KR20070031281A - How to make A4N - Google Patents

Abstract

In the process for preparing compound AQ4N of formula (2) or a salt or solvate thereof, the reaction step of oxidizing compound AQ4 of formula (1) to compound AQ4N of formula (2) with an oxidizing agent at a reaction temperature not exceeding 10 ° C. Manufacturing method comprising.

AQ4N, AQ4

Description

Process for the Preparation of AQ4N

The present invention relates to AQ4N, and to a process for preparing the salts and solvates thereof. In particular, the method is available on an industrial scale and is suitable for the preparation of pharmaceutically pure compounds.

AQ4N is a non-toxic prodrug useful for the treatment of cancer. The active drug is the cytotoxic compound AQ4, which is produced in vivo from AQ4N by reductive metabolism in hypoxic cells. This process is the reverse reaction of the oxidation step used to synthesize AQ4N from AQ4.

It is often convenient or desirable to prepare, purify, and / or handle the corresponding solvates or salts of AQ4N, such as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are described in Berge et al, 1977, "Pharmaceutically Acceptable Salts," J. Pharm. Sci. , Vol. 66, pp. Discussed in 1-19. AQ4N has been reported in the form of many salts or solvates ( J. Chem. Soc., Perkin Trans. I , 1999, 2755; WO 00/05194; WO 03/078387).

However, a problem with known methods of preparing AQ4N and its salts or solvates is that the resulting product contains varying degrees of impurities known as AQMN. AQMN or 1-amino-4-{[2- (dimethylamino) ethyl] amino} -5,8-dihydroxyanthraquinone is formed by the decomposition of AQ4N. AQMN is an undesirable contaminant in compounds intended to be administered as nontoxic prodrugs.

AQ4N and its salts or solvates can be prepared using a process employing several steps of reactions as described in WO 00/05194 and below. This method was performed on a small scale (~ 0.1 moles). One step of this process is 1,4-difluoro-5,8-dihydride of 3,6-difluorophthalic anhydride (DFPA) and p-hydroquinone by Friedel-Craft acylation with an aluminum chloride catalyst. Conversion to oxy anthracene (DDA).

This reaction was carried out by heating a powder mixture of solids (4), (5), sodium chloride and aluminum trichloride to a temperature of 220 ° C.

Next, the fluorine atom of DDA is substituted with N, N-dimethylethylenediamine to produce AQ4 as in the following reaction.

In the process described in WO 00/05194, this reaction step showed only moderate product yield (-40%), even on a laboratory size scale of about 0.1 mole.

Next, a subsequent reaction step is performed to oxidize AQ4 to AQ4N.

The process described in WO 00/05194 uses Davis reagent (2-benzene-sulfonyl-3-phenyl-oxaziridine) as oxidant and the reaction is carried out at room temperature.

At this point AQ4N can be separated off or further converted to salts or solvates in further reaction steps. Inorganic dihydrochloride was prepared on a laboratory scale by treating the methanol solution of the AQ4N crude product with anhydrous HCl gas at room temperature (WO 00/05194). Organic acid salts of AQ4N were also prepared by adding a methanol solution containing organic acid (WO 03/078387).

Disclosure of the Invention

The present invention discloses an improved process for preparing AQ4N and salts or solvates thereof. The process can be carried out on an industrial scale (eg, at least 0.2 mol) and includes improved methods of synthesizing intermediate compounds. These improved methods aim to produce reduced levels of contaminants in the final product that can be pharmaceutically pure. The process of the invention generally utilizes the reaction sequences and intermediates described above.

Oxidation of AQ4 to AQ4N

The problem with the conversion of AQ4 to AQ4N is that incomplete oxidation of AQ4 can lead to the production of partially oxidized byproduct AQ4M (7). However, the harsh conditions employed to ensure complete oxidation often result in the degradation of AQ4N to AQMN. Degradate AQMN is obtained even under relatively moderate conditions (WO 03/078387). This degradation route reduces both the yield and purity of the final product.

One aspect of the invention is the oxidation of AQ4 to AQ4N at temperatures not exceeding 10 ° C. The reaction temperature is preferably below 5 ° C., more preferably below 0 ° C., and if possible the reaction temperature does not exceed −7 ° C. The reaction is usually carried out at temperatures higher than -20 ° C. When the reaction solution is at a temperature not exceeding 0 ° C., more preferably below −7 ° C., even more preferably, the addition of an oxidant to the reaction mixture is carried out when the reaction solution temperature does not exceed −10 ° C. A solvent suitable for the reaction temperature should be selected.

An oxidant which selectively oxidizes AQ4 to AQ4N is preferably used in this embodiment of the present invention. Suitable oxidizing agents include hydrogen peroxide, oxaziridine or peracids or salts of peracids, such as m-chloroperbenzoic acid, perbenzoic acid, peracetic acid and magnesium monoperoxyphthalate. The oxidant is preferably hydrogen peroxide or more preferably magnesium monoperoxyphthalate. The oxidizing agent magnesium monoperoxyphthalate is stable and water soluble in air, making it easier to handle in large scale use. The solvent used must be compatible with the oxidant selected.

Suitable solvents for the oxidation of AQ4 to AQ4N include solvent mixtures of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, toluene, 1,2-propanediol or any combination of these solvents. All these solvents may be used as mixtures with or without aliphatic alkyl alcohols. The reaction solvent is preferably 1,2-propanediol or more preferably a solvent mixture of dichloromethane and aliphatic alkyl alcohol.

Thus, a preferred embodiment uses magnesium monoperoxyphthalate. The addition of magnesium monoperoxyphthalate is carried out at temperatures of -15 ° C to -5 ° C, more preferably about -11 ° C. After addition of the oxidizing agent, the reaction is allowed to stir at a temperature of -15 ° C to 5 ° C, more preferably about 0 ° C. Preferred solvents for this reaction are mixtures of methanol and dichloromethane, preferably in a volume ratio of 1: 1.5 to 1: 2.5.

Salt Formation of AQ4N

In conventional methods, dihydrochloride of AQ4N was prepared by reacting an AQ4N solution with anhydrous HCl gas (WO 00/05194). The use of HCl gas reagents makes it difficult to scale up this reaction step. If a salt of AQ4N is needed, it can be prepared by reacting a solution of AQ4N with an acid dissolved in a solvent. The reaction of AQ4N with acid is preferably carried out at temperatures of -20 ° C to -11 ° C. The acid can be dissolved in a solvent and added to the reaction, or can be generated in-situ in the reaction solution by the addition of appropriate reagents. For example, hydrochloric acid can be produced in situ by adding acetyl chloride and ethanol reagent to the reaction solution.

Suitable inorganic acids include hydrochloric acid, bromic acid, phosphoric acid and sulfuric acid. Suitable organic acids include acetic acid, dichloroacetic acid, malonic acid, maleic acid, tartaric acid, pimelic acid, lactic acid, citric acid and benzenesulfonic acid.

Suitable solvents for salt formation of AQ4N include solvent mixtures of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, toluene, 1,2-propanediol or any combination of these solvents. All these solvents may be used as mixtures with or without aliphatic alkyl alcohols. The reaction solvent is preferably 1,2-propanediol or more preferably a solvent mixture of dichloromethane and aliphatic alkyl alcohol.

Purification of AQ4N or its salts

The existing literature methods have not been effective in removing major impurities from the salts of AQ4N. In another embodiment of the present invention, it is preferred that one of the purification steps associated with AQ4N or a salt of AQ4N is to pass a solution of this compound through activated charcoal. This is an unusual method of purifying colored compounds because charcoal treatment is well known in the art as a method of removing colored impurities. The final product obtained from this step is J. Chem. Soc., Perkin Trans. There is no need to recrystallize as described in I , 1999, 2755.

Suitable solvents for this step include solvent mixtures of dichloromethane, chloroform, dichloroethane, carbon tetrachloride, toluene, 1,2-propanediol or any combination of these solvents. All these solvents may be used as mixtures with or without aliphatic alkyl alcohols. The reaction solvent is preferably 1,2-propanediol or more preferably a solvent mixture of dichloromethane and aliphatic alkyl alcohol. Typically, the compound to be purified is in the solvent from which it is produced.

Friedel-Craft Acylation

Friedel-Craft acylation of p-hydroquinone was carried out by reaction between solid reagents at 220 ° C. in WO 00/05194. High temperature and solid phase reaction conditions make this step difficult to perform on an industrial scale. Large amounts of gas are generated during this reaction step.

Another aspect of the invention is to carry out this reaction step in a solvent at a temperature not exceeding 200 ° C. The use of a solvent allows the reaction to be stirred, which in turn means that a lower reaction temperature can be used. Lower temperatures reduce the rate of gas evolution from the reaction.

Suitable solvents for the Friedel-Craft acylation of p-hydroquinone are 1,1,1,2-tetrachloroethane, 1,1,2,2-tetrachloroethane, nitrobenzene, chlorobenzene, 1,2- Dichlorobenzene, toluene or sulfone. These solvents can be used independently or in any combination with others. The sulfone is preferably tetramethylene sulfone. The reaction is preferably carried out at a temperature not exceeding 180 ° C. with stirring of the reaction mixture.

After completion of the Friedel-Crafts reaction step, the removal of aluminum-containing byproducts from the DDA crude product poses a problem, especially when the reaction is carried out in solid phase. Reducing the aluminum content at this point is important because it reduces the number of purification cycles in subsequent steps of the process. This is an important consideration because potential exposure to subsequent cytotoxic products such as AQ4 can be minimized.

After performing the Friedel-Crafts reaction as described above, it is desirable to completely remove or reduce the aluminum containing byproducts that contaminate the DDA crude product.

A preferred method of reducing the amount of aluminum containing byproducts is slurry formation with the reaction solution by acid addition. The reduction of the aluminum content in the DDA crude product is achieved by slurrying the reaction solution several times, preferably with aqueous hydrochloric acid.

Another preferred method that can be used independently or in conjunction with the slurry process is the addition of the chelating agent to the reaction solution. Chelating agents form aluminum complexes with aluminum containing impurities, which promote removal. The selection of the appropriate chelating agent allows for the removal of the aluminum complex by precipitation from the solution, use of phase transfer conditions, or other size exclusion or use of filtration techniques.

Formation of AQ4

AQ4 synthesis from DDA described in WO 00 / 05194A shows moderate product yields (-40%). This reaction step is carried out at a temperature in the range of 0 ° C to 100 ° C. Suitable solvents for carrying out this reaction are tetrahydrofuran, collidine, lutidine, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, diglyme and sulfolane. These solvents may be used in any combination with other.

The present invention relates to the separation of AQ4 from acidic byproducts arising in this reaction step. Neutralization of the acid byproducts is carried out with a suitable base. Suitable bases are dimethyl aminopyridine, N-methyl piperidine, N-methyl pyrrolidine, any tertiary amine, any water soluble tertiary amine, or any of these bases attached to a solid support, group 1 alkali metal Carbonates and bicarbonates. Preferably, the acid by-product of the reaction is neutralized with an aqueous ammonium hydroxide / brine cooling solution. Preferably, the workup of AQ4 is carried out at a temperature in the range of 10 ° C to 30 ° C. This method leads to improved yield of AQ4, even when the reaction is carried out on a large scale.

As will be appreciated by those skilled in the art, features and preferred embodiments of one aspect of the present invention also relate to other aspects of the present invention.

Justice

As used herein, the term pharmaceutically pure refers to a compound that is pure enough to be used as a medicament.

The term oxaziridine as used herein relates to a compound having a functional group containing a saturated three-membered heterocycle ring formed of C, N and O as follows.

Particularly suitable oxaziridines are 2-benzene-sulfonyl-3-phenyl-oxaziridines and those shown below.

The term peracid, as used herein, relates to a compound containing a -C (= 0) OOH functional group. Particularly suitable peracids include m-chloroperbenzoic acid, peracetic acid, perbenzoic acid, trifluoroperacetic acid and 3,5-dynitroperoxybenzoic acid.

The term salt of peracid, as used herein, relates to compounds containing suitable cations and -C (= 0) OO ^- anionic functional groups as defined below. Particularly suitable salts of peracids include magnesium monoperoxyphthalate, sodium peracetate and zinc peracetate.

The term aliphatic alkyl alcohol as used herein relates to a compound in the form of R-OH, wherein R is a saturated linear or branched alkyl group. The term alkyl as used herein relates to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom from a saturated hydrocarbon compound having 1 to 7 carbon atoms. Examples of saturated linear alkyl groups are methyl (C ₁ ), ethyl (C ₂ ), n-propyl (C ₃ ), n-butyl (C ₄ ), n-pentyl (amyl) (C ₅ ), n-hexyl (C ₆ ), and n-heptyl (C ₇ ). Examples of saturated branched alkyl groups are iso-propyl (C ₃ ), iso-butyl (C ₄ ), sec-butyl (C ₄ ), tert-butyl (C ₄ ), iso-pentyl (C ₅ ) and neo-pentyl (C ₅ ). Particularly suitable aliphatic alkyl alcohols include methanol, ethanol, propanol and propan-2-ol.

The term sulfone as used herein relates to a compound containing a CS (═O) ₂ -C functional group. Particularly suitable sulfones are tetramethylene sulfones.

The term chelating agent, as used herein, relates to a compound that binds to a metal from two or more positions. The bonding atoms in the chelate compound may form part of the linear compound or part of the cyclic structure. Examples of chelating agents are ethylenediaminetetraacetic acid (EDTA), ethylenediamine (EDA) and diethylenetriamine (DETA), and their anions. Examples of cyclic chelating agents are crown ethers such as 18-crown-6 or 15-crown-5, crytand, spherand or porphyrin.

Unless stated otherwise, what is described above includes well-known ions, salts, solvates, and protected forms of these compounds.

For example, if the compound is anionic, or, if having a functional group which may be anionic (e.g. -COOH is -COO ^- may be), it can form salts with suitable cations. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na ⁺ and K ⁺ , alkaline earth metal cations such as Ca ²⁺ and Mg ²⁺ , and other cations such as Al ³⁺ . Examples of suitable organic cations include, but are not limited to, ammonium ions (ie NH ₄ ⁺ ), and substituted ammonium ions (eg, NH ₃ R ⁺ , NH ₂ R ₂ ⁺ , NHR ₃ ⁺ , NR ₄ ⁺ ). . Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzyl Amino acids such as amines, phenylbenzylamine, choline, meglumine and tromethamine, as well as lysine and arginine. An example of a common quaternary ammonium ion is N (CH ₃ ) ₄ ⁺ .

If the compound is cationic or has a functional group that can be a cation (eg -NH ₂ can be -NH ₃ ⁺ ), it can form a salt with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric acid, bromic acid, iodic acid, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, phosphoric acid and phosphorous acid.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetoxybenzoic acid, acetic acid, ascorbic acid, aspartic acid, benzoic acid, camphorsulfonic acid, cinnamic acid, citric acid, edetic acid, ethane Disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxymaleic acid, hydroxynaphthalene carboxylic acid, isethionic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, Malic acid, methanesulfonic acid, mucic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, pantothenic acid, phenylacetic acid, phenylsulfonic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanic acid, tartaric acid, toluene Sulfonic acid and valeric acid. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

As used herein, the term “solvate” is used as a conventional concept to refer to a complex of a solute (such as the active compound, salt of the active compound) and a solvent. If the solvent is water, solvates may conveniently be referred to as hydrates such as monohydrate, dihydrate, trihydrate, and the like.

As used herein, the term “prodrug” refers to a compound that produces the desired active compound upon metabolism (eg, in vivo). Typically, prodrugs are inactive or less active than the active compound, but can provide advantageous handling, administration, or metabolic properties.

Composite details

Preparation of DDA (6) Crude Product

0.3 kg (1.63 mol) of DFPA, 0.2 kg (1.82 mol) of p-hydroquinone, 1.1 kg (8.25 mol) of anhydrous AlCl ₃ powder, and tetramethylene sulfone (1.8 L) for approximately 12 hours at a temperature of 155 ° C to 180 ° C. Stirred. The reaction mixture was then quenched with ice cold water (1.0 L) and treated with 2M aqueous hydrochloric acid solution (1.0 L). The suspension is filtered and the solid result is dried at 45 ° C. under vacuum. After drying a fine red powder (DDA crude product) was obtained. This reaction was carried out on several batches of the same scale, yielding a yield of about 68%. The separated DDA was contaminated with aluminum-containing impurities, and the aluminum content in the separated product ranged from 3290 ppm to 975 ppm as shown in Table 1.

All batches used 300 g as 1 molar equivalent of DDA except for 200 g for batch 5A.

Yield and Purity of DDA Crude Products Batch number Yield (g) (% yield) Analytical Data Al (ppm) 1A 2A 3A 4A 5A 302 (67%) 296 (66%) 305 (68%) 310 (69%) 256 (85%) 975 1150 3290 1165 1640

The organic component of the product was determined to be pure using HPLC.

Purification of DDA Crude Products

The solid DDA crude product obtained using the previous method was treated with 2M aqueous hydrochloric acid solution (1.0 L) to form a slurry. The suspension was filtered to separate the solids. The solid was slurried and filtered several times and the solid was dried at 45 ° C. under vacuum to give a fine red powder. The mass recovery of this step is typically 90%. This step resulted in a reduction in the aluminum content in the DDA crude product for all batches as shown in Table 2.

Yield and Purity after Slurry of DDA Crude Batch number Yield (g) (% yield) Analytical Data Al (ppm) 1A 2A 3A 4A 5A 283 (94%) 276 (93%) 268 (88%) 280 (90%) 229 (89%) 714 801 875 865 526

The organic component of the product was determined to be pure using HPLC.

Preparation and Purification of AQ4

(AQ4 was prepared by modifying the method listed in WO 00/05194). 0.5 kg (1.81 mol) of DDA, 1.3 L (12.08 mol) of N, N-dimethylethylene diamine and pyridine (3.6 L) obtained in the previous step were stirred at 40 ° C. for 22 hours under a nitrogen atmosphere. The reaction mixture was worked up by adding 2 L of a 30% aqueous ammonium hydroxide solution / 23% brine cooled to 0 ° C. The slurry result was stirred at 0 ° C. for 3-4 hours and the blue solid product was separated by filtration. The solid was washed with 10% aqueous ammonium hydroxide solution (1.0 L) and dried under vacuum to constant weight at 40 ° C to 50 ° C. This step consistently produced about 540 g (~ 73%) of AQ4.

The purified DDAs obtained above were combined and then divided into several 500 g batches and used at this stage.

Yield and Purity of AQ4 Batch number Yield (g) (% yield) Analytical Data Al (ppm) 1B 2B 3B 4B 543 (73%) 554 (74%) 560 (75%) 529 (71%) 560 546 638 510

The purity of the product was confirmed using HPLC.

Synthesis of AQ4N

Methanol solution (0.5 L) containing 0.26 kg (0.67 mol) of magnesium monoperoxyphthalate was prepared by adding 0.2 kg (0.48 mol) of AQ4 from the previous step, methanol (0.8 L) and dichloromethane (2.9 L). Dropwise was added to the stirred solution cooled to 11 ° C. After the addition was completed, the reaction solution was allowed to warm to 0 ° C. and stirred for 18 hours. Next, AQ4N can be separated at this stage using the procedure in the literature.

Preparation and Purification of AQ4N Dihydrochloride (AQ4N.2HCl)

Ethyl acetate (4.0 L) and ethanol (0.8 L) were added to the same AQ4N solution as the reaction solution from the previous step and the solution temperature was maintained at 0 ° C. After stirring for 1 hour at this temperature, the stirred solution was cooled to about −11 ° C. and 0.2 L (2.8 mol) of acetyl chloride was added dropwise. The slurry result was stirred at this temperature for 10 minutes before the reaction mixture was filtered quickly. A solid crude product was obtained which was washed with a mixture of ethanol and water (2 L) and dried under vacuum until constant weight. As shown in Table 4, 220 g (˜88%) of AQ4N.2HCl with good purity were typically obtained. HPLC confirmed the purity of the organic content of the product.

Yield and Purity of AQ4N.2HCl Batch number Yield (g) (% yield) Analysis data Purity (% Area) 1C 2C 3C 4C 217 (86%) 235 (94%) 196 (78%) 225 (90%) 95 95 95 95

For pharmaceutical purity, 100 g of the product obtained above was further purified. The crude AQ4N.2HCl product was dissolved in water (0.6 L) and treated with activated carbon (0.06 kg). Activated carbon was removed from the suspension result by filtration. Ethanol was added (1.4 L) and the solution cooled to 0 ° C. to precipitate the product from the mother liquor. The precipitate was separated by filtration and washed with ethanol (4.0 L). The AQ4N.2HCl product was dried under vacuum at room temperature. The mass recovery at this stage was about 60%.

Purification of AQ4N.2HCl Batch number Yield (g) (% Recovery) Analysis data Purity (% Area) 1D 2D 61.7 (61.7%) 62 (62.0%) 97 97

HPLC showed that the purity of the organic content of the product was increased.

Claims (11)

Compound AQ4N of Formula (2)

Or in the process for preparing the salt or solvate, reaction step

And oxidizing compound AQ4 of formula (1) to compound AQ4N of formula (2) with an oxidizing agent at a reaction temperature not exceeding 10 ° C., wherein the oxidizing agent is a peracid or a salt of peracid, and the oxidizing agent does not exceed 0 ° C. The production method to add at a temperature. The method of claim 1 wherein the oxidant is magnesium monoperoxyphthalate. The process according to claim 1 or 2, wherein the reaction is carried out at a temperature not exceeding 0 deg. The process according to any one of claims 1 to 3, wherein the reaction solvent is 1,2-propanediol, dichloromethane or aliphatic alkyl alcohol. The method for producing a salt of AQ4N according to any one of claims 1 to 4, wherein a salt of AQ4N or a solvate thereof is prepared by reaction of compound AQ4N of formula (2) with a hydrochloric acid solution. The method according to any one of claims 1 to 5, wherein the solution containing AQ4N or a salt of AQ4N is treated with activated carbon. Compound AQ4N of Formula (2)

In the preparation method of, the reaction step

To include, wherein the reaction step is carried out in a solvent capable of stirring at a temperature not exceeding 200 ℃. 8. A process according to claim 7, wherein said solvent is tetramethylene sulfone. The process according to claim 7 or 8, wherein the crude compound DDA of the formula (6) is slurried several times with an aqueous hydrochloric acid solution. The process according to any one of claims 7 to 9, wherein the crude compound DDA of the formula (6) is treated by adding a chelating agent. Compound AQ4N of formula (2) of claim 1

In the preparation method of, the reaction step

To include, wherein the reaction solution of the reaction step is treated with ammonium hydroxide and brine solution cooled to 0 ℃.