HRP960171A2 - Process for the preparation of 1-hydroxybisphosphonates - Google Patents

Description

According to the International Classification of Patents, this invention belongs to group C07F-009/38.

This invention relates to a process for the preparation of substituted 1-hydroxybisphosphonates.

State of the art

Bisphosphonates are from a family of compounds that have recently been particularly used as pharmaceutical agents in the treatment of bone diseases and calcium metabolism, such as Paget's disease and osteoporosis. They seem to inhibit the bone resorption process mediated by osteoclasts.

Several procedures for obtaining bisphosphonates have been published. Most, such as 3,962,432 by Henkel & Cie, GMBH, or 5,159,180 and 5,019,651, both by Merck & Co, use acidic reaction conditions. Relatively few reports refer to the preparation of bisphosphonates using basic conditions.

McConnell and Coover, 1956, J. Am. Chem. Soc. 78 : 4450 were the first to describe the synthesis of I-hydroxybisphosphonates from the base-catalyzed addition of dialkyl phosphites to acylphosphonates obtained from the Michaelis-Arbuz reaction of trialkyl phosphites and acid chlorides. Later, Fitch and Moedritzer, 1962, J. Am. Chem. Soc. 84:1876 showed that McConnel and Coover incorrectly assigned the structure of 1-hydroxybisphosphonate to dialkyl 1-(dialkoxyphosphonyl)alkyl phosphate.

It is preferable to use a procedure for the preparation of the 1-hydroxybisphosphonate that uses milder conditions and minimizes the carryover that often occurs in base reactions.

Detailed description of the invention

This invention relates to a new process for the preparation of 1-hydroxybisphosphonates and substituted 1-hydroxybisphosphonates of formula 1

[image]

where:

R1 and R2 are independently H, or C1-6 normal or branched chain alkyl, benzyl, aryl, or Na, Ca, Li, or K; and R1 can be the same as R2; and

R 3 is C 1-10 normal or branched chain alkyl, benzyl, or aryl, which is either unsubstituted or substituted with one or more C 1-6 alkyl, phenyl, -NR 25 , -SR 5 , or –OR 5 , where R 5 is independently selected from the group consisting of hydrogen, C1-10 alkyl and aryl; which includes the reaction of dialkyl phosphite anions of formula II and formula III

[image]

where R 1 and R 2 are independently C 1-6 straight or branched chain alkyl, benzyl or aryl; and R1 can be the same as R2;

with any (i) acid halide of the formula

R3-C(O)-X

wherein R 3 is as defined above and X is Cl, F or Br; or (ii) with a compound that has an activated carbonyl part, with the presence of a base and the possibility of converting it into a salt form.

Another aspect of this invention is a process for obtaining aminoalkylhydroxy bisphosphonates of formula IV

[image]

which includes degrees.

(a) reaction of an acyl compound selected from the group consisting of formula V and formula Va

[image]

where R 4 is a protecting group, or where, in compound (V), two R 4 S groups form part of a cyclic group; with dialkyl phosphite anions of formula II and formula III, in the presence of a base, whereby compounds of formula VI are obtained

[image]

and deprotection of compounds of formula VI with a deprotection agent, whereby compounds of formula IV are obtained.

The dialkyl phosphite anion can be derived from any salt form, such as a lithium, potassium and sodium salt. The preferred form of salt is the potassium salt form, since it has been observed that the use of potassium salt usually gives a higher yield of the desired product than with other forms of salt. Salts such as lithium usually give a lower yield of the desired hydroxybisphosphonate product, to produce more of the translocation product, dialkoxyphosphonyl phosphate.

In one embodiment, an excess amount of dialkyl phosphite anion is added relative to the acid halide. A total of at least about two equivalents of dialkyl phosphite is primarily added. In the case where R1 and R2 are the same, (ie compounds of formula II are the same as those of formula III) preferably at least about two equivalents of anion are used.

For compounds where it is not the same as R2, the total is preferably at least two equivalents of anion, but in principle, any ratio of compounds of formula II to compounds of formula III can be added, although this may affect the ratio of the final products obtained. In a preferred embodiment, where R 1 is not the same as R 2 , the ratio of the compound of formula II to the compound of formula III is approximately a statistical mixture, which depends on the ratio used. Preferably, R 3 or C 4 is normal chain alkyl substituted with an amino group or with an aryl such as cinnamoyl.

It is particularly suitable that the acid halide is an acid chloride, and that it does not have a bulky substituent at the α-position. In accordance with the present invention, it has been found that the presence of a large substituent at the α -position of the acid chloride facilitates the displacement, so that the corresponding (alkoxyphosphinyl) phosphate will be obtained. Therefore, the use of such acid chlorides is not suitable. Primary acid chlorides include hydrocinnamoyl chloride, phenylacetyl chloride, and hexanoyl chloride.

In an alternative embodiment of the present invention, the phosphite anions react better with the compound having an activated carbonyl moiety than with the acid halide. In these reactions, primary reactants include imidazoles, 2-thiopyridyl, and 4-phthalmido butanoyl chloride.

While the main base can be any base, suitable bases include LiHMDS, KHMDS, and NaHMDS, with KHMDS being preferred. At least about 2 equivalents of base should be present in the reaction.

Basically, in order to reduce the tendency to transfer to dialkylphosphonyl phosphate, the reaction should be carried out at a lower temperature. Typical temperatures are those below room temperature (approximately 25°C), and even more suitable are those below the freezing point (0°C), and even more suitable up to -100°C.

In accordance with the present invention, salts may be obtained by subjecting a compound of formula 1 where R 1 = H, and then converting to the salt using conventional procedures.

Primary products obtained in accordance with the present invention include aminoalkylhydroxybisphosphonates. These compounds are useful as pharmaceuticals, and particularly as agents for treating osteoporosis and other diseases associated with abnormal bone resorption. A particularly suitable compound is 4-amino-1-hydroxybutylidene-1,1-biphospholic acid, also known as alendronate.

Alendronate is primarily obtained by the reaction of a compound of formula V or Va with anions of formula II and formula III. In this embodiment of the invention, the N-part of formula V and Va is protected during the initial reaction, with the help of protecting groups. In preferred embodiments, the R4 protecting groups together form part of the cyclic group. R4 groups are primarily selected from: phthalimide-, methyl-, ethyl-, silyl-, carboxymethyl- and any known moiety that can act to prevent N- from participating in the following reaction. Other protecting groups include anhydrides such as malic, succinic, glutenic, t-butylmaleic, 1,8-naphthalene carboxylic, phthalic, tetrachlorophthalic, 2,3-naphthalene dicarboxylic acids, and 1,4,5,8-naphthalene tetracarboxylic acids. In the next step, the R4 protecting group is removed by contacting the protecting groups with a deprotecting agent such as tetrabutylammonium fluoride HCl.

When alendronate is obtained, it is preferred that the compounds of formula II and formula III are the same, and that R1 and R2 are selected from C1-6 alkyl- and CH2-phenyl-parts, more preferably from the CH2-phenyl part.

Alendronate can be converted into a pharmaceutically acceptable salt form. Pharmaceutically acceptable salts of alendronate include salts of alkali metals (eg, Na, K), alkaline earth metals (eg, tea, salts of inorganic acids, such as HCl, and salts of organic acids, such as citric acid and amino acids. The most suitable forms are sodium salts, especially monosodium salt in trihydrate form.

The compounds obtained in accordance with the present invention can be administered in oral dosage forms, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, pastes, tinctures, suspensions, syrups and emulsions. Likewise, these compounds can be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all forms used being well known to those skilled in the pharmaceutical art.

The dosage regimen using the compounds according to the method of the present invention is selected in accordance with various factors including the type, age, weight, sex and medical condition of the patient; the severity of the condition to be treated, the patient's kidney and liver function; method of administering the drug. An averagely trained physician or clinical physician can easily determine the effective amount of the drug in preventing bone fractures.

Oral doses according to this invention range from between 0.05 mg per kg of body weight per day (mg/kg/day) to about 1.0 mg/kg/day. Preferred oral doses in humans may range from total daily doses of about 2.5-50 mg/day during the effective treatment period, and the preferred amount is 5, 10 or 20 mg/day. Doses can be changed over time, so that a patient can receive a higher dose, such as 20 mg/day, for a treatment period of two years, and then a lower dose thereafter, such as 5 mg/day later. A lower dose (ie approximately 5 mg) can also be administered over a longer period of time with similar effective effects.

Alendronate can be administered as a single daily dose or in divided doses. Preferably, the dose is administered without food, preferably approximately 30 minutes to 2 hours before a meal, such as breakfast, to allow adequate absorption.

In the methods of this invention, the active component is typically administered with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as "carriers") appropriately selected with respect to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups, and the like. , and in accordance with common pharmaceutical practices, for example, for oral administration in the form of a tablet or capsule, the active component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium steatite, mannitol, sorbitol and the like; for oral administration in liquid form, the oral components of the drug can be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerin, water, etc.

In addition, when desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be incorporated into the mixture of active component(s) and inert carrier materials. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, non-powdering lactose, beta lactose and corn malt, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose, polyethylene glycol , waxes, and the like. Lubricants used in these dosage forms include oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. A particularly suitable tablet formulation is described in U.S. Patent 5,358,941, which is incorporated herein by reference.

The compounds used in this procedure can also be coupled to suitable soluble polymers as targeted drug carriers. Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxypropyl methacrylamide, and the like.

The following non-limiting examples are provided to better illustrate the present invention.

Example 1

Preparation of 1-diethoxyphosphinyl-1-hydroxy-3-phenylpropyl phosphonic acid diethyl ester (1a).

Throughout the examples, the numbers printed in bold refer to the structures that appear in the tables accompanying the examples.

A 0.5 M solution of potassium bis(trimethylsilyl)amide, (14.5 ml, 3.9 mmol) was added at -78°C to a solution of diethyl phosphite (1.0 g, 7.3 mmol) in 36 ml of THF. The mixture is stirred at -78°C for 30 minutes, cooled to -100°C and 536 μl (3.6 mmol) of hydrocinnamoyl chloride is added. The mixture is stirred at -100°C for 10 seconds and -40 ml of saturated ammonium chloride solution is added. The mixture is concentrated under reduced pressure until all the THF evaporates and 50 ml of ethyl acetate is added. The separated aqueous layer was extracted with ethyl acetate (4 x 50 ml) and the combined organic layers were washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give 1.5 g of an oil. Flash chromatography (ethyl alcohol ethyl acetate/l:99 to 1:9) of the residue gave 887 mg (60%) of product 1a in the table below as an oil, 126 mg (9%) of phosphate 2a, and 59 mg (3%) ester 3a. Rf values (ethyl alcohol ethyl acetate/l:99) for 1a = 0.10, 2a = 0.55, and 3a = 0.25.

Example 2-5

Working according to the general procedures of Example 1, with the conditions given in Table 1, below, the following products are obtained:

(1b) diethyl ester of 1-diethoxyphosphinyl-1-hydroxy-2-phenyl-ethyl phosphonic acid;

(1c) diethyl ester of 1-diethoxyphosphonyl-1-hydroxyhexyl phosphonic acid;

(3a) dibenzyl ester of 1-bis(benzyloxyphosphinyl)-1-hydroxyhexyl phosphonic acid

TABLE 1

Addition of dialkyl phosphite anion to acid chlorides

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[image]

a) Ratios were determined from 1H nmr of the crude reaction mixture.

b) Yield refers to combined yields of isolated pure compounds

c) Small amounts ( < 10%) of the corresponding ester RC (OCOR) (P(O) (OEt)2)23 were also isolated

dnd: not detected.

Products listed below:

[image]

Example 6

Preparation of tetramethyl (4-phthalmido-1-hydroxybutylidene)-bisphosphonate

A 0.5 M solution of potassium bis(trimethylsilyl)amide (14.5 ml, 3.9 mmol) was added at -78°C to a solution of diethyl phosphite (1.0 g, 7.3 mmol) in 36 ml of THF. The mixture is stirred at -78°C for 30 minutes and then cooled to -100°C. A solution of 0.91 g (3.6 mmol) of 4-phthalimidobutanoyl chloride in 5 ml of THF was added and allowed to stand for 150 seconds before quenching with 40 ml of saturated ammonium chloride solution. The mixture is heated and extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried with anhydrous MgSO4, filtered and concentrated. The desired compound is obtained by chromatography.

Claims (19)

1. Preparation procedure of 1-hydroxybisphosphonate of formula l [image] where are they R1 and R2 are independently H, or C1-6 normal or branched chain alkyl, benzyl, aryl, or Na, Ca, Li, or K; and R1 can be the same as R2; and R 3 is C 1-10 normal or branched chain alkyl, benzyl, or aryl, which is either unsubstituted or substituted with one or more C 1-6 alkyl, phenyl, -NR 25 , -SR 5 , or –OR 5 , where R 5 is independently selected from the group consisting of hydrogen, C1-10 alkyl and aryl; characterized in that it comprises the reaction of dialkyl phosphite anions of formula II and formula III [image] where R 1 and R 2 are independently C 1-6 straight or branched chain alkyl, benzyl or aryl; and R1 can be the same as R2; with any (i) acid halide of the formula R3-C(O)-X wherein R 3 is as defined above and X is Cl, F or Br; or (ii) with a compound having an activated carbonyl part, in the presence of a base and converting it into a salt form. 2. The process according to claim 1, characterized in that the process is performed at a temperature lower than 25°C. 3. The method according to claim 2, characterized in that the dialkyl phosphite anions react with the acid halide. 4. The method according to claim 3, characterized in that the dialkyl phosphite anion is present in an amount of at least about two equivalents. 5. The method according to claim 4, characterized in that R1 is the same as R2. 6. The method according to claim 5, characterized in that the dialkyl phosphite anions are derived from the salt form. 7. The method according to claim 6, characterized in that the salt form is selected from the group consisting of lithium, potassium and sodium salts, 8. The method according to claim 3, characterized in that the acid halide is acid chloride. 9. The method according to claim 8, characterized in that the acid chlorides are selected from the group consisting of: hydrocinnamoyl chloride, phenacetyl chloride and hexanoyl chloride. 10. The method according to claim 1, characterized in that phosphite anions react with a compound having an activated carbonyl part. 11. The method according to claim 10, characterized in that the compound having an activated carbonyl part is selected from the group consisting of: imidazole, 2-thiopyridyl, and 4-phthalmidobutanoyl chloride. 12. The method according to claim 1, characterized in that the base is present in an amount of at least two equivalents. 13. The method according to claim 12, characterized in that the base is selected from the group consisting of: LiHMDS, KHMDS, and NaHMDS. 14. Process for obtaining aminoalkylhydroxybisphosphonates of formula IV [image] characterized by the fact that it includes degrees: (a) reaction of an acyl compound selected from the group consisting of formula V and formula Va: [image] where R 4 is a protecting group, or where, in compound (V), two R 5 S together form part of a cyclic group; with dialkyl phosphite anions of formula II and formula III, [image] in the presence of a base, whereby compounds of formula VI are obtained [image] and deprotection of the compound of formula VI with a deprotection agent, whereby compounds of formula IV are obtained. 15. The method according to claim 14, characterized in that R4 is selected from the group consisting of: phthalimide-, methyl-, ethyl-, silyl- and carboxylmethyl- parts 16. The method according to claim 14, characterized in that the protecting group is an anhydride selected from the group consisting of: malic, succinic, glutaric, t-butylmaleic, 1,8-naphthalic, phthalic, tetrachlorophthalic, 2,3-naphthalene dicarboxylic acids , and 1,4,5,8-naphthalene tetracarboxylic acids. 17. The method according to claim 15, characterized in that R1 is selected from the group consisting of C1-6alkyl- and CH2-phenyl. 18. The method according to claim 14, characterized in that n = 4. 19. The method according to claim 15, characterized in that the deprotecting agent is tetrabutylammonium fluoride and HCl.