WO1996033199A1

WO1996033199A1 - Process for making 1-hydroxybisphosphonates

Info

Publication number: WO1996033199A1
Application number: PCT/US1996/005222
Authority: WO
Inventors: Rejean Ruel; Robert N. Young; Jean-Pierre Bouvier; Gerard R. Kieczykowski
Original assignee: Merck & Co., Inc.; Merck Frosst Canada Inc.
Priority date: 1995-04-20
Filing date: 1996-04-16
Publication date: 1996-10-24
Also published as: YU24396A; AR005965A1; AU5485596A; AR001629A1; TW393488B; HRP960171A2

Abstract

This invention relates to an addition reaction between anions of dialkyl phosphites and acid halides to produce 1-hydroxybisphosphonates and substituted hydroxybisphosphonates. It is preferred that this reaction takes place at a low temperature in a base so that rearrangement to dialkyl (dialkoxyphosphinyl)phosphates is minimized.

Description

TITLE OF THE INVENTION

PROCESS FOR MAKING 1 -HYDROXYBISPHOSPHONATES

DESCRIPTION OF THE INVENTION This invention relates to a method of making substituted 1 - hydroxybisphosphonates.

BACKGROUND OF THE INVENTION

Bisphosphonates are a family of compounds which have found recent use as pharmaceuticals in the treatment of disea.ses of bone and calcium metabolism, such as Paget's disease and osteoporosis. They appear to inhibit the process of bone resorption through the mediation of osteoclasts.

Several methods for the preparation of bisphosphonates have been reported. Most, such as 3,962,432 to Henkel & Cie, GMBH, or 5,159,180 and 5,019,651 , both assigned to Merck & Co, use acidic reaction conditions. Comparatively few reports deal with the preparation of bisphosphonates using basic conditions.

McConnell and Coover, 1956, J. Am. Chem Soc. 78:4450 first described the synthesis of 1 -hydroxybisphosphonates from the base- catalyzed addition of dialkyl phosphites to acylphosphonates which were obtained from Michaelis-Arbuzov reaction of trialkyl phosphite and acid chloride. Later, Fitch and Moedritzer, 1962, J. Am. Chem. Soc. #4:1876 showed that McConnell and Coover had erroneously assigned the 1 - hydroxybisphosphonate structure to dialkyl 1 -(dialkoxy-phosphinyl)alkyl phosphate.

It would be desirable to use a process to produce 1 - hydroxybisphosphonates using milder conditions and minimize the rearrangement which often occurs in basic reactions.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to a novel process for producing 1 - hydroxybisphosphonates and substituted 1 -hydroxybisphosphonates of the Formula I

wherein:

R1 and R2 are independently H, or straight or branched C \. 6alkyl, benzyl, aryl, or Na, Ca, Li, or K; and R 1 may be the same as R2; and

R3 is C 1-10 straight chain or branched alkyl, benzyl, or aryl, which is either unsubstituted or substituted with one or more: Cl-6alkyl, phenyl, -NR2⁵, -SR⁵, or -OR⁵, wherein R⁵ is independently selected from the group consisting of hydrogen, C l-lθalkyl, and aryl; comprising reacting dialkyl phosphite anions of the Formula II and Formula HI

wherein R 1 and R2 are independently straight or branched

Cl -6 alkyl, benzyl or aryl; and Rl may be the same as R^; with either (i) an acid halide of the formula

R3— C(0)— X

wherein R 3 is as defined above and X is Cl, Fl or Br; or (ii) a compound having an activated carbonyl moiety, in the presence of a base, and optionally converting to a salt form.

Another aspect of this invention is a method of making an aminoalkylhydroxy bisphosphonate of the Formula IV

comprising the steps of:

(a) reacting an acyl compound selected from the group consisting of Formula V and Formula Va

wherein R4 is a protecting group, or where, in Compound (V), the two R^s together form a part of a cyclic group; with dialkyl phosphite anions of the Formula II and Formula HI, supra, in the presence of a base to obtain compounds of the Formula VI

and deprotecting the compounds of Formula VI with a deprotecting agent to yield compounds of the Formula IV.

The dialkyl phosphite anion may be derived from any salt form, such as the lithium salt, the potassium salt and the sodium salt. The preferred salt form is the potassium salt form since it has been observed that use of the potassium salt generally results in a greater yield of desired product than other salt forms. Salts such as lithium tend to yield less of the desired hydroxybisphosphonate product, and tend to produce more of a rearranged product, a dialkoxyphosphinyl phosphate.

In one embodiment an excess amount of dialkyl phosphite anion be added relative to the acid halide. Preferably a total of at least about two equivalents of dialkyl phosphite are added. In the case where R! and R^ are the same, (i.e., compounds of Formula II are the same as those of Formula III) a total of at least about two equivalents of anions are preferably used.

For compounds where Rl is not the same as R^, a total of at least about two equivalents of anions are preferred, and virtually any ratio of compounds of Formula II to compounds of Formula HI may be added, although this will affect the ratio of final products obtained. In a preferred embodiment, where R 1 is not the same as R^, the ratio of compounds of Formula II to compounds of Formula III is approximately a statistical mix, depending on the ratios used. It is preferred that R3 be either a straight chain, such as a C4 alkyl substituted with an amino group or an aryl such as cinnamoyl.

It is particularly preferred that the acid halide be an acid chloride, and that it not have a sterically bulky substituent at the α- position. It has been found in accordance with this invention that the presence of a bulky substituent on the α-position of the acid chloride will favor a rearrangement, such that the corresponding (alkoxy-phosphinyl) phosphate will result. Therefore use of such acid chlorides is not preferred. Preferred acid chlorides include: hydrocinnamoyl chloride, phenylacetyl chloride, and hexanoyl chloride.

In an alternative embodiment of this invention, the phosphite anions are reacted with a compound having an activated carbonyl moiety rather than an acid halide. In these reactions, preferred reactants include imidazoles, 2-thiopyridyl, and 4-phthalimido butanoyl chloride. While, in general, the base may be any base, suitable bases include LiHMDS, KHMDS, and NaHMDS, while KHMDS is preferred. At least about 2 equivalents of the base should be present in the reaction. In general, in order to lessen the tendency for rearrangement to the dialkoxyphosphinyl phosphate, the reaction should be carried out at a low temperature. Typical temperatures are those below room temperature (approximately 25°C) and more preferably below freezing (0°C), and even more preferably as low as -100°C.

Salts may be made in accordance with this invention by subjecting compounds of Formula I where Rl is H, and then converting to a salt using conventional processes.

Preferred products made in accordance with this invention include the aminoalky -hydroxybisphosphonates. These compounds are useful as pharmaceutical products, and more particularly as agents for treating osteoporosis and other diseases involving abnormal bone resorption. A particularly preferred compound is 4-amino-l- hydroxybutyIidene-l ,l -bisphosphonic acid, also known as alendronate. Alendronate is preferably made by reacting compounds of Formula V or Va with the anions of Formula II and Formula IE. In this embodiment of the invention, the N- moiety of Forumula V and Va is protected during the initial reaction by protecting groups. In preferred embodiments, the R^ protecting groups together form part of a cyclic group. R groups are preferably selected from: phthalimide methyl-, ethyl-, silyl-, carboxymethyl- and any other known moiety which can act to prevent the N- from participating in the ensuing reaction. Other protecting groups include anhydrides such as malic, succinic, glutaric, r-butylmaleic, 1 ,8-naphthalic, phthalic, tetrachlorophthalic, 2,3- naphthalene dicarboxylic acid, and 1 ,4,5,8-napthelene tetracarboxylic acid. In a subsequent step, the R^ protecting group is removed by contacting the protecting groups with a deprotecting reagent such as tetrabutylammonium fluoride and HC1.

When making alendronate, it is preferred that the compounds of Formula E and Formula El be the same, and that R 1 and R^ be selected from C l -6alkyl- and CH2-phenyl- moieties, more preferably from the CH2-phenyl moiety.

Alendronate can be converted into a pharmaceutically acceptable salt form. The pharmaceutically acceptable salts of alendronate include salts of alkali metals (e.g., Na, K), alkali earth metals (e.g., Ca), .salts of inorganic acids, such as HC1 and salts of organic acids such as citric acid and amino acids. Sodium salt forms are preferred, particularly the monosodium salt trihydrate form.

Compounds made in accordance with this 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, paste, tinctures, suspensions, syrups, and emulsions. Likewise they may be administered in an intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

The dosage regime utilizing the compounds of the present invention method is selected in accordance with a variety of factors including type, age, weight, sex, and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent bone fractures.

Oral dosages of the present invention will 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 dosages in humans may range from daily total dosages of about 2.5-50 mg/day over the effective treatment period, and a preferred amount is 5, 10 or 20 mg/day. The dosages may be varied over a period of time, such that a patient may receive a high dose, such as 20 mg/day for a treatment period, such as two years, followed by a lower dose thereafter, such as 5 mg/day thereafter. Alternatively, a low dose (i.e., approximately 5 mg) may also be administered for a longer term with similar beneficial effects.

Alendronate may be administered in a single daily dose or in a divided dose. It is desirable for the dosage to be given in the absence of food, preferably from about 30 minutes to 2 hours prior to a meal, such as breakfast to permit adequate absorption.

In the methods of the present invention, the active ingredient is typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier materials") suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules, elixirs, syrups and the like and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of a tablet or capsule, the active ingredient 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 drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture of active ingredient(s) and inert carrier materials. Suitable binders may include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta- lactose, and com sweeteners, 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 sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. A particularly preferred tablet formulation is that described in U.S. Patent 5,358,941 , which is hereby incorporated by reference.

The compounds used in the instant method may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran co-polymer, polyhydroxyl- propylmethacryl amide and the like.

The following non-limiting Examples are presented to better illustrate the invention. EXAMPLE 1

Production of l-Diethoxyphosphynyl-l -hydroxyl-3-phenylpropyl pho.sphonic acid diethyl ester ( la) Throughout die Examples, numbers in boldface refer to the structures appearing in the Tables following the Examples.

A 0.5M 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 THF. The mixture was stirred at -78°C for 30 minutes, cooled to -100°C and 536 μL (3.6 mmol) hydrocinnamoyl chloride was added. The mixture was stirred at -100°C for 10 seconds and 40 ml of a saturated solution of ammonium chloride was added. The mixture was concentrated under reduced pressure until all THF was evaporated and 50 ml ethyl acetate was added. The separated aqueous layer was extracted with ethyl acetate (4 x 50 ml) and the combined organic layers were washed in brine, dried with anhydrous MgS04, filtered and evaporated to give 1.5 g of an oil. Flash-chromatography (ethyl alcohol: ethyl acetate/1 :99 to 1 :9) of the residue gave 887 mg (60%) of the product la in the table below as an oil, 126 mg (9%) of the phosphate 2a, and 59 mg (3%) of the ester 3a. The Rf values (ethyl alcohol: ethyl acetate/1 :99) of la = 0.10; 2a = 0.55; and 3a = 0.25.

EXAMPLES 2-5

Following the general procedures of Example 1 , with the conditions noted in Table 1 , below, the following products were made: (lb) 1 -diethoxyphosphinyl- 1 -hydroxy-2-phenylethyl pho.sphonic acid diethyl ester; (lc) 1 -diethoxyphosphinyl- 1 -hydroxyhexyl phosphonic acid diethyl ester; (3a) 1 -bis(benzyloxyphosphinyl)- 1 -hydroxyhexyl phosphonic acid dibenzyl ester TABLE 1

Addition of dialkyl phosphite anion to acid chlorides

₂

2

2(RO)2P(0)H + 2 BASE + X(CH2)nC(0)Cl -100°C, THF PRODUCTS^

reaction time (t)

Base R Acid t (seconds) Products Yield (%) Chloride

LiHMDS Bn X = H 10 3a, 4a 90 n = 5

KHMDS Bn X = H 10 3a, 4a 75 n = 5 ratio 3: 1

^a Ratios were determined from ^H nmr of the crude reaction mixture. ^Yield refers to combined yields of the isolated pure compounds. ^rSmall amounts (<10%) of the correspponding ester RC(OCOR) (P(0)(OEt)2)2 3 were also isolated, <^nd: not detected. ^PRODUCTS given below:

(

EXAMPLE 6

Production of tetramethyl (4-phthalimido-l-hydroxybutylidene)- bisphosphonate A 0.5M 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 was .stirred at -78°C for 30 min, 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 aged for 150 seconds before quenching with 40 ml of a saturated solution of ammonium chloride. The mixture was warmed and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried with anhydrous MgSθ4, filtered and concentrated. Chromatography afforded the desired compound.

Claims

WHAT IS CLAIMED IS:

1. A process for making 1 -hydroxybisphosphonates of the Formula I

wherein

R! and R2 are independently H, or straight or branched C i- 6alkyl, benzyl, aryl, or Na, Ca, Li, or K; and Rl may be the same as R2; and

R3 is C 1-10 .straight chain or branched alkyl, phenyl, benzyl, or aryl, which is either unsubstituted or substituted with one or more: C l- 6alkyl, phenyl, -NR2⁵. -SR⁵, or -OR⁵, wherein R⁵ is independently selected from the group consisting of: hydrogen, Cl-i()alkyl and aryl; comprising reacting dialkyl phosphite anions of the Formula

E and Formula El

R¹0-P— OR¹ R²0- P— OR²

(II) (III)

O O

wherein R 1 and R^ are independently straight or branched Cl-6alkyl, benzyl or aryl, and R 1 may be the same as R2; with either (i) an acid halide of the formula R3__C(0)_X

wherein R 3 is as defined above and X is Cl, Fl or Br; or (ii) a compound having an activated carbonyl moiety; in the presence of a base, and optionally converting to a salt form.

2. A process according to Claim 1 wherein the process occurs at a temperature which is less than 25°C.

3. A process according to Claim 2 wherein the dialkyl phosphite anions are reacted with an acid halide.

4. A process according to Claim 3 wherein the dialkyl phosphite anion is present in an amount of at least about two equivalents.

5. A process according to Claim 4 wherein Rl is the same as R2.

6. A process according to Claim 5 wherein the dialkyl phosphite anions are derived from a salt form.

7. A process according to Claim 6 wherein the salt form is selected from the group consisting of lithium salt, potassium salt and sodium salt.

8. A process according to Claim 3 wherein the acid halide is an acid chloride.

9. A process according to Claim 8 wherein the acid chlorides are selected from the group consisting of: hydrocinnamoyl chloride, phenylacetyl chloride and hexanoyl chloride.

10. A process according to Claim 1 wherein the phosphite anions are reacted with a compound having an activated carbonyl moiety.

11. A process according to Claim 10 wherein the compound having an activated carbonyl moiety is selected from the group consisting of: imidazoles, 2-thiopyridyl, and 4-phthalimido butanoyl chloride.

12. A process according to Claim 1 wherein the base is present in an amount of at least about two equivalents.

13. A process according to Claim 12 wherein the base is selected from the group consisting of: LiHMDS, KHMDS, and

NaHMDS.

14. A process of making an aminoalkylhydroxy bisphosphonate of the Formula IV

comprising the steps of:

(a) reacting an acyl compound selected from the group consisting of Formula V and Formula Va:

wherein R^ is a protecting group, or where, in Compound (V), the two R^s together form part of a cyclic group; with dialkyl phosphite anions of the Formula II and Formula IE,

R¹0-P-OR¹ R²0-P— OR²

O C O ("') in the presence of a base to obtain compounds of the Formula VI

15. A process according to Claim 14 wherein R^ is selected from the group consisting of: phthalimide-, methyl-, ethyl-, silyl-, and carboxylmethyl- moieties.

16. A process according to Claim 14 wherein the protecting group is an anhydride selected from the group consisting of: malic, succinic, glutaric, /-butylmaleic, 1 ,8-naphthalic, phthalic, tetrachlorophthalic, 2-3 -naphthalene dicarboxylic acid, and 1 ,4,5,8- naphthelene tetracarboxylic acid.

17. A process according to Claim 15 wherein Rl is selected from the group consisting of C 1-6 alkyl- and CH2-phenyl-.

18. A process according to Claim 14 wherein n=4.

19. A process according to Claim 15 wherein the deprotecting agent is tetrabutylammonium fluoride and HC1.