Process for preparing ixazomib citrate and intermediates therefor

Abstract

A process for making ixazomib citrate of formula VI comprising reacting a compound of formula V with citric acid to form ixazomib citrate of formula VI: ##STR00001## wherein R is hydrogen or an amide protecting group.

Claims

1. A process for making ixazomib citrate of formula VI comprising reacting a compound of formula V with citric acid to form ixazomib citrate of formula VI: ##STR00016## wherein R is hydrogen or an amide protecting group.

2. The process of claim 1 further comprising a step of fluorinating a compound of formula IV to provide the compound of formula V: ##STR00017##

3. The process of claim 1 wherein the amide protecting group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butoxycarbonyl (Boc), and 9-fluorenylmethoxycarbonyl (Fmoc) groups.

4. An organotrifluoroborate salt of formula V, ##STR00018## wherein R is hydrogen or an amide protecting group.

5. The organotrifluoroborate salt of claim 4, wherein the amide protecting group is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butoxycarbonyl (Boc), and 9-fluorenylmethoxycarbonyl (Fmoc) groups.

6. A process for making a compound of formula V comprising: fluorinating a compound of formula IV to form the compound of formula V; ##STR00019## wherein R is hydrogen or an amide protecting group.

7. The process of claim 6, wherein the amide protecting group is selected from group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butoxycarbonyl (Boc), and 9-fluorenylmethoxycarbonyl (Fmoc) groups.

8. The process of claim 6 further comprising coupling a compound of formula III with a boronate trifluoroacetate salt of formula VII to provide the compound of formula IV ##STR00020##

9. The process of claim 8 further comprising reducing a compound of formula II to provide the compound of formula III: ##STR00021##

10. The process of claim 9 further comprising protecting a compound of formula I to provide the compound of formula II: ##STR00022## wherein R is the amide protecting group.

11. The process of claim 10 further comprising a step of benzylating a compound of formula ii to provide the compound of formula I ##STR00023##

Description

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS

(1) The following embodiments are provided to illustrate, but not to limit the instant invention.

(2) As utilized herein, the term protecting group refers to a moiety that is formed to render a functional moiety unreactive. The protecting group can be removed so as to restore the functional moiety to its original state. Various protecting groups and protecting reagents, including amide protecting groups, are well known to one of ordinary skill in the art and include compounds that are disclosed in Protective Groups in Organic Synthesis, 4th edition, T. W. Greene and P. G. M. Wuts, John Wiley & Sons, New York, 2006, which is incorporated herein by reference in its entirety.

(3) Unlike the synthetic route via a boronic acid or a boroxin intermediate described in Scheme 1, according to a preferred embodiment of the present invention, a route via intermediate V as shown in Scheme 2 below is used for the preparation of ixazomib citrate. The intermediate V, an organotrifluoroborate salt, has the following advantages in synthetic chemistry: i) it can be easily prepared and easily purified by recrystallization; ii) it is generally air and moisture stable at ambient temperature; iii) it has defined stoichiometric of reagents for next transformation step; and iv) it is tolerant of a broad range of functional groups and leads to non-toxic by-products.

(4) ##STR00012## ##STR00013##

(5) As depicted in Scheme 2 above, the synthesis of ixazomib citrate in accordance with an embodiment of the present invention commences from commercially available dipeptide I, which is transformed to the acid III through the protection of I followed by reduction of the resulted benzyl ester II to the acid of III. Subsequent coupling the acid III with boronate trifluoroacetate salt provides the protected boronate IV, wherein R is an amide protecting group. Deprotection of IV via fluorinating condition provides the intermediate V which is subjected to esterification with citric acid to form the citrate VI. Deprotection of citrate VI provides ixazomib citrate isolated as a white solid.

(6) The following Table A summarizes the advantages or characteristics of the embodiments of the instant invention compared with the processes reported in the art.

(7) TABLE-US-00001 Relevant Advantage of the information to Embodiments of embodiments of this Reference this invention this Invention Differences invention U.S. Formation of Formation of 1. Different 1. Organoboranes Pat. No. ixazomib ixazomib citrate is intermediates shown in e.g., U.S. 9,175,018 citrate is achieved through are employed. Pat. No. 9,175,018 B2 are achieved the reaction 2. Novel generally not stable through the between a transformation under atmospheric condensation potassium is applied. conditions, particularly reaction borontrifluoride alkyl- and between a and citric acid alkynylboranes. The boronic acid followed by a lack of stability of (e.g., deprotection organoboranes is due ixazomib) and reaction. to the vacant orbital on citric acid. boron, which can be attacked by oxygen or water, resulting in decomposition of the reagent. Based on the embodiments of the present invention, the borontrifluoride intermediate, organotrifluoroborate salt shows exceptional stabilities toward nucleophilic compounds as well as air and moisture, which offer a stable alternative to commonly used organoboron compounds. The organotrifluoroborate salt can be stored under normal atmospheric conditions for extended periods without noticeable degradation or decomposition as compared to some of their boronic acid, boronate ester, and haloborane counterparts. 2. Generally common borontrifluorides have the limitation of being insoluble in organic media, and require polar solvents like MeCN and H.sub.2O at elevated temperatures for dissolution. Based on the embodiments of this invention, protecting group R is used in intermediate of formula V for the added advantage of being readily soluble in organic media, which made the subsequent citrate formation easier and faster.

(8) The following examples are provided to further illustrate, but not to limit, certain aspects of the present invention.

EXAMPLES

(9) ##STR00014## ##STR00015##

Example 1

Synthesis of benzyl 2-[(2,5-dichlorobenzoyl)amino]acetate (I)

(10) To a 250 mL, 3-necks, round-bottomed flask equipped with a magnetic stir bar (2.5 cm Teflon-coated, oval-shaped) was charged 2-[(2,5-dichlorobenzoyl)amino]acetic acid (ii) (3.00 g, 12.3 mmol, 1.00 equiv.), benzyl bromide (2.2 mL, 18 mmol, 1.50 equiv.) and acetone (30 mL), and the mixture was cooled to 0 to 5 C. Triethylamine (3.4 mL, 24 mmol, 2.00 equiv.) was added and the reaction mixture was slowly warmed to 20 to 30 C. and stirred for completion. After stirring for 20 hrs, the reaction mixture was added 1.0 N HCl aqueous solution (10 mL) followed by H.sub.2O (20 mL). The resulted suspension was filtered and the cake was washed by acetone (5.0 mL) and water (10.0 mL). The wet cake was dried at room temperature under vacuum to afford benzyl 2-[(2,5-dichlorobenzoyl)amino]acetate (I) (2.98 g) as a white solid in 73% yield.

Example 2

Synthesis of benzyl 2-[(tert-butoxycarbonyl)(2,5-dichlorobenzoyl)amino]acetate (iii)

(11) To a 100 mL, 3-necks, round-bottomed flask equipped with a magnetic stir bar (2.5 cm Teflon-coated, oval-shaped) under N.sub.2 was charged benzyl 2-[(2,5-dichlorobenzoyl)amino]acetate (I) (10.00 g, 29.57 mmol, 1.00 equiv.), DMAP (1.80 g, 14.73 mmol, 0.50 equiv.), triethylamine (5.0 mL, 35.5 mmol, 1.20 equiv.) and THF (150 mL), and the mixture was cooled to 0 to 5 C. (Boc).sub.2O (13.0 mL, 57.0 mmol, 1.90 equiv.) was added, and the reaction mixture was slowly warmed to 20 to 30 C. and stirred for 16 hrs. The reaction mixture was cooled to 0 to 5 C. and added 0.5 N HCl aqueous solution (38 mL) followed by H.sub.2O (62 mL). The mixture was added EtOAc (200 mL) and then concentrated to remove THF until the volume of the remained mixture was about 300 mL at less than 40 C. The mixture was added EtOAc (100 mL) and then concentrated to remove THF until the volume of the remained mixture was about 300 mL at less than 40 C. The resulted biphasic mixture was separated, and the organic layer was concentrated to give the crude oil which was dissolved in DCM/n-heptane (1/6, v/v) and subjected to flash column chromatography over silica gel (DCM/n-heptane, 1/6, v/v). The desired fractions were collected and concentrated to afford benzyl 2-[(tert-butoxycarbonyl)(2,5-dichlorobenzoyl)amino]acetate (iii)(13.27 g) as a brown oil in quantitative yield.

Example 3

Synthesis of [tert-Butoxycarbonyl-(2,5-dichloro-benzoyl)-amino]-acetic acid (iv)

(12) A 25 cc 2-neck, round-bottomed flask equipped with magnetic stirring bar under N.sub.2 was added benzyl 2-[(tert-butoxycarbonyl)(2,5-dichlorobenzoyl)amino]acetate (iii) (500.2 mg, 1.14 mmol, 1.00 equiv.), Methanol (5 mL) and Palladium on carbon (10%) (50.1 mg, 0.047 mmol, 0.04 equiv.) at 20 to 30 C. subsequently. The reaction flask was evacuated and purged with hydrogen (4 cycles) and the suspension was stirred at 20 to 30 C. under a balloon of H.sub.2. After stirring at 20 to 30 C. for 16 hrs, the reaction mixture was filtered through celite with MeOH (5 mL) rinse. The filtrate was concentrated to give a colorless oil as the crude product of [tert-Butoxycarbonyl-(2,5-dichloro-benzoyl)-amino]-acetic acid (iv) which was used directly without further purification.

Example 4

Synthesis of 2,5-dichloro-N-(tert-butoxycarbonyl)-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioaxaborol-2-yl]butyl}amino)-2-oxoethyl}benzamide (v)

(13) A 100-mL round-bottomed flask equipped with a magnetic stir bar (1.5 cm Teflon-coated, oval-shaped) under N.sub.2 was charged acid (iv) (370.1 mg, 1.063 mmol, 1.000 equiv.), a boronate trifluoroacetate salt of formula VII (420.2 mg, 1.11 mmol, 1.04 equiv.), TBTU (360.1 mg, 1.12 mmol, 1.06 equiv.) and DCM (11 mL) at 20 to 30 C. The resulting suspension was cooled to 2.5 C. and added dropwise with N,N-diisopropylethylamine (560 L, 3.22 mmol, 3.03 equiv.). After the addition was completed, the resulting mixture was stirred at 0 to 5 C. for 2.5 hrs and stirred for completion. After the reaction was completed, the reaction was quenched with aqueous 0.5 N HCl (2 mL). The mixture was separated, and the organic layer was washed by 1.0 M NaHCO.sub.3 (3 mL) followed by concentration to give a yellow liquid as the crude products. The crude products was then dissolved in DCM/n-heptane (1/1, v/v) and subjected to flash column chromatography over silica gel (EtOAc/n-heptane, 1/4, v/v). The resulting fractions were collected and concentrated to give 2,5-dichloro-N-(tert-butoxycarbonyl)-N-[2-({(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioaxaborol-2-yl]butyl}amino)-2-oxoethyl}benzamide (v) (441.2 mg) as a yellow liquid in 70% yield.

Example 5

(14) Synthesis of potassium [(1R)-1-[[2-[tert-butoxycarbonyl-(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methyl-butyl]-trifluoro-boranuide (vi)

(15) A 100-mL round-bottomed flask equipped with a magnetic stir bar (2.5 cm Teflon-coated, oval-shaped) under N.sub.2 was charged boronate (v) (440.1 mg, 0.74 mmol, 1.00 equiv.) and methanol (10 mL) at 20 to 30 C. After stirring for 10 minutes, the resulting clear solution was added 4.5 M potassium hydrogen fluoride aqueous solution (1 mL, 4.5 mmol, 6.10 equiv.) at 20 to 30 C. and then stirred for 17 hrs. The resulting biphasic mixture was concentrated to give a wet white solid. The obtained wet cake was added n-heptane (10 mL), strongly stirred for 10 minutes and the resulted slurry was filtered. The obtained wet cake was added n-heptane (10 mL), strongly stirred for 10 minutes and the resulted slurry was filtered. The cake was washed by n-heptane (10 mL) and dried under vacuum to give the desired potassium borontrifluoride salts (vi) (376.2 mg) in 97% yield.

Example 6

Synthesis of (R)-2,2-(2-(1-(2-(2,5-dichlorobenzamido)acetamido)-3-methylbutyl)-5-oxo-1,3,2-dioxaborolane-4,4-diyl)diacetic acid (ixazomib citrate)

(16) A 10-mL round-bottomed flask equipped with a magnetic stirring bar (1.0 cm Teflon-coated, oval-shaped) under nitrogen was charged with potassium borontrifluoride salts (vi) (129.2 mg, 0.25 mmol, 1.000 equiv.) and ethyl acetate (3 mL). After stirring for 5 minutes at 20 to 30 C., TMSCI (400 L, 3.15 mmol, 6.06 equiv.) was added and the mixture was stirred at 20 to 30 C. for another 40 minutes. The resulted white slurry mixture was added the solution of citric acid monohydrate (52.3 mg, 0.25 mmol, 1.00 equiv.) in ethyl acetate (3 mL) at 20 to 30 C. The slurry was then heated at 65 C. After stirring for 2 hrs, the reaction mixture was slowly cooled to 20 to 30 C. and stirred for 16 hrs. The resulting mixture was filtered under N.sub.2 and the filtrate was concentrated to give yellow oil which was directly used for the next step without purification.

(17) The obtained yellow oil was added TFA (3 mL) and stirred for 5.0 hrs. After the reaction was completed, the mixture was concentrated under reduced pressure to give the crude products. The crude product was added EtOAc (20 mL), stirred at 20 to 30 C. for 16 h, and filtered to give the desired Ixazomib citrate (83.1 mg) in 65% yield.

(18) The invention is not limited by the embodiments described above which are presented as examples only but can be modified in various ways within the scope of protection defined by the appended patent claims.