138449-24-8

Upstream product

• 56583-58-5 N-tert-butoxycarbonyl-3-(2-naphthyl)-L-alanine 
• 103-67-3 benzyl-methyl-amine 
• 543-27-1 isobutyl chloroformate 
• 602301-10-0 C₃₆H₄₀N₂O₇ 
• 636572-72-0 C₂₃H₂₉NO₆ 

Downstream Products

• 138449-07-7 N₂-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-prolyl]-N-methyl-N-phenylmethyl-3-(2-naphthyl)-L-alaninamide 
• 138449-25-9 Boc-(2S,4R)-Hyp-L-Nap-NMeBzl 
• 138449-60-2 (2S,4R)-Hyp-L-Nap-NMeBzl 

Relevant academic research and scientific papers

Using mixed anhydrides from amino acids and isobutyl chloroformate in N-acylations: A case study on the elucidation of mechanism of urethane formation and starting amino acid liberation using carbon dioxide as the probe

A case study on the elucidation of mechanism of urethane by-product formation and starting amino acid liberation during the conventional two-step isobutyl chloroformate mediated N-acylation is described using carbon dioxide offgas as the probe. The main reason for the urethane formation and starting amino acid liberation was found to be the formation of the symmetrical anhydride of the amino acid during the preparation of the mixed carboxylic-carbonic anhydride intermediate, as determined by quantifying the evolved carbon dioxide. New conditions were developed to minimize this side reaction.

Process development of a large-scale synthesis of TKA731: A tachykinin receptor antagonist

An efficient and chromatography-free large-scale synthesis of a tachykinin receptor antagonist TKA731 (1), utilizing the coupling of dipeptide 7 and 2-chloro-4(3H)-quinazolinone (13) as the key step, is described. The overall yield of 1 from BOC-L-3-(2-naphthyl)alanine (2) in six linear steps (total of eight steps) is 63%. This new convergent approach avoided the use of methyl iodide and the formation of methanethiol byproduct in the last step involving the construction of the quinazolinone ring in the original discovery synthesis. Four chromatographies were also eliminated. The main cause of the side reaction, leading to the urethane byproduct (I) formation and starting amino acid (2) liberation during the coupling of 2 with N-benzylmethylamine using well-known isobutyl chloroformate mediated mixed carboxylic-carbonic anhydride method, was found to be the symmetrical anhydride (III) formation from 2 as determined by the CO2 offgas formation. A new procedure for the coupling of 2 with N-benzylmethylamine involving a reverse addition of 2 and the base to the coupling agent isobutyl chloroformate, followed by the addition of the amine, was developed that minimized the symmetrical anhydride formation. A novel, water-assisted N-methylation of 5 with dimethyl sulfate in the presence of sodium hydride in THF was also developed that eliminated the use of methyl iodide, silver oxide, and KCN. Deprotection of the BOC group in 6 with sulfuric acid circumvented the formation of diketopiperazine and tetrapeptide observed with HCl and trifluoroacetic acid, respectively.

CO2 Offgas as a Mechanistic Probe and Scale-up Tool in N-Acylations Using Mixed Anhydrides from Amino Acids and Isobutyl Chloroformate

The reaction pathways of an N-acylation reaction, involving a mixed anhydride intermediate produced from reaction of an amino acid with isobutyl chloroformate, were analyzed using a novel technique involving the quantitation of CO2 evolved during various parts of the process. Under the normal mode of addition, in which chloroformate is added to a carboxylate anion solution, the dominant mode of yield loss to undesired product was shown to be the formation of a symmetric anhydride, implying that byproduct urethane formation was almost exclusively due to reaction of unreacted chloroformate with amine. This result suggests that inferred high concentrations of carboxylate anion present with the normal addition mode should be minimized to decrease yield loss. This hypothesis was confirmed by demonstrating that symmetric anhydride formation is almost eliminated when the reverse addition (viz., addition of carboxylate anion solution to chloroformate) was carried out These results, in conjunction with the relative temperature insensitivity of the pathways occurring after amine addition, were used to deduce that the higher amounts of remaining starting acid observed on scale-up were due to slower mixing at larger scales, resulting in greater symmetric anhydride yields. The reverse addition, although forming much lower symmetric anhydride amounts, is nevertheless a rapid reaction whose selectivity could be impacted adversely on scale-up due to slower mixing. The offgas methodology presented here can be used to quantify reaction selectivity as a function of scale and thus serve as a diagnostic tool for assessing mixing efficiency at larger scales.

Process development of (2-nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-n-benzyl-n- methylamide (SDZ NKT343)

(2-Nitrophenylcarbamoyl)-(S)-prolyl-(S)-3-(2-naphthyl)alanyl-N-benzyl-N- methylamide (1; SDZ NKT343) is a human NK-1 tachykinin receptor antagonist. The development of a robust process for a multikilogram scale, chromatography-free preparation of this compound is described. The new four-step synthesis was based on a convergent approach, which utilized a peptide coupling of 1-[(2-nitrophenylamino)carbonyl]-L-proline (11) with free base of (S)-3-(2-naphthyl)alanyI-N-benzyl-N-methylamide hydrochloride (4) as the key step in the presence of 1,3-dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as coupling agents. A scale-up of the well-known mixed anhydride coupling method, using isobutyl chloroformate, to produce 4 was found to be problematic due to coupling of the amine at the undesired carbonyl group of the mixed anhydride. This problem was overcome. The drug substance, initially an amorphous powder, was obtained with the desired purity without any chromatography. A process for crystallization of 1 was also developed.

Modification of the potent peptide FK888 with unusual aminoacids: Effects on activity on neurokinin receptors

We report on the synthesis and the pharmacological properties of a new series of tachykinin antagonists based on the peptide N2-[(4R)-4-hydroxy-1-[(1-methyl-1H-indol-3-yl)carbonyl]-L-prolyl]-N-m ethyl-N-(phe-nylmethyl)-3-(2-naphthyl)-L-alaninamide (FK888) modified on the (2-naphthyl)-L-alanine and the [(1-methyl-1H-indol-3-yl)carbonyl] moieties. The compounds were tested on guinea pig ileum for NK-1, rat colon for NK-2 and rat portal vein for NK-3 receptors. The two most potent peptides of this series, 1b and 2d, were selective for the NK-2 receptor (pA2 = 7.5 and 7.3, respectively).

Studies of Neurokinin Antagonists. 4. Synthesis and Structure-Activity Relationships of Novel Dipeptide Substance P Antagonists: N2--L-prolyl>-N-methyl-N-(phenylmethyl)-3-(2-naphthyl)-L-alaninamide and Its Related Compounds

As an extension of our studies on discovering a novel substance P (SP) antagonist, we modified the previously reported dipeptide, N2-2-(1H-indol-3-ylcarbonyl)-L-lysyl>-N-methyl-N-(phenylmethyl)-L-phenylalaninamide (2b).The lysine part in 2b was first optimized to a (2S,4R)-hydroxyproline derivative (3h), which is 2-fold more potent than 2b in SP binding assay using guinea pig lung membranes.Next we modified the 1H-indol-3-ylcarbonyl part in 3h.Introduction of a methyl group at the indole nitrogen enhanced the oral activity, while retaining the binding activity.Finally, we modified the phenylalanine part to culminate in the most potent compound 7k (FK888), which is a potent SP antagonist with NK1 selectivity as well as oral activity.