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(12) Patent Application Publication (10) Pub. No.: US 2012/0142939 A1 ALLEGRIN Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0142939 A1 ALLEGRIN Et Al US 2012O142939A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0142939 A1 ALLEGRIN et al. (43) Pub. Date: Jun. 7, 2012 (54) PROCESS FOR THE PREPARATION OF (30) Foreign Application Priority Data FOSINOPRIL AND INTERMEDIATES THEREOF Dec. 6, 2010 (IT) .......................... MI2O1 OAOO2249 (75) Inventors: Pietro ALLEGRINI, San Donato Publication Classification Milanese (MI) (IT); Emanuele (51) Int. Cl. ATTOLINO, Palagiano (TA) (IT): C07F 9/32 (2006.01) Alessandro DE MARCO, Reggio CI2P 4L/00 (2006.01) Calabria (RC) (IT): Fausto C07F 9/572 (2006.01) GORASSINI, Udine (IT); Mario MICHIELETTI, Novara (IT) (52) U.S. Cl. .......................... 548/413: 560/193; 435/280 (57) ABSTRACT (73) Assignee: DIPHARMA FRANCIS S.r.l., Baranzate (MI) (IT) The present invention relates to a process for the preparation of intermediates useful in the synthesis of 1S(R).2C.4f (21) Appl. No.: 13/286,421 4-cyclohexyl-1-(2-methyl-1-oxypropoxy)propoxy (4-phe nylbutyl phosphinyl)acetyl L-proline, and the synthesis (22) Filed: Nov. 1, 2011 thereof, in particular as sodium salt (fosinopril Sodium). US 2012/O 142939 A1 Jun. 7, 2012 PROCESS FOR THE PREPARATION OF FOSINOPRIL AND INTERMEDIATES -continued THEREOF FIELD OF INVENTION Condensing agent - -- (I) 0001. The present invention relates to a process for the enzymatic preparation of intermediates useful in the synthe sis of 1S(R).2C.4B-4-cyclohexyl-1-(2-methyl-1-ox N ypropoxy)propoxy (4-phenylbutyl phosphinyl)acetyl-L- COOH proline, and the synthesis thereof, in particular as Sodium salt (III) (fosinopril sodium). 0004. The synthesis of optically pure proline derivatives is PRIOR ART relatively simple, as reported, for example, in U.S. Pat. No. 0002 Fosinopril sodium, namely 1S(R).2C.4B-4-cy 4.912.231 and U.S. Pat. No. 4,937,355. However, the synthe clohexyl-1-(2-methyl-1-oxypropoxy)propoxy (4-phenyl sis of the optically active phosphine derivative of formula (II), as disclosed in U.S. Pat. No. 4,873,356 and U.S. Pat. No. butyl phosphinyl)acetyl L-proline, sodium salt (compound 5,008,399, is far more complex. In fact, it is prepared accord of formula (I), wherein M-Na), is a known compound with antihypertensive activity. ing to Scheme 2 below. Scheme 2 (I) 1) H2, Pd/C O---O -- 2) crystallisation QCOOM O- OH O P 1N 1.O DCO O M = Na,ch fosinopril sodium salt (II) M = H, fosinopril acid (S) O I OH 0003 U.S. Pat. No. 4,337,201 discloses its synthesis by ^ condensation between the optically active 2-methyl-1-ox O ypropoxy)propoxy (4-phenylbutyl phosphinyl)acetic acid of formula (II) and trans 4-cyclohexyl-L-proline of formula (III), with the use of a condensing agent or by activating the (V) acid of formula (II), as shown in Scheme 1 1) L-cinchonidine 2) Seperation of salts Scheme 1 by crystallisation 3) HC 37% US 2012/O 142939 A1 Jun. 7, 2012 0005 Briefly, the synthesis involves the preparation of the covalently bonded to an inert medium, typically silica or ester derivative of formula (IV), as a mixture of four diaste polymer resins, which can constitute up to 90-99% of the total reoisomers (the asterisk indicates the Stereogenic centres), mass of the enzymatic formulation used; 2) those involving followed by removal of the protective benzyl group and sub encapsulation of the enzyme in organic and/or inorganic gels; sequent crystallisation to isolate two of the four diastereoiso and 3) those in which the enzyme proteins are cross-linked. mers as a racemic mixture of the compounds of formulas (II) 0013. In particular, cross-linked proteins include Cross and (V). The racemate is then resolved by formation of dias Linked Enzyme Crystals (CLECs), which are crystallised tereomeric salts by reaction with a resolving agent, such as coprecipitated proteins of very high purity, and Cross-Linked L-cinchonidine. The salt of the acid of formula (II) with Enzyme Aggregates (CLECs). The latter are proteins precipi cinchonidine is then treated with a strong acid to obtain the tated from a solution by adding a salt oran anti-solvent, which isomer of formula (II), as free acid. Five consecutive crystal consequently remain insoluble in the reaction medium, but lisations of the cinchonidine salt are performed to obtain with an “immobilised tertiary structure identical to the one derivative (II) with high enantiomeric purity. active in Solution. 0006. However, although this method has been applied on 0014. The major problem connected with the use of immo an industrial scale it is very expensive, laborious and ineffi bilised enzymes on an inert or cross-linked matrix is that these cient, even if the cinchonidine is recycled. enzymatic formulations unfortunately always possess far 0007 US 2010/0297711 reports a process ofenantioselec lower activity than the enzyme in Solution, the active units tive enzymatic hydrolysis of a racemic mixture of compounds being equal. This is due to the low conformational mobility of of formula (II) and (V), or a salt thereof, in the presence of an the protein in solid phase, and the lower availability in rela enzyme, for example belonging to the hydrolase class, and in tion to the substrate to be processed, which is present in particular to the lipase, protease and esterase Sub-classes. Solution. 0008 Specifically, the preparation of the enantiomer of 0015. An enzymatic system is therefore needed which formula (II), which is useful as intermediate in the prepara supplies the phosphine derivative of formula (II), or a salt tion of fosinopril from a racemic mixture of compounds of thereof, with high enantiomeric purity, without contaminants formula (II) and (V), which corresponds to selective hydroly and, above all, with the use of methods which are cheaper and sis of the compound of formula (V), can be performed with a more Suitable for its preparation on an industrial scale. protease obtained from bacteria of the genus Bacillus licheni formis, such as one of the proteases designated as Pro SUMMARY OF THE INVENTION leather(R) supplied by Amano or one of the Alcalases(R Sup plied by Clea or Novozym. 0016 A process has now been found which allows the 0009. The use of enzymatic preparations in solution, for phosphine compound of formula (II), or a salt thereof, to be example as disclosed in US 2010/0297711, is an effective, obtained as sole enantiomer, by enantioselective enzymatic economical method for the enzymatic resolution of the race catalytic hydrolysis of the ester function of the single isomer mic mixture of the compounds of formula (II) and (V); how of formula (V) of the racemic mixture of compounds of ever, Such use can cause difficulties in processing the end-of formula (II) and (V). The process according to the invention reaction mixture, because of precipitation of part of the is unexpectedly advantageous on an industrial scale com constituents of said enzymatic solution. It is known that liquid pared with known methods due to the use of a solid-phase enzymatic preparations must beformulated with buffers, sur enzyme, which allows cheaper and more efficient preparation factants, Sugars and various other additives to preserve the of fosinopril or a salt thereof, particularly due to the possibil stability and activity of the enzyme over time. ity of recycling the enzyme. 0010. By repeating the experiments disclosed in US 2010/ 0297711, it was observed that, for example by using one of BRIEF DESCRIPTION OF ANALYSIS METHODS the Alcalases(R supplied by Clea, although the reaction pro 0017. The mixture of enantiomers of 2-methyl-1-ox ceeds with high enantioselectivity, at the work-up stage the ypropoxy)propoxy (4-phenylbutyl)-phosphinyl)acetic acid precipitation of the constituents of the enzymatic solution in of formula (II+V) was analysed by HPLC, for example using the form of mucilage or gel makes it particularly difficult to a CHIRALCELOD-HR) column (24x0.46 cm). The analysis separate the so obtained enantiomerically pure compound of was conducted by injecting a 10 Jul sample of Solution formula (II) from the rest of the mixture, thus requiring long obtained by dissolving 10 mg of mixture in 10 mL of isopro filtration times. panol (iProH) containing 0.05% trifluoroacetic acid (TFA), 0011. This aspect constitutes a technical problem during with a constant flow of 0.3 mL/min of petroleum ether (ETP)/ use of the enzymatic method for resolution of the racemic iPrOH=7/3. The retention time of the distomer of formula (V) mixture of compounds of formula (II) and formula (V) on an was approx. 16 minutes, while the retention time of the industrial scale. Moreover, the enzymatic preparation in liq eutomer of formula (II) was about 14 minutes. The iPrOH uid form is unsuitable for recycling of the biocatalyst, used for the eluent mixture also contains 0.05% TFA. because it is perfectly soluble in the aqueous reaction mix 0018. The tests of hydrolytic enzymatic activity were con ture. This problem constitutes a further drawback in the ducted by dissolving 5 mg of racemic mixture of compounds industrial exploitation of the enzymatic method for resolution of formula (II+V) in 1 mL of 0.05 Mphosphate buffer at pH of the racemic mixture of compounds of formula (II) and 7.50 at about 50° C., and restoring the solution to ambient formula (V). temperature. 5 to 50 mg of protease enzyme (depending on 0012. There are various insoluble enzymatic formulations whether the enzyme was pure or crude) was added to the on the market which allow recovery and recycling of the solution, which was left to stand overnight. The solution was enzyme, for example those in which the enzymes are immo tested by HPLC, according to the method described above, on bilised.
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