An Alternative Approach to Achieve Enantiopure (3S)-4-Benzyl-3- (4-fluorophenyl)morpholin-2-one:  A Key Intermediate of Aprepitant, an NK1 Receptor Antagonist

Elati C.R., Kolla N., Vankawala P.J., Gangula S., Chalamala S., Sundaram V., Bhattacharya A., Vurimidi H., Mathad V.T.

Research work presented here describes an approach to achieve the enantiopure escitalopram (1) via didesmethyl escitalopram (4), which is easily resolvable compared to citalopram (1a) through diastereomeric salt crystallization. The resolved intermediate (didesmethylcitalopram) was subsequently used for the preparation of the desired drug. This simple modification of the substrate makes a remarkable difference in the chemical resolution process. The first resolution of didesmethylcitalopram (±)-4 to furnish (+)-4, a novel key intermediate to assemble escitalopram (1) was achieved via diastereomeric salt resolution using (−)-di-p-toluoyltartaric acid (DPTTA). The resolution conditions were optimized; a key feature of this process is the addition of specific quantity of water at a specific temperature to the reaction mixture.

Carey J.S., Laffan D., Thomson C., Williams M.T.

The purpose of this perspective is to indicate the range of chemistries used in the manufacture of drug candidate molecules and to highlight certain gaps in current technologies. To do this a survey was carried out of chemical syntheses within the Process Chemistry R&D departments of GlaxoSmithKline, AstraZeneca and Pfizer.

Zhao M.M., McNamara J.M., Ho G., Emerson K.M., Song Z.J., Tschaen D.M., Brands K.M., Dolling U., Grabowski E.J., Reider P.J., Cottrell I.F., Ashwood M.S., Bishop B.C.

A streamlined and high-yielding synthesis of aprepitant (1), a potent substance P (SP) receptor antagonist, is described. The enantiopure oxazinone 16 starting material was synthesized via a novel crystallization-induced dynamic resolution process. Conversion of 16 to the penultimate intermediate cis-sec-amine 9 features a highly stereoselective Lewis acid-catalyzed trans acetalization of chiral alcohol 3 with trichloroacetimidate 18 followed by inversion of the adjacent chiral center on the morpholine ring. The six-step process for the synthesis of 9 was accomplished in extremely high overall yield (81%) and with only two isolations.

Hale J.J., Mills S.G., MacCoss M., Finke P.E., Cascieri M.A., Sadowski S., Ber E., Chicchi G.G., Kurtz M., Metzger J., Eiermann G., Tsou N.N., Tattersall F.D., Rupniak N.M., Williams A.R., et. al.

Structural modifications requiring novel synthetic chemistry were made to the morpholine acetal human neurokinin-1 (hNK-1) receptor antagonist 4, and this resulted in the discovery of 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-ox o-1 ,2,4-triazol-5-yl)methyl morpholine (17). This modified compound is a potent, long-acting hNK-1 receptor antagonist as evidenced by its ability to displace [125I]Substance P from hNK-1 receptors stably expressed in CHO cells (IC50 = 0.09 +/- 0.06 nM) and by the measurement of the rates of association (k1 = 2.8 +/- 1.1 x 10(8) M-1 min-1) and dissociation (k-1 = 0.0054 +/- 0.003 min-1) of 17 from hNK-1 expressed in Sf9 membranes which yields Kd = 19 +/- 12 pM and a t1/2 for receptor occupancy equal to 154 +/- 75 min. Inflammation in the guinea pig induced by a resiniferatoxin challenge (with NK-1 receptor activation mediating the subsequent increase in vascular permeability) is inhibited in a dose-dependent manner by the oral preadmininstration of 17 (IC50 (1 h) = 0.008 mg/kg; IC90 (24 h) = 1.8 mg/kg), indicating that this compound has good oral bioavailbility and peripheral duration of action. Central hNK-1 receptor stimulation is also inhibited by the systemic preadministration of 17 as shown by its ability to block an NK-1 agonist-induced foot tapping response in gerbils (IC50 (4 h) = 0.04 +/- 0.006 mg/kg; IC50 (24 h) = 0.33 +/- 0.017 mg/kg) and by its antiemetic actions in the ferret against cisplatin challenge. The activity of 17 at extended time points in these preclinical animal models sets it apart from earlier morpholine antagonists (such as 4), and the piperidine antagonists 2 and 3 and could prove to be an advantage in the treatment of chronic disorders related to the actions of Substance P. In part on the basis of these data, 17 has been identified as a potential clinical candidate for the treatment of peripheral pain, migraine, chemotherapy-induced emesis, and various psychiatric disorders.

Alabaster R.J., Gibson A.W., Johnson S.A., Edwards J.S., Cottrell I.F.

The simple and efficient preparation of enantiomerically pure N -benzyl-3-( S )-(+)-(4-fluorophenyl)-1,4-oxazin-2-one by a crystallisation induced asymmetric transformation of its racemate is reported. A key feature of this process is the use of [(1 S )-(endo,anti)]-(−)-3-bromocamphor-8-sulfonic acid as both resolving agent for the pure ( S )-enantiomer, and in situ racemising agent of the unwanted enantiomer, affording the title compound in high yield. A simple and efficient preparation of N-benzyl-3-(S)-(+)-(4-fluorophenyl)-1,4-oxazin-2-one from its racemate is reported. A key feature of this process is the use of [(1S)-(endo,anti)]-(−)-3-bromocamphor-8-sulfonic acid as both resolving agent for the pure (S)-enantiomer, and in situ racemising agent of the unwanted enantiomer.

Pallavicini M., Valoti E., Villa L., Piccolo O.

Hydrogen phthalates of ( R )- and ( S )-isopropylidene glycerol, obtainable from racemic isopropylidene glycerol by reaction with phthalic anhydride and successive resolution with ( S )- and ( R )-1-phenylethylamine or, alternatively, from ( R )-and ( S )-isopropylidene glycerol, were regarded as potential new resolving agents. A range of important 1-arylethylamines was selected to test their resolving capability. In particular, trial resolutions were carried out using equivalent amounts of racemic and hydrogen phthalate of ( R )-isopropylidene glycerol. The salts of the S isomers selectively crystallized from methanol or 2-propanol allowing to recover the ( S )-1-arylethylamines in high chemical and optical yields.

Ten Hoeve W., Wynberg H.

Synthese et structure cristalline du chloro-2' phenyl-4 dimethyl-5,5 dioxaphosphorinanne-1,3,2ol-2 oxyde-2

Lin C., Wu Z., Tang X., Hao C., Zheng R., Zheng Y.

To develop a highly efficient method for aprepitant chiral intermediate (S)-4-fluorophenylglycine, a continuous reaction system was established in packed bed bioreactor using amidase covalently immobilized on epoxy resin as biocatalyst. The epoxy resin was firstly modified by metal-chelate method and functional groups (Cu2+-IDA) generated were able to rapidly adsorb amidases, which were further covalently bound onto the modified resin with 90.1% immobilization yield and 80.2% activity recovery. The immobilized amidase exhibited excellent thermal stability with the longest half-life of 1456.8 h at 40 °C ever reported. (S)-4-fluorophenylglycine was continuously produced using the reaction system with 49.9% conversion, 99.9% ee, and an outstanding space-time yield of 5.29 kg L-1 d-1. Moreover, the efficient reaction system exhibited a high operational stability and retained 86.3% catalytic activity after 25-day continuous operation. This efficient continuous bioprocess presents great industrial potential for large-scale production of (S)-4-fluorophenylglycine.

Lin C., Tang X., Zheng R., Zheng Y.

An efficient chemoenzymatic route was developed for synthesis of (S)-α-amino-4-fluorobenzeneacetic acid, a valuable chiral intermediate of Aprepitant, using immobilized penicillin amidase catalyzed kinetic resolution of racemic N-phenylacetyl-4-fluorophenylglycine. The optimum temperature, pH and agitation rate of the reaction were determined to be 40 °C, 9.5 and 300 rpm, respectively. Kinetic resolution of 80 g L-1N-phenylacetyl-4-fluorophenylglycine by immobilized amidase 20 g L-1 resulted in 49.9% conversion and >99.9% e.e. within 3 h. The unreacted N-phenylacetyl-4-fluorophenylglycine can be easily racemized and then recycled as substrate. The production of (S)-α-amino-4-fluorobenzeneacetic acid was further amplified in 1 L reaction system, affording excellent conversion (49.9%) and enantioselectivity (99.9%). This chemoenzymatic approach was demonstrated to be promising for industrial production of (S)-α-amino-4-fluorobenzeneacetic acid.

Simon M., Donnellan P., Glennon B., Jones R.C.

Mazuela J., Antonsson T., Johansson M.J., Knerr L., Marsden S.P.

The organocatalytic asymmetric transfer hydrogenation of N-alkyl aryl imino esters for the direct synthesis of N-alkylated arylglycinate esters is reported. High yields and enantiomeric ratios were obtained, and tolerance to a diverse set of functional groups facilitated the preparation of more complex molecules as well as intermediates for active pharmaceuticals. A simple recycling protocol was developed for the Brønsted acid catalyst which could be reused through five cycles with no loss of activity or selectivity.

Fan D., Lu J., Liu Y., Zhang Z., Liu Y., Zhang W.

Catalyzed by a rhodium complex of P-stereogenic diphosphine ligand trichickenfootphos (TCFP), asymmetric hydrogenation of racemic aldimines via dynamic kinetic resolution has been realized for the preparation of chiral arylglycines with good yields and enantioselectivities.

Wang S.

AbstractA facile, economical, and practical method for the preparation of (S)-3-(4-fluorophenyl)morpholin-2-one [(S)-9] has been developed from ethyl 2-(4-fluorophenyl)-2-oxoacetate (7) in three steps through cyclization, hydrogenation, and resolution, providing a new and convenient access to the key intermediate of antiemetic drug aprepitant.

Wang J., Sánchez-Roselló M., Aceña J.L., del Pozo C., Sorochinsky A.E., Fustero S., Soloshonok V.A., Liu H.

Wan W., He Y., Guan M., Li X., Cheng X., Wu Y.

The synthesis of two isomers of Aprepitant (APT) and three isomers of Fosaprepitant (FPT), crucial components for quality control in manufacturing, is described. Herein, three chiral centers in the isomers of Aprepitant are established in high yield by induced crystallization and chiral reduction. Additionally, the isomers of Aprepitant are utilized to synthesize the isomers of Fosaprepitant with the same stereochemistry. All the target compounds were confirmed by elemental analyses, IR, NMR and MS data analysis.

Wang Y., Chen A.

Crystallization has been used widely from bench top to manufacturing scale for the separation and purification of enantiomers. Provided in this chapter are 1) an overview of various crystallization processes used for enantiomer separation and purification, 2) detailed discussions on two main‐stream processes—chiral separation through diastereomeric salts formation and chiral purification by crystallization, as well as 3) a brief review of chiral resolution by preferential crystallization. The two mainstream crystallization processes are reviewed from fundamental concepts to experimental steps taken to develop a robust process. Representative industrial examples of chiral resolution through diastereomeric salt formation are also discussed.

K. Gurjar M., Sun C., S. Yellol G., K. Mohapatra D.

Ramalingam B., Seayad A.M., Chuanzhao L., Garland M., Yoshinaga K., Wadamoto M., Nagata T., Chai C.L.

Lowe J.A.

Gangula S., Elati C.R., Nardela A., Bhattacharya A., Bandichhor R., Ashok D.

A protocol for regeneration of key intermediate of aprepitant from its undesired diastereomers is described. This work features the recycling of at least one-third of the undesired isomers (ent-6, 7 and ent-7) to desired isomer 4 as the key early intermediate for the synthesis of aprepitant 1. The key step in our strategy involves diastereomeric salt preparation.

Mtyus P., Tpolcsanyi P.