistent with that of the reference.

Example 11) in aqueous solution [ PtCl₂(NH₃) (2, 6-lutidine)]Synthesis of (2)

A25 mL round bottom flask was charged with 1.7412 g (3.224mmol) of K [ PtCl ]₃(2, 6-lutidine)]1.24KCl and 3ml of 2.5N KCl solution. 1.3478 g (17.48mmol) of ammonium acetate trihydrate were dissolved in 6.4 ml of 2.5N ammonium hydroxide and the solution was added to the stirred Pt mixture. The total volume of reactants was approximately 9.5 mL. In the dark, the orange mixture was immersed in a 45 ℃ oil bath and stirred at > 1000rpm for 40 hours. The orange mixture gradually turned into a yellow mixture. The yellow precipitate was collected by vacuum filtration through a frit filter, washed 2 times with 5mL portions of water, followed by acetone (3X 5 mL). The precipitate was dried under vacuum at ambient temperature for 16-24 hours and then weighed. Yield 0.9791 g (78%).¹H NMR(300MHz，DMF-d⁶): 7.87(t, 1 lutidine H); 7.49(d, 2-lutidine H); 4.28(bs, 3 NH)₃H) of (e); 3.49(s, 6 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): consistent with the reference. C₇H₁₂N₂Cl₂Calculated Pt (found): c, 21.55 (21.70); h, 3.10 (3.13); n, 7.18 (7.07); cl, 18.17 (18.28).

Example 12) aqueous solution [ PtCl₂(NH₃) (2, 5-dimethylpyrazine)]Synthesis of (2)

In a 15mL round bottom flask was added 0.5325 g (0.8665mmol) of K [ PtCl ]₃(2, 5-dimethylpyrazine)]2.2KCl and 1.0mL of 2.5M KCl solution. 0.335 g (4.35mmol) of ammonium acetate are dissolved in 1.75 ml of a 2.5M (4.38mmol) ammonium hydroxide solution and this solution is added to the stirred solutionIn the reaction mixture. The reaction mixture was immersed in an oil bath at 45 ℃. After 15 minutes, the compound turned yellow. After 1 hour, the compound was cooled to ambient temperature and the yellow precipitate was collected by vacuum filtration using a frit filter. The precipitate was washed 2 times with 10mL of water, followed by acetone (1X 10mL) and dried in vacuo at ambient temperature.¹H NMR(300MHz，DMF-d⁷): 9.16(s, 1 pyrazine H); 8.80(s, 1 pyrazine H); 4.70(bs, 3 NH)₃H) of (e); 3.26(s, 3 methyl H); 2.69(2, 3 methyl H).

Example 13) N-methylpyrrolidone in Water [ PtCl ]₂(NH₃) (2-methylpyridine)]Synthesis of (2)

1.84 g (14.0mmol) of ammonium acetate trihydrate were dissolved in 4.63 ml of 2.9N ammonium hydroxide. The aqueous solution was added to a solution containing 2.68mmol of [ PtCl ]₃(2-methylpyridine)]^-2.5ml of N-methylpyrrolidone. The reaction solution was stirred at 45 ℃ for 80 minutes. A yellow precipitate formed. The precipitate was collected by vacuum filtration using a frit filter and washed with water (2X 5mL) and acetone (3X 5 mL). The precipitate was dried in vacuo at ambient temperature for 16-24 hours and then weighed. Yield 0.3391 g (34%). C₆H₁₀N₂Cl₂Calculated Pt (found): c, 19.16 (19.22); h, 2.68 (2.69); n, 7.45 (7.23); cl, 18.85 (18.83).¹H NMR(300MHz，DMF-d⁶): 9.2(d, 1 pyridine H); 8.0(t, 1 pyridine H); 7.2(d, 1 pyridine H); 7.5(t, 1 pyridine H); 3.4(s, 3 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and [ PtCl ] prepared by methods well known in the art₂(NH₃) (2-methylpyridine)]Is/are as follows¹⁹⁵The Pt NMR spectra were consistent. HPLC (cationic HPLC method): the retention time is consistent with that of the reference.

Example 14) dimethylformamide/Water solution [ PtCl₂(NH₃) (2-methylpyridine)]Synthesis of (2)

As described in example 13) [ PtCl ]₂(NH₃) (2-methylpyridine)]In dimethylIn formamide/water solution. C₆H₁₀N₂Cl₂Calculated Pt (found): c, 19.16 (19.30); h, 2.68 (2.62); n, 7.45 (7.18); cl, 18.85 (18.59).¹H NMR(300MHz，DMF-d⁶): 9.1(d, 1 pyridine H); 8.1(t, 1 pyridine H); 7.3(d, 1 pyridine H); 7.4(t, 1 pyridine H); 3.4(s, 3 methyl H).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and [ PtCl ] prepared by methods well known in the art₂(NH₃) (2-methylpyridine)]Is/are as follows¹⁹⁵The Pt NMR spectra were consistent.

Example 15) acetone/Water solution [ PtCl₂(NH₃) (diisopropylamine)]Synthesis of (2)

6mL of 2.5N ammonium hydroxide was added to 2.5mL of a solution containing [ PtCl ]₃(NH₃) (2-methylpyridine)]^-(about 2.69mmol) in acetone. The pH of the solution was 12. The solution was stirred at 45 ℃ for 48 hours. A yellow precipitate formed. The precipitate was collected by vacuum filtration using a frit filter and washed with water (2X 5mL) and diethyl ether (3X 5 mL). The precipitate was dried under vacuum at ambient temperature for 16-24 hours. C₆H₁₈N₂Cl₂Pt·0.095C₆H₃₀N₂Cl₂Calculated Pt (found): c, 20.00 (19.98); h, 4.90 (4.89); n, 7.16 (7.12); cl, 18.11 (17.93).¹H NMR(300MHz，DMF-d⁷): 4.5(bs, H of 1 diisopropylamine), 3.9(bs, 3 HN)₃H) of (e); 3.3(m, methine H in 2 diisopropyl); 1.7 (methyl H in d, 6 isopropylamine); 1.5(d, methyl H in 6 isopropylamine).¹⁹⁵Pt NMR(300MHz，DMF-d⁶): and [ PtCl ] prepared by methods well known in the art₂(NH₃) (diisopropylamine)]Is/are as follows¹⁹⁵Pt NMR was consistent.

Example 16) aqueous solution [ PtCl₂(2-methylpyridine) (NH₂CH₃)]Synthesis of (2)

In a 15mL round bottom flask was added 0.5055 g (1.17mmol) of K [ PtCl ]₃(2-methylpyridine)]And 1ml of 2.5M KCl solution. Immersing the suspension inIn an oil bath at 45 ℃ and stirred at a rate of approximately 1000 rpm. After 5 minutes, a solution consisting of 0.1704 g of 40% methylamine (2.19mmol) and 1ml of water was added to the reaction mixture. The pH of the solution was 12. Heating was stopped after 1 hour of total reaction time. The reaction mixture was then cooled to ambient temperature. A pale yellow precipitate was collected by vacuum filtration using a frit filter and washed with water (2X 20mL) and acetone (3X 20 mL). The precipitate was dried under vacuum at ambient temperature for 16 hours. C₇H₁₂N₂Cl₂Calculated Pt (found): c, 21.55 (21.73); h, 3.10 (3.09); n, 7.18 (7.14); cl, 18.17 (18.20).¹H NMR(300MHz，DMF-d⁷): 9.24(d, 1 pyridine H); 8.06(t, 1 pyridine H); 7.75(d, 1 pyridine H); 7.55(t, 1 pyridine H); 5.22(bs, 2 methylamine H); 3.35 (methyl H of s, 32-methylpyridine); 2.45(t, methyl H of 3 methylamine).

Example 17) aqueous solution [ PtCl₂(2-methylpyridine) (NH (CH)₃)₂)]Synthesis of (2)

In a 15mL round bottom flask was added 0.5459 g (1.26mmol) of K [ PtCl ]₃(2-methylpyridine)]And 1.5 ml of 2.5M KCl solution. The suspension was immersed in an oil bath at 45 ℃ and stirred vigorously. After 5 minutes, a solution consisting of 0.1426 g of 40% dimethylamine (1.27mmol) and about 1ml of water was added to the reaction mixture. The pH of the solution was 12. Heating was stopped after 1 hour of total reaction time. The reaction mixture was then cooled to ambient temperature. The yellow precipitate was collected by vacuum filtration using a frit filter and washed with water (2X 20mL) and acetone (2X 10 mL). The precipitate was dried under vacuum at ambient temperature for 16 hours. C₈H₁₄N₂Cl₂Calculated Pt (found): c, 23.77 (24.00); h, 3.48 (3.49); n, 6.93 (6.80); cl, 17.54 (17.63).¹H NMR(300MHz，DMF-d⁷): 9.31(d, 1 pyridine H); 8.09(t, 1 pyridine H); 7.78(d, 1 pyridine H); 7.58(t, 1 pyridine H); 6.06(bs, 1 NHH); 3.37(s, methyl H of 3 methylpyridine); 2.76(d, methyl H of 3 dimethylamine); 2.70(d, methyl H of 3 dimethylamine).

Example 18) aqueous solution [ PtCl₂(2-methylpyridine) (NBu₃)]Synthesis of (2)

In a 15mL round bottom flask was added 0.6289 g (1.45mmol) of K [ PtCl ]₃(2-methylpyridine)]And 1.0ml of 2.5M KCl solution. The reaction mixture was immersed in an oil bath at 45 ℃ and stirred vigorously for 5 minutes. 0.2735 g (1.47mmol) of tributylamine was dissolved in 1.0ml of water and the solution was added to the orange reaction mixture. The pH of the solution was 12. After 1 hour of reaction, heating was stopped. After cooling the reaction mixture to ambient temperature, the precipitate was collected by vacuum filtration through a frit filter. The collected precipitate was dried under vacuum at ambient temperature.¹H NMR(300MHz，DMF-d⁷): 9.14(d, 1 pyridine H); 7.90(t, 1 pyridine H); 7.60(d, 1 pyridine H); 7.42(t, 1 pyridine H); 3.41 (methyl H of s, 32-methylpyridine); 3.28(d, methylene H of 2 tributylamine); 1.88(tt, methylene H of 2 tributylamine); 1.56(m, methylene H of 2 tributylamine); 1.10(t, methyl H for 3 tributylamine).

Examples 19-23 illustrate additional steps of the process.

Example 19) c, t, c- [ PtCl₂(OH)₂(NH₃) (2-methylpyridine)]Synthesis of (2)

5.0 ml of water and 5.0 ml of 30% H₂O₂To a suspension of 3.142 g ZD0473 in 15-20 ml heptane. The mixture was stirred at about 80 ℃ for 2 hours. The mixture was then cooled to room temperature and then stirred in an ice bath for 1 hour. The bright yellow solid was collected by vacuum filtration and washed with water and methanol. The product was dried under vacuum at ambient temperature overnight. Yield 2.975 g (87%). C₆H₁₂N₂Cl₂O₂Calculated Pt (found): c, 17.57 (17.67); h, 2.95 (2.93); n, 6.83 (6.79); cl, 17.29 (17.38).

Example 20) c, t, c- [ PtCl₂(OH)₂(NH₃) (2, 3-dimethylpyrazine)]Synthesis of (2)

2.5ml of water and 3.5 ml of 30% H₂O₂To a reactor containing 1.6731 g of cis- [ PtCl₂(NH₃) (2, 3-dimethylpyrazine)]In 10ml of heptane suspension. The mixture was stirred and maintained at a temperature of about 80 ℃ for two hours. The mixture was cooled to room temperature and then stirred in an ice bath for 1 hour. The bright yellow solid was collected by vacuum filtration and washed with water and methanol. The product was dried under vacuum at ambient temperature overnight. Yield 1.1341 g (62%). C₆H₁₃N₃Cl₂O₂Calculated Pt (found): c, 16.95 (16.81); h, 3.08 (3.12); n, 9.88 (9.66); cl, 16.68 (16.44).

Example 21 [ PtCl (OH)₃(NH₃) (2-methylpyridine)]Synthesis of (2)

0.246 g of LiOH H₂O was dissolved in 5mL of water. 2.402 g of c, t, c- [ PrCl [ ]₂(OH)₂(NH₃) (2-methylpyridine)]Suspended in this solution. The mixture was stirred at ambient temperature overnight. The yellow solid gradually dissolved overnight. The pH of the solution was adjusted to 7. The solvent was removed under reduced pressure to give a yellow solid. To wash out the LiCl produced, the solid was stirred in 10mL of ethanol for 30 minutes. The mixture was centrifuged and the supernatant decanted. This washing process was repeated until LiCl was removed. The product was dried under vacuum at ambient temperature overnight. Yield was 1.209 (50%). C₆H₁₃N₂ClO₃Pt·2H₂O) · calculated 0.12LiCl (found): c, 16.65 (16.45); h, 3.96 (4.04); n, 6.47 (6.75); cl, 9.17 (9.47).

Example 22) [ PtCl (OAc)₃(NH₃) (2-methylpyridine)]Synthesis of (2)

At 0 deg.C, 0.352 g [ PtCl (OH)₃(NH₃) (2-methylpyridine)]To 1.1 ml of acetic anhydride in small portions. The mixture was stirred vigorously at ambient temperature. After 3 days, the solid was dissolved in the solution. The solvent was removed under reduced pressure to give a yellow solid. The product was dried under vacuum at ambient temperature overnight. The yield is0.314(70％)。C₁₂H₁₉N₂ClO₆Calculated Pt (found): c, 27.83 (27.93); h, 3.70 (3.66); n, 5.41 (5.34); cl, 6.85 (7.00).

Example 23) [ PtCl₂(OAc)₂(NH₃) (2-methylpyridine)]Synthesis of (2)

At 0 deg.C, 1.367 g of c, t, c- [ PtCl₂(OH)₂(NH₃) (2-methylpyridine)]To 3.1mL of acetic anhydride in small portions. The mixture was stirred vigorously at room temperature. After 4 days, the solid was collected by vacuum filtration and washed with diethyl ether. The product was dried under vacuum at ambient temperature overnight. Yield 1.318 g (96%). C₁₀H₁₆N₂Cl₂O₄Calculated Pt (found): c, 24.30 (24.32); h, 3.26(3.15), H, 5.67 (5.66); cl, 14.35 (14.29).

TABLE 1 formation of intermediates of formula Ia [ PtA₃(L)]^1-Summary of the embodiment of step 1 of the method of

TABLE 2 summary of the examples for step 2 of the process for forming cisplatin complexes of formula Ia

TABLE 3 summary of examples of platinum complexes of the formula Ib

The invention has been described by way of direct illustration and example. As mentioned above, the examples are only illustrative and not intended to limit the invention in any sense. In addition, it will be apparent to those of ordinary skill in the art from a review of this specification and the claims that follow that equivalents exist to the claims. The inventors intend for those equivalents to be included within the scope of the claims that follow.

Claims

1. A process for preparing a platinum complex of formula Ia:

wherein A is chloride and L' is NH₃L is a substituted heteroaromatic amine coordinated to Pt through its ring N atom, the method comprising:

a) first, let [ PtA₄]^2-With L in an aprotic solvent to form [ PtA₃L]^-Wherein the aprotic solvent is selected from the group consisting of acetone, chloroform, dimethylacetamide, dichloromethane, dimethylformamide, N-methylpyrrolidone, and tetrahydrofuran;

b) second step, let [ PtA₃L]^-And NH₄Reacting with OH aqueous solution to form cis- [ PtA₂(L’)(L)]。

2. The method of claim 1, wherein the aprotic solvent is NMP.

3. The method of claim 1 or 2, wherein L is pyridine substituted with C1-C6 alkyl in the vicinity of N.

4. The method of claim 1, 2 or 3, wherein L is 2-methylpyridine.

5. The method of any one of claims 1-4, wherein the pH of step (b) is from 7 to 12.

6. The method of any one of claims 1-5, wherein the NH is₄OH also contains KCl.