Synthesis of 2-(5-(2-Aminopropyl)-2-hydroxyphenyl)acetic Acid, a Metabolite of the Drug 5-APB
Round 1
Reviewer 1 Report
In this manuscript the Authors present the synthesis of the main metabolite of 5-APB. The relevance of the title compound in the literature context is well depicted in the introduction, and the topic is interesting for Molbank readers. Also, the synthetic method is novel, and the title compound is obtained with an overall acceptable yield of 11%. However, the scheme's quality is poor; In the pdf provided to me there are typos and overlap (for ex. in scheme 1). In the experimental section the reported values m/z found for compounds 7 and 1 are quite outstanding (as they are identical to the calculated ones). My main concern is with the final product's characterization. NMR spectra (particularly C13 NMR) are very poor and insufficient to provide a conclusive elucidation of the product structure and composition (its purity) obtained as a hydrobromide salt.
Author Response
Response to Reviewer 1 Comments
In this manuscript the Authors present the synthesis of the main metabolite of 5-APB. The relevance of the title compound in the literature context is well depicted in the introduction, and the topic is interesting for Molbank readers. Also, the synthetic method is novel, and the title compound is obtained with an overall acceptable yield of 11%.
Point 1: However, the scheme's quality is poor; In the pdf provided to me there are typos and overlap (for ex. in scheme 1).
Response 1: We apologize for the poor quality of the PDF something that occurred on the upload of the file. However, we would like to assure you that all figures and schemes have been thoroughly checked and validated for accuracy. We appreciate your understanding and thank you for bringing this to our attention.
Point 2: In the experimental section the reported values m/z found for compounds 7 and 1 are quite outstanding (as they are identical to the calculated ones). My main concern is with the final product's characterization. NMR spectra (particularly C13 NMR) are very poor and insufficient to provide a conclusive elucidation of the product structure and composition (its purity) obtained as a hydrobromide salt.
Response 2: HRMS due to the sensitivity and accuracy of the technique allows fast analysis and reduce the required sample which circunvent the final amount of compound 1. The acuracy of the obtained results relays on the good calibration asured by the institution responsible, the University of Salamanca (Spain) at the Elemental Analysis, Chromatography and Mass Spectrometry Service (NUCLEUS). From our acknowledge this institution has a good reputation, which gives us confidence in the results. Although the small amount of final compound that was explicity by the low intensity of the 13C NMR no other impirities could be observed even on the 1H NMR sepectra. Furthermore, in the supplementary information the adduct of the HBr salt and ACN could be detected, which further supports the identity of the compound.
Reviewer 2 Report
This is an interesting manuscript concerning the synthesis o2-(5-(2-aminopropyl)2-hydroxyphenyl)acetic acid, a metabolite of 5-(2-aminopropyl)benzofuran. There are just a few remarks as specified below:
- Page 2, line 47, ref. [13] is not referred to the comparison of metabolism of 5-APB and 6-APB, but to dose translation from animals to human.
- Page 5, line 193: there is one aliphatic carbon more in 13C-NMR spectrum of compound 7.
Author Response
Response to Reviewer 2 Comments
This is an interesting manuscript concerning the synthesis o2-(5-(2-aminopropyl)2-hydroxyphenyl)acetic acid, a metabolite of 5-(2-aminopropyl)benzofuran. There are just a few remarks as specified below:
.
Point 1: - Page 2, line 47, ref. [13] is not referred to the comparison of metabolism of 5-APB and 6-APB, but to dose translation from animals to human.
Response 1: We would like to acknowledge that there was a mistake in our reference and we have since corrected it to the following reference:
- Brandt, S. D.; Walters, H. M.; Partilla, J. S.; Blough, B. E.; Kavanagh, P. V.; Baumann, M. H., The Psychoactive Aminoalkylbenzofuran Derivatives, 5-Apb and 6-Apb, Mimic the Effects of 3,4-Methylenedioxyamphetamine (Mda) on Monoamine Transmission in Male Rats. Psychopharmacology 2020, 12.doi: 10.1007/s00213-020-05648-z.
We apologize for any inconvenience or confusion this may have caused. Thank you for bringing it to our attention.
Point 2: - Page 5, line 193: there is one aliphatic carbon more in 13C-NMR spectrum of compound 7.
Response 2: The signal at 42.55 ppm in the NMR spectrum belongs to DIPEA.HCl, as marqued on the sepctrum in suplementary information. We acknowledge that this signal should have been removed from the compound description and apologize for any confusion this may have caused.
Reviewer 3 Report
The paper describes the synthesis of 2-(5-(2-aminopropyl)-2-hydroxyphenyl) acetic acid, a metabolite of 5-(2-aminopropyl)benzofuran.
Although the proposed synthesis seems to leave space for further optimization, as confirmed by the very low amount of the target compound obtained, the title carboxylic acid 1 has not been described before and therefore the manuscript might be published on Molbank.
The main issue is related to the use of diazomethane in the first step. Although authors mention the reagent is toxic, I believe the hazard related to the use of diazomethane should be more clearly highlighted in the text and/or in the experimental part. Indeed, diazomethane is a dangerous compound to work with not only because is very toxic (more toxic than HCN) but also because is explosive. Therefore, detailed information about manipulation of this reagent should be added (for example J. Org. Chem. 2016, 81, 5814−5823). The page of the book mentioned as a reference should also be added.
Some minor points are described below:
· APB is not a useful keyword. It might be replaced by aminopropylbenzofuran
· I would place Figure 1 in the first page of the manuscript (line 31)
· polyhydroxylated (Figure 2)
· methylation of the hydroxyl group (line 80)
· the quality of Scheme 1 (at least as it looks like in the pdf file available) should be increased (overlapping of Cl2CHOCH3 and SnCl4 and compound number superscript)
· under inert atmosphere at 0 °C (line 90)
· previous procedure (line 94)
· spectroscopic data are in accordance (throughout the experimental part)
· NMR should replace RMN throughout the experimental part
· 2 x 5 ml (line 186)
· HSiCl3 (line 284)
· Methyl 2-(5-(2-aminopropyl)-2-methoxyphenyl)acetate (7) hydrochloride (page 4, supp. Information)
Author Response
Response to Reviewer 3 Comments
The paper describes the synthesis of 2-(5-(2-aminopropyl)-2-hydroxyphenyl) acetic acid, a metabolite of 5-(2-aminopropyl)benzofuran.
Although the proposed synthesis seems to leave space for further optimization, as confirmed by the very low amount of the target compound obtained, the title carboxylic acid 1 has not been described before and therefore the manuscript might be published on Molbank.
The main issue is related to the use of diazomethane in the first step. Although authors mention the reagent is toxic, I believe the hazard related to the use of diazomethane should be more clearly highlighted in the text and/or in the experimental part. Indeed, diazomethane is a dangerous compound to work with not only because is very toxic (more toxic than HCN) but also because is explosive. Therefore, detailed information about manipulation of this reagent should be added (for example J. Org. Chem. 2016, 81, 5814−5823). The page of the book mentioned as a reference should also be added.
Response: We appreciate the reviewer's comment and have taken it into account. In response, we have added an explicit comment in our manuscript regarding the hazards associated with this reagent (page 3, line 83). We have also included the sujected reference that addresses alternative methods to diazomethane preparation, which may help reduce the risks associated with its use.
Some minor points are described below:
- APB is not a useful keyword. It might be replaced by aminopropylbenzofuran
Response: Amendment made
- I would place Figure 1 in the first page of the manuscript (line 31)
Response: Changing the position of the figure is acceptable after line 31, but we leave this change/suggestion to the editor
- polyhydroxylated (Figure 2)
Response: Amendment made
- methylation of the hydroxyl group (line 80)
Response: Amendment made
- the quality of Scheme 1 (at least as it looks like in the pdf file available) should be increased (overlapping of Cl2CHOCH3 and SnCl4 and compound number superscript)
Response: This was something pointed out by reviewer 1 and the correction was made
- under inert atmosphere at 0 °C (line 90)
Response: Amendment made
- previous procedure (line 94)
Response: Amendment made
- spectroscopic data are in accordance (throughout the experimental part)
Response: Amendment made
- NMR should replace RMN throughout the experimental part
Response: Amendment made
- 2 x 5 ml (line 186)
Response: Amendment made
- HSiCl3 (line 284)
Response: Amendment made
- Methyl 2-(5-(2-aminopropyl)-2-methoxyphenyl)acetate (7) hydrochloride (page 4, supp. Information)
Response: Amendment made in page 5, supp. Information
Round 2
Reviewer 1 Report
I guess the paper could be published now, although I still believe that such low molecular weight molecules should be presented with nmr spectra with an acceptable base-line.
