tert-Butyl (6-(3-(3-Fluorophenyl)ureido)hexyl)carbamate

Round 1

Reviewer 1 Report

The manuscript submitted by Burmistrov et al. describes the synthesis of tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate (3) as a useful building block for the preparation of the unsymmetrical diureas. The authors also succeeded in obtaining a good crystal of compound 3 suitable for the analysis by single crystal X-ray diffraction. Since some 1,3-disubstituted ureas are known to inhibit human soluble epoxide hydrolase (sEH), syntheses and structural analyses of the title compound are important in medicinal chemistry. In addition, the structure of compound 3 was fully supported by ¹H and ¹³C NMR, HRMS, and elemental analyses. Therefore, I recommend that the manuscript be published in Molbank after addressing the following minor remarks.

• Because the following literature demonstrates the synthesis of tert-butyl (6-(3-phenylureido)hexyl)carbamate from compound 1 and phenyl isocyanate, please consider to cite this literature (possibly at the end of the Introduction).

Li, Y.; Qiu, Z. Concise Syntheses and Antitumor Activities of a-Hydroxy(mercapto)amide Derivatives. Asian J. Chem. 2014, 26, 3219–3223. https://doi.org/10.14233/ajchem.2014.15894

• In the middle of page 2, the authors described “Apparently, over the extra 40 hours, the ether became hydrated, which led to the precipitation of urea.”. However, anhydrous ether was used in this reaction, and there was no chance of releasing water molecules in this reaction. How can ethers form hydrates? Where water come from? Please explain this in the Results and Discussion sections.
• Scheme 1: The yields for the reactions of 1 to 3 are missing. In addition, there are two experimental procedures for the synthesis of compound 3 (8 h + 1 h vs. 48 h), while only 58% yield is described in the experimental section. Please insert both yields of 8 h + 1 h reaction and 48 h reaction.
• Because compound 3 contains a fluorine atom, please add the ¹⁹F NMR spectroscopic data.

Other points:

• Author names: Put an asterisk for the corresponding author(s).
• P2L16: Correct “a undergraduate” to “an undergraduate”.
• P2Scheme 1 caption: Correct “3-fluorophenylisocyanate” to “3-fluorophenylisocyanate”. Also inP4L38.
• P2L27: Remove unnecessary space between “unit” and period.
• P2L34: Correct “BOC” to “Boc”.
• P2L35: Insert “a” between “gives” and “torsion angle”.
• P2L36: Insert a period at the end of the sentence.
• P3,last line: Correct “Deutschland” to “Germany”.
• P4L6: Correct “um” to “µm”. Also in L7
• P4L28: Correct “Colourless” to “Colorless”
• P4L43: Insert a comma after “Alternatively”.
• P4L43: Insert a space between “48” and “h”.
• P4L45: Italicize “m/z”.
• P5L10: Insert a space between “MS” and “and”.
• Reference 7: Correct “IJMS” to “ J. Mol. Sci.”.
• Reference 8: The journal name should be abbreviated.
• References 11,12,13,14: Insert periods in the abbreviated journal names.

Author Response

Reviewer comments.

The manuscript submitted by Burmistrov et al. describes the synthesis of tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate (3) as a useful building block for the preparation of the unsymmetrical diureas. The authors also succeeded in obtaining a good crystal of compound 3 suitable for the analysis by single crystal X-ray diffraction. Since some 1,3-disubstituted ureas are known to inhibit human soluble epoxide hydrolase (sEH), syntheses and structural analyses of the title compound are important in medicinal chemistry. In addition, the structure of compound 3 was fully supported by ¹H and ¹³C NMR, HRMS, and elemental analyses. Therefore, I recommend that the manuscript be published in Molbank after addressing the following minor remarks.

 Thank you for the review.

• Because the following literature demonstrates the synthesis of tert-butyl (6-(3-phenylureido)hexyl)carbamate from compound 1and phenyl isocyanate, please consider to cite this literature (possibly at the end of the Introduction).

Li, Y.; Qiu, Z. Concise Syntheses and Antitumor Activities of a-Hydroxy(mercapto)amide Derivatives. Asian J. Chem. 2014, 26, 3219–3223. https://doi.org/10.14233/ajchem.2014.15894

Citation added.

• In the middle of page 2, the authors described “Apparently, over the extra 40 hours, the ether became hydrated, which led to the precipitation of urea.”. However, anhydrous ether was used in this reaction, and there was no chance of releasing water molecules in this reaction. How can ethers form hydrates? Where water come from? Please explain this in the Results and Discussion sections.

Sorry for the misunderstanding. We meant that anhydrous ether took some water from the air. We changed that phrase to “took water from the atmosphere since the flask was not sealed”.

• Scheme 1: The yields for the reactions of 1to 3 are missing. In addition, there are two experimental procedures for the synthesis of compound 3 (8 h + 1 h vs. 48 h), while only 58% yield is described in the experimental section. Please insert both yields of 8 h + 1 h reaction and 48 h reaction.

Yield was added to Scheme 1. Both methods gave practically the same yield. We added “(for both methods)” to the experimental procedure.

• Because compound 3contains a fluorine atom, please add the ¹⁹F NMR spectroscopic data.

Thank you for the valuable comment. The presence of a fluorine atom in the meta-position in the structure of the molecule is confirmed by the ¹³C NMR spectra, which is clearly shown in the coupling constants through 1 bond (J1= 240.1 Hz), through 2 bonds (J2=21.2 and 26.6 Hz) and through 3 bonds (J3 = 9.7 and 11.4 Hz).

Other points:

• Author names: Put an asterisk for the corresponding author(s).

Corrected.

• P2L16: Correct “a undergraduate” to “an undergraduate”.

Corrected.

• P2Scheme 1 caption: Correct “3-fluorophenylisocyanate” to “3-fluorophenylisocyanate”. Also inP4L38.

Corrected.

• P2L27: Remove unnecessary space between “unit” and period.

Corrected.

• P2L34: Correct “BOC” to “Boc”.

Corrected.

• P2L35: Insert “a” between “gives” and “torsion angle”.

Corrected.

• P2L36: Insert a period at the end of the sentence.

Corrected.

• P3,last line: Correct “Deutschland” to “Germany”.

Corrected.

• P4L6: Correct “um” to “µm”. Also in L7

Corrected.

• P4L28: Correct “Colourless” to “Colorless”

Corrected.

• P4L43: Insert a comma after “Alternatively”.

Corrected.

• P4L43: Insert a space between “48” and “h”.

Corrected.

• P4L45: Italicize “m/z”.

Corrected.

• P5L10: Insert a space between “MS” and “and”.

Corrected.

• Reference 7: Correct “IJMS” to “ Mol. Sci.”.

Corrected.

• Reference 8: The journal name should be abbreviated.

Corrected.

• References 11,12,13,14: Insert periods in the abbreviated journal names.

Corrected.

Academic Editor’s comments

1. Clarification of change required at P2 scheme 1 caption and P4 line

38 - 3-fluorophenyl isocyanate should be 2 separate words

Corrected.

2. The melting point of the product 3 should be determined and added to the experimental data.

The melting point of the product 3 added to the experimental section along with the apparatus used for its determination.

3. Ref 7 should be Int. J. Mol. Sci.

Corrected.