GB2414238A - Method for the preparation of trilostane - Google Patents
Method for the preparation of trilostane Download PDFInfo
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- GB2414238A GB2414238A GB0411464A GB0411464A GB2414238A GB 2414238 A GB2414238 A GB 2414238A GB 0411464 A GB0411464 A GB 0411464A GB 0411464 A GB0411464 A GB 0411464A GB 2414238 A GB2414238 A GB 2414238A
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- acid
- precursor compound
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- trilostane
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- 238000000034 method Methods 0.000 title claims abstract description 52
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 title claims abstract description 42
- 229960001670 trilostane Drugs 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 53
- 239000002243 precursor Substances 0.000 claims abstract description 53
- 239000002253 acid Substances 0.000 claims abstract description 37
- 239000002585 base Substances 0.000 claims abstract description 37
- 239000000047 product Substances 0.000 claims abstract description 31
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 239000002244 precipitate Substances 0.000 claims abstract description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000011054 acetic acid Nutrition 0.000 claims abstract description 5
- 229910052500 inorganic mineral Inorganic materials 0.000 claims abstract description 5
- 239000011707 mineral Substances 0.000 claims abstract description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 4
- 150000007524 organic acids Chemical class 0.000 claims abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019253 formic acid Nutrition 0.000 claims abstract description 3
- 238000002955 isolation Methods 0.000 claims abstract description 3
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims abstract description 3
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 3
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 3
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 3
- 150000001735 carboxylic acids Chemical class 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims description 46
- 238000003776 cleavage reaction Methods 0.000 claims description 20
- 230000007017 scission Effects 0.000 claims description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 230000000694 effects Effects 0.000 claims description 7
- -1 alkali metal alkoxide Chemical class 0.000 claims description 5
- 239000011260 aqueous acid Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 8
- 150000001298 alcohols Chemical class 0.000 abstract description 4
- 150000002170 ethers Chemical class 0.000 abstract description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 2
- 150000007513 acids Chemical class 0.000 abstract 2
- 150000004703 alkoxides Chemical class 0.000 abstract 1
- 235000005985 organic acids Nutrition 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000012467 final product Substances 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000007142 ring opening reaction Methods 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical group C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000000717 retained effect Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QARAXUHORATRQJ-UHFFFAOYSA-N 1,4-dioxane;pyridine Chemical compound C1COCCO1.C1=CC=NC=C1 QARAXUHORATRQJ-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000017701 Endocrine disease Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000010067 Pituitary ACTH Hypersecretion Diseases 0.000 description 1
- 208000020627 Pituitary-dependent Cushing syndrome Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
- C07J71/0005—Oxygen-containing hetero ring
- C07J71/001—Oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Steroid Compounds (AREA)
Abstract
A method for the preparation of trilostane from (4 a ,5 a ,17 b )-4,5-epoxyandrost-2-eno(2,3-d)isoxazol-17-ol, without the need for recrystallisation, comprising a) dissolving the precursor in methanol; b) treating the precursor with a base to cleave the (2,3-d)isoxazole ring; c) adding acid and water to the product of step b) to precipitate the trilostane; and d) isolating the trilostane precipitate. Preferred bases are alkali metal hydroxides or alkoxides, particularly sodium or potassium hydroxide and sodium or potassium methoxide, with at least one mole equivalent of base being used. Suitable acids for step c) are organic acids, for example carboxylic acids such as formic acid, acetic acid, propanoic acid and butanoic acid, or mineral acids such as hydrochloric acid and sulphuric acid. The acid may be added to the product of step b) before, during or after the water is added. Isolation of the trilostane precipitate may be achieved by filtration. The use of solvents other than methanol for step a) is also claimed. Suitable solvents include alcohols or ethers, particularly ethanol, isopropanol and tetrahydrofuran (THF).
Description
24 1 4238
METHOD FOR THE PREPARATION OF TRILOSTANE
-
The present invention relates to a method for the preparation of Trilostane.
Trilostane ((4a,5a,17,B)-4,5-epoxy-3,17-dihydroxyandrost-2-ene-2carbonitrile; 2) is used in human and veterinary medicine to treat endocrine disorders. Its primary indication is as an anticancer agent but it is also used in the treatment of Cushing's disease and other hyperadrenocortical conditions.
Trilostane is produced using multi-step syntheses. A typical example of the final step in a synthesis of Trilostane is shown in reaction scheme 1. This step involves the conversion of (4a,5a,170)-4,5-epoxyandrost-2-eno(2,3-d)isoxazol-17-ol (1) to Trilostane (2). A base (methoxide ion) is used to remove the labile isoxazole proton which causes the (2,3- d)isoxazole ring to open and produce an enolate which is then acidified using aqueous acid to yield Trilostane (2).
CH3 -OCH CH3 |/H / HOWL/ (1) (2) Reaction Scheme 1 Following production of Trilostane (2) it is necessary to carry out at least one recrystallization to obtain a final product of satisfactory purity. Having to recrystallize the product is clearly undesirable since it further complicates the overall synthetic process and is likely to reduce significantly the final product yield obtained.
Neumann et al.i describe the use of sodium methoxide in tetramethylurea to effect an isoxazole ring-opening reaction to yield Trilostane followed by recrystallization from dimethylformamide. A crude product yield of 97. 4 % was obtained but, following recrystallization, the purified product yield was only 56.0 %. A further problem with this method is that because dimethylformamide has a relatively high boiling point (153 C) an undesirable level of dimethylformamide is likely to be retained in the recrystallized product.
Neumann et al.t appear to have tested one or more hydroxylic solvents (alcohols) as alternative recrystallization solvents. However, poor yields were obtained which the authors presume was due to decomposition of the 2-cyano-3-keto product with the evolution of toxic hydrogen cyanide since, "an HCN-type odor was usually noted". The decomposition products were not investigated further but it was noted from TLC studies that the 2-cyano-3-keto spots had almost completely disappeared and several new spots had appeared. This work indicates that hydroxylic solvents are unsuitable for use in the final step in the synthesis of Trilostane because they degrade the intended reaction product such that final product yields are significantly reduced and are liable to generate highly toxic hydrogen cyanide.
Further processes for the production of 2-cyano-3-keto-steroids have been described. US 3,135,743 discloses the preparation of a 2-cyano-3-keto-steroid involving an isoxazole ring- opening step similar to that of reaction scheme l in which sodium methoxide is used in ether to effect the ring-opening step. The final product is then recrystallized twice from an ether- hexane mixture. US 3,296,255 discloses the preparation of a series of 2- cyano-3-keto-steroids from isoxazole precursors. In this case the isoxazole ring-opening step is carried out using sodium methoxide or sodium ethoxide in diethyl ether or tetrahydrofuran and a number of different recrystallization solvents then used, e.g. methyl ethyl ketone, or mixtures of tetrahydrofuran-ethyl acetate or pyridine-dioxane. GB 1, 123,770 describes the synthesis of a 2-cyano-4,5-epoxy androstane steroid in which the isoxazole ring of the precursor is cleaved using sodium methoxide in tetrahydrofuran. A pyridine-dioxane mixture is then used as a recrystallization solvent to purify the final product.
An object of the present invention is to obviate or mitigate one or more of the aforementioned problems to provide an improved method for the preparation of Trilostane.
According to a first aspect of the present invention there is provided a method for the preparation of Trilostane from (4a,5a,17,B)-4,5epoxyandrost-2-eno(2,3-d)isoxazol-17-ol as a precursor compound, the method comprising the steps of: a) dissolving the precursor compound in methanol; b) treating the precursor compound with a base to effect cleavage of the (2,3-d)isoxazole ring of the precursor compound; c) adding acid and water to the product of step b) to obtain a precipitate of Trilostane; and d) isolating the precipitate of Trilostane.
Preparing Trilostane in accordance with this aspect of the invention enables a high yield of a satisfactorily pure product to be obtained without the need to carry out one or more recrystallisations. This represents a major improvement in the preparation of this drug since it enables Trilostane to be produced with significantly greater efficiency than using current methods. Not only is it surprising that carrying out the ring-opening reaction in methanol negates the need to recrystallize the final product, the fact that methanol can be used at all in the final step in the production of Trilostane was very unexpected in view of the observations of Neumann et al. which strongly suggested that solvents such as methanol would be highly unsuitable for this purpose. Additionally, since methanol has a much lower boiling point (65 C) than, for example, dimethylformamide, problems related to residual solvent remaining in the final product are greatly reduced.
Any suitable base may be used in this aspect of the invention provided it is sufficiently basic to remove the labile isoxazole proton so as to initiate cleavage of the isoxazole ring of the precursor compound when the precursor compound is dissolved in methanol. Preferably the base is an alkali metal hydroxide. More preferably the base is selected from the group consisting of sodium hydroxide and potassium hydroxide. Alternatively, the base may be an alkali metal alkoxide, e.g. methoxide, ethoxide or the like. A particularly preferred alkali metal alkoxide may be selected from the group consisting of: sodium methoxide and potassium methoxide.
It is preferred that cleavage of the (2,3-d)isoxazole ring of the precursor compound is effected using at least one mole equivalent of the base compared to the precursor compound.
Preferably cleavage of the (2,3-d)isoxazole ring of the precursor compound is effected using 1.00 to 1.50 mole equivalents of the base compared to the precursor compound. More preferably cleavage of the (2,3-d)isoxazole ring of the precursor compound is effected using 1.05 to 1.30 mole equivalents of the base compared to the precursor compound. It is particularly preferred that more than one mole equivalent of base compared to the precursor compound is used so that the excess base not required to effect cleavage of the isoxazole ring can react with any acidic contaminants which may be present.
While cleavage of the isoxazole ring may be effected at room temperature or below given a sufficiently long reaction time, in a preferred embodiment of this aspect of the invention cleavage of the isoxazole ring is effected at an elevated temperature, such as a temperature at which the precursor can be treated with base under reflux conditions. Preferably cleavage of the (2,3-d)isoxazole ring of the precursor compound is effected at a temperature in the range C to a temperature at which the precursor can be treated with base under reflux conditions. More preferably cleavage of the (2,3-d)isoxazole ring of the precursor compound is effected at a temperature in the range 30 to 50 C. Yet more preferably cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected at a temperature in the range 40 to 45 C.
Preferably the precursor compound is treated with the base over a time period of up to 4 hours. More preferably the precursor compound is treated with the base over a time period of 2 to 3 hours. Most preferably the precursor compound is treated with the base over a time period of approximately 2 hours.
In order to obtain a precipitate of Trilostane the product of step b) of this aspect of the invention is acidified using acid and water. It is preferred that the acid is added to the product of step b) before the addition of the water. Further preferred embodiments of this aspect of the invention comprise the addition of the acid to the product of step b) during or after the addition of the water. The acid may be an aqueous acid. If an aqueous acid is used it may or may not be necessary to add additional water before, during or after addition of the aqueous acid.
Whilst any appropriate acid may be used in this aspect of the invention, an important factor in deciding upon a suitable acid is the ease with which it can be removed from the Trilostane product. This is partly determined by the relative solubility of the salt form of the acid in water compared to its solubility in methanol. A salt of the acid with a higher relative aqueous solubility will be preferentially retained in the aqueous phase of the reaction mixture to a greater extent than a salt form of the acid with a lower relative aqueous solubility. Thus, a salt of the acid with a higher relative aqueous solubility can be more readily separated from the Trilostane product which will be retained in the methanolic phase.
Preferably the acid is an organic acid, such as a carboxylic acid. The carboxylic acid may be selected from the group consisting of formic acid, acetic acid, propanoic acid and butanoic acid. Acetic acid is preferred because of the high relative aqueous solubility of certain preferred salts of the acetate ion. Alternatively, a mineral acid may be used, for example, the mineral acid may be selected from the group consisting of hydrochloric acid and sulphuric acid.
It is preferred that 1.15 to 1.30 mole equivalents of the acid compared to the base is added to the product of step b). 1.20 to 1.25 mole equivalents of the acid compared to the base may be added to the product of step b).
In a preferred embodiment of this aspect of the invention the product of step b) is maintained at a temperature in the range 15 C to a temperature at which the precursor can be treated with base under reflux conditions during addition of the acid and water. Preferably the product of step b) is maintained at a temperature of 30 to 50 C, more preferably 40 to 45 C, during addition of the acid and water.
Isolation of the precipitate of Trilostane is preferably carried out by filtering the product of step c). It is preferred that the product of step c) is maintained at a temperature in the range 15 to 25 C during filtration.
The first aspect of the present invention is directed to the preparation of Trilostane using methanol as solvent, which is in contrast to the teaching of Neumann et aft. As stated above, the use of methanol in this way provides a number of important advantages over current methods. It has been found, however, that solvents other than methanol may also be used.
Thus, according to a second aspect of the present invention there is provided a method for the preparation of Trilostane from (4a,5a,170)-4,5epoxyandrost-2-eno(2,3-d)isoxazol-17-ol as a precursor compound, the method comprising the steps of: a) dissolving the precursor compound in a solvent; b) treating the precursor compound with a base to effect cleavage of the (2,3-d)isoxazole ring of the precursor compound; c) adding acid and water to the product of step b) to obtain a precipitate of Trilostane; and d) isolating the precipitate of Trilostane.
It is preferred that when using a method in accordance with the second aspect of the present invention the solvent does not cause decomposition of Trilostane or the precursor compound.
The solvent may be an alcohol or an ether. Preferred alcohols include lower alcohols such as methanol, ethanol, isopropanol and the like. Preferred ethers include tetrahydrofuran and the like.
The invention is illustrated with reference to the following non-limiting Example.
EXAMPLE
The following procedure may be used for the conversion of (4a,5a, 17,8)-4, 5-epoxyandrost-2- eno(2,3-d)isoxazol- 17-ol (1) to Trilostane ((4a,5a, 1 70)-4,5-epoxy-3,17- dihydroxyandrost-2- ene-2-carbonitrile; 2).
/ CH3 / H CH3 i/ (I) NaOH, MeOH CH3 it\ Nip- (u) AcOH, water A/ (1) (2) Inventory Reagent Wt / g mmoles Molar equivalent Compound (1) 10.0 30.4 1. 0 Sodium Hydroxide solid 1.49 37.3 1.23 Methanol 150 ml Acetic Acid glacial 2.74 45.6 1.50 Water 150 ml Process 1. Charge compound (1) (lO.O g, 30.4 mmols, l.O equiv) to a round- bottomed flask fitted with a stirrer.
2. Charge methanol (150 ml) and sodium hydroxide (1.49 g, 37.3 mmols, 1. 23 equivs) to the flask and leave to stir-out.
3. Leave the solution to stir-out with warming (40 - 45 C, two hours).
4. Hold the temperature of the stirred reaction mixture (40 - 45 C) and slowly charge acetic acid (2.74 g) over two-hours.
5. Add water in minimum time consistent with maintaining the temperature of the resulting slurry at 40 - 45 C.
6. Leave the slurry to stir-out and cool to 18 - 20 C.
7. Collect the solid by filtration and wash with water.
8. Charge filter cake to a vacuum oven to dry (at 40 - 50 C) to constant weight.
The above procedure provided a final yield of Trilostane (2) of 9.5 g (95%).
REFERENCED
1. Neumann H. C., Potts G. O., Ryan W. T. and Stoner F. W., "Steroidal Heterocycles.
XIII. 4a,5-Epoxy-5a-androst-2-eno[2,3-d]isoxazoles and Related Cmpounds", J. Med. Chem., 1970,13, 948-951.
Claims (33)
1. A method for the preparation of Trilostane from (4a,5a,170)-4,5epoxyandrost-2- eno(2,3-d)isoxazol-17-ol as a precursor compound, the method comprising the steps of: a) dissolving the precursor compound in methanol; b) treating the precursor compound with a base to effect cleavage of the (2,3- d)isoxazole ring of the precursor compound; c) adding acid and water to the product of step b) to obtain a precipitate of Trilostane; and d) isolating the precipitate of Trilostane.
2. A method in accordance with claim 1, wherein the base is an alkali metal hydroxide.
3. A method in accordance with claim 2, wherein the alkali metal hydroxide is selected from the group consisting of sodium hydroxide and potassium hydroxide.
4. A method in accordance with claim 1, wherein the base is an alkali metal alkoxide.
5. A method in accordance with claim 4, wherein the alkali metal alkoxide is selected from the group consisting of sodium methoxide and potassium methoxide.
6. A method in accordance with any preceding claim, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected using at least one mole equivalent of the base compared to the precursor compound.
7. A method in accordance with any one of claims 1 to 5, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected using 1.00 to 1.50 mole equivalents of the base compared to the precursor compound.
8. A method in accordance with any one of claims 1 to 5, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected using 1.05 to 1.30 mole equivalents of the base compared to the precursor compound.
9. A method in accordance with any preceding claim, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected at a temperature in the range C to a temperature at which the precursor can be treated with base under reflux conditions.
10. A method in accordance with any one of claims 1 to 8, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected at a temperature in the range to 50 C.
11. A method in accordance with any one of claims 1 to 8, wherein cleavage of the (2,3- d)isoxazole ring of the precursor compound is effected at a temperature in the range to 45 C.
12. A method in accordance with any preceding claim, wherein the precursor compound is treated with the base over a time period of up to 4 hours.
13.A method in accordance with any one of claims 1 to 11, wherein the precursor compound is treated with the base over a time period of 2 to 3 hours.
14.A method in accordance with any one of claims 1 to 11, wherein the precursor compound is treated with the base over a time period of approximately 2 hours.
15. A method in accordance with any preceding claim, wherein the acid is added to the product of step b) before addition of the water.
16. A method in accordance with one of claims 1 to 14, wherein the acid is added to the product of step b) during or after addition of the water.
17. A method in accordance with any preceding claim, wherein the acid is an aqueous acid.
18. A method in accordance with any preceding claim, wherein the acid is an organic acid.
19. A method in accordance with claim 18, wherein the organic acid is a carboxylic acid.
20. A method in accordance with claim 19, wherein the carboxylic acid is selected from the group consisting of formic acid, acetic acid, propanoic acid and butanoic acid.
21. A method in accordance with any one of claims 1 to 17, wherein the acid is a mineral acid.
22. A method in accordance with claim 21, wherein the mineral acid is selected from the group consisting of hydrochloric acid and sulphuric acid.
23.A method in accordance with any preceding claim, wherein 1.15 to 1.30 mole equivalents of the acid compared to the base is added to the product of step b).
24. A method in accordance with any one of claims 1 to 22, wherein 1.20 to 1.25 mole equivalents of the acid compared to the base is added to the product of step b).
25. A method in accordance with any preceding claim, wherein the product of step b) is maintained at a temperature in the range 15 C to a temperature at which the precursor can be treated with base under reflux conditions during addition of the acid and water.
26. A method in accordance with any one of claims 1 to 24, wherein the product of step b) is maintained at a temperature in the range 30 to 50 C during addition of the acid and water.
27. A method in accordance with any one of claims 1 to 24, wherein the product of step b) is maintained at a temperature in the range 40 to 45 C during addition of the acid and water.
28. A method in accordance with any preceding claim, wherein isolation of the precipitate of Trilostane is carried out by filtering the product of step c).
29. A method in accordance with claim 28, wherein the product of step c) is maintained at a temperature in the range 15 to 25 C during filtration.
30. A method for the preparation of Trilostane from (4a,5a,170)-4,5epoxyandrost-2- eno(2,3-d)isoxazol-17-ol as a precursor compound, the method comprising the steps of: a) dissolving the precursor compound in a solvent; b) treating the precursor compound with a base to effect cleavage of the (2,3- d)isoxazole ring of the precursor compound; c) adding acid and water to the product of step b) to obtain a precipitate of Trilostane; and d) isolating the precipitate of Trilostane.
31. A method in accordance with claim 30, wherein the solvent is an alcohol or an ether.
32. A method in accordance with claim 31, wherein the alcohol is selected from the group consisting of methanol, ethanol and isopropanol.
33. A method in accordance with claim 31, wherein the ether is tetrahydrofuran.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0411464A GB2414238B (en) | 2004-05-22 | 2004-05-22 | Method for the preparation of trilostane |
| PCT/GB2004/003170 WO2005113577A1 (en) | 2004-05-22 | 2004-07-22 | Method for the preparation of trilostane |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0411464A GB2414238B (en) | 2004-05-22 | 2004-05-22 | Method for the preparation of trilostane |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB0411464D0 GB0411464D0 (en) | 2004-06-23 |
| GB2414238A true GB2414238A (en) | 2005-11-23 |
| GB2414238B GB2414238B (en) | 2006-12-13 |
Family
ID=32607797
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB0411464A Expired - Fee Related GB2414238B (en) | 2004-05-22 | 2004-05-22 | Method for the preparation of trilostane |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2414238B (en) |
| WO (1) | WO2005113577A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115028674A (en) * | 2022-06-01 | 2022-09-09 | 山东沾化浩瀚药业有限公司 | Preparation method of medicine troostine for treating breast cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1123770A (en) * | 1966-11-15 | 1968-08-14 | Sterling Drug Inc | 2-cyano-3-oxo-steroids |
| GB2155018A (en) * | 1984-02-25 | 1985-09-18 | Sterwin Ag | 2x-cyano-4d,5x-epoxy-androstane -3,17-dione |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3296255A (en) * | 1963-11-29 | 1967-01-03 | Sterling Drug Inc | 2-cyano steroids |
| US4160027A (en) * | 1977-12-20 | 1979-07-03 | Sterling Drug Inc. | Steroid cyanoketones and intermediates |
| GB8328929D0 (en) * | 1983-10-29 | 1983-11-30 | Sterwin Ag | Steroid compounds |
-
2004
- 2004-05-22 GB GB0411464A patent/GB2414238B/en not_active Expired - Fee Related
- 2004-07-22 WO PCT/GB2004/003170 patent/WO2005113577A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1123770A (en) * | 1966-11-15 | 1968-08-14 | Sterling Drug Inc | 2-cyano-3-oxo-steroids |
| GB2155018A (en) * | 1984-02-25 | 1985-09-18 | Sterwin Ag | 2x-cyano-4d,5x-epoxy-androstane -3,17-dione |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2005113577A1 (en) | 2005-12-01 |
| GB0411464D0 (en) | 2004-06-23 |
| GB2414238B (en) | 2006-12-13 |
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| Date | Code | Title | Description |
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| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 20080522 |