<i>N</i>-Monoalkylation of Primary Aromatic and Heteroaromatic Amines with Trialkyl Orthocarboxylates and Sodium Borohydride

Crochet, Roy A.; Blanton, C. DeWitt

doi:10.1055/s-1974-23242

Cited by 43 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As it was clear that the acetamide was too stable to be easily reduced to the amine, we chose to make the more easily reducible acetimidate. The literature contains conflicting recommendations for making acetimidates of aromatic amines.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)

Perrault¹,

Shephard²,

Lapean³

et al. 1997

Org. Process Res. Dev.

View full text Add to dashboard Cite

A practical synthesis of atevirdine mesylate, Pharmacia & Upjohn's first-generation non-nucleoside reverse transcriptase (RT) inhibitor for treatment of AIDS, is described. The route consists of three steps. In the first step, the starting material, 3-amino-2-chloropyridine, is N-ethylated by conversion into the acetimidate (1.25 equiv of trimethyl orthoacetate, 0.003 equiv of HOTs·H2O, neat; then distill off the MeOH to drive the amine/imidate equilibrium to imidate) followed by reduction with DIBAL (2.27 equiv, toluene, <−10 °C). In the second step, the N-ethyl derivative is heated in 5.13 equiv of piperazine at ∼170 °C in a closed system under moderate pressure (∼10 psig) to give 3-(N-ethylamino)-2-(1-piperazinyl)pyridine, which is purified by crystallization from water. An X-ray crystallographic study revealed that the crystal contains five molecules of water per molecule of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine. The molecules pack in an interesting way, with two layers of piperazinylpyridine molecules sandwiched between layers of water molecules, as in the lipid bilayer structure of the biological cell membrane. The yield for the first two steps is 79.2% (overall, average of six plant runs). In the third step, the pentahydrate is coupled with 5-methoxyindole-2-carboxylic acid (MICA; 1.07 equiv of CDI, CH2Cl2, 30 °C, 2−3 h; then add 1.06 equiv of 3-(N-ethylamino)-2-(1-piperazinyl)pyridine, CH2Cl2, 30 °C) to give atevirdine free base, which is converted into the mesylate salt (1.01 equiv of MeSO3H, methanol, 25 °C) and crystallized. The yield of the third step is 83.3% (overall from MICA; average of eight plant runs). The bulk drug typically contains <0.1% total impurities (by HPLC). This process was used to produce multiton quantities of bulk drug used in phase II clinical trials.

show abstract

Section: Resultsmentioning

confidence: 99%

“…On the basis of a paper that recommends use of NaBH 4 for reduction of formimidates to N -methylamines, we initially tried to reduce the acetimidate to the desired N -ethyl secondary amine using NaBH 4 (1.67 equiv, MeOH, Δ, 3.5 h). However, at most, ∼20% conversion to 2-chloro-3-( N -ethylamino)pyridine occurred.…”

Section: Resultsmentioning

confidence: 99%

Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)

Perrault¹,

Shephard²,

Lapean³

et al. 1997

Org. Process Res. Dev.

View full text Add to dashboard Cite

show abstract

“…The crude product was recrystallized from methanol to yield the rearranged product (10) The amine 5a (2.4 g., 0.01 mole) and 15 ml. of triethyl orthoformate was refluxed with vigorous stirring for 2 hours (20). Excess triethyl orthoformate was removed in uacuo.…”

Section: -Carbethoxy-46-dihydroxy-l-methylpyrrolo[23-b]pyridine-5-mentioning

confidence: 99%

Synthesis of pyrrolo[2,3‐b]azepine‐4,7‐dione derivatives

Vora

Blanton

1981

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

“…This methodology is also limited if groups sensitive to reductants or base are present. In a two-step process, reduction of N-arylformamide 11,12 and N-arylformimidate 13 derivatives also yielded N-monomethylated anilines. N-Arylaminomethylsuccinimides, 14 N-[(benzotriazol-1-yl)methyl]anilines, 15 2-imino-3-methyl-2,3-dihydrobenzothiazols, 16 and iminophosphoranes 17 have also been used to prepare N-monomethyl anilines.…”

Section: Introductionmentioning

confidence: 99%

Highly Efficient N‐Monomethylation of Primary Aryl Amines

Peng¹,

Liu

Tang

et al. 2009

Chin. J. Chem.

View full text Add to dashboard Cite

A highly efficient method for specific synthesis of N-monomethylarylamines is presented. Anilines were treated with acetic anhydride and triethylamine in dry CH 2 Cl 2 to give the corresponding acetamides. The subsequent N-monomethylation of acetyl aryl amines with methyl iodide and NaH in THF introduced methyl group. Acid hydrolysis of the N-methyl acetanilides in ethylene glycol generated the corresponding N-methyl-N-aryl amines in high yields. This method was also used to synthesize (E)-2-bromo-5-(4-methylaminostyryl)pyridine that may be useful as an amyloid imaging agent for Alzheimer's disease.

show abstract

N-Monoalkylation of Primary Aromatic and Heteroaromatic Amines with Trialkyl Orthocarboxylates and Sodium Borohydride

Cited by 43 publications

References 0 publications

Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)

Production Scale Synthesis of the Non-Nucleoside Reverse Transcriptase Inhibitor Atevirdine Mesylate (U-87,201E)

Synthesis of pyrrolo[2,3‐b]azepine‐4,7‐dione derivatives

Highly Efficient N‐Monomethylation of Primary Aryl Amines

Contact Info

Product

Resources

About