Epoxide Syntheses and Ring-Opening Reactions in Drug Development

Round 1

Reviewer 1 Report

The reviewed paper consist asymmetric synthesis of epoxides and their industrial utilization in preparation of drugs. In principle the procedures of preparation of drugs (according to listed points 1-20) are described in good style with many interesting comments concerning those processes.

However, the general layout of the review publication is not acceptable. Main improvements should be considered:

- there is no Introduction and also on the end no conclusions. When we look for such kinds of review papers we can find that in all cases there are a normalized style which is based on the editorial rules (Abstract; Keywords, Introduction, Main Text, Conclusions, References).

- additionally ‘Table of Contents’ can be added. Abstract sounds like a part of Introduction. Especially, in the first sentence “There are 14 approved epoxide-containing drugs that exemplify the importance of this functionality in drug action.” with no examples, no structures, no references is an empty phrase. Should be expand in Introduction accompanied with background info concerning epoxide chemistry. The abstract should contain the essence of the presented review without details to encourage chemists to read the article. In Keywords should be given most straight words to cover the essence of your review content e.g., epoxides; catalytic asymmetric epoxidation; epoxide ring opening; drug development; industrial processes; key intermediates etc. The drug names should be omitted.

Taking into account those general remarks the paper requires major changes, and then it should be ready for detailed revision.

Additionally some selected detailed comments:

The abbreviations of chemicals should be clearly described. In the case of common chemicals such as methylene chloride (DCM) or tetrahydrofurane (THF) it is not particularly required. However, for the special chemicals is obligate when the compound appear at the first time e.g., in line 88 for magnesium monoperoxyphthalate  the MMPA should be add in the text; in line 138 “mCPBA provided higher enantioselectivities than MMPP or bleach and addition of NMO was” – insert full name; see also lines 289, 350, 360, 480, 783, 823, 1058, 1098,1315 etc. In the Schemes 16, 34, 43, 45, 46, 48, etc., there are abbreviations without explanation in the text. Check carefully all abbreviations.

Others selected remarks

Lines 75, 80 - change italic to normal style

Line 118 – reference for “which can be easily prepared from (R)-α-methyl benzylamine” should be added

Line 254 – “d-(-) (R) lactic acid” and line 267 “l-(+) (S) lactic” should be L-(+)-lactic acid and D-(-)-lactic acid; or (R)-lactic acid and (S)-lactic acid, not mixed like in text.

Line 284 – “b-methyl 2,4-difluoro phenyl styrene oxide” should be ”β-methyl-2,4-difluorostyrene oxide” or systematically “2-(2,4-Difluorophenyl)-3-methyloxirane”

Line 1146 - TsOH is used , but in lines 350 and 360 pTSA and TSA is shown; use only one expression

Lines 1204, 1275, 1310, 1459 - wrong number of Schemes

In all captions for Schemes number of substance should be in bold style.

Finally language problem: Authors used very frequently the word “telescoped” to describe chemical processes which is in use rarely in chemical literature. Instead authors can use word "one-pot" or alternatively "merged" or "condensed". (See more: Chem. Sci., 2016, 7, 866)

Comments for author File: Comments.pdf

Author Response

Dear Reviewer

Many thanks for your constructive comments. Please note that we have already addressed most of the points raised as they were common with those made by the other two reviewers (eg. introduction, conclusion, numbering etc). It is unfortunate that you joined at an advanced stage of the revision process and saw an earlier version of the manuscript but we welcome your additional comments which rest assured we will integrate these in the final version. One comment if I may about the term "telescoped". This is a process term to describe a reaction that despite work up, washes, filtration of unwanted materials (inorganics, charcoal) etc, avoids any isolation and a solution of the intermediate is carried forward in the next step, not necessarily in the same vessel. The  "one-pot" term implies no processing/work up and the reagents for the next step are added sequentially in the same vessel. In my 10 year process development career at GlaxoSmithKline I have never come across or heard the terms "merged" and "condensed" for this type of processing by my colleagues or fellow process chemists from other companies. I understand that not everyone is familiar with aspects of large scale processing but you have my word the terminology I have used is the one adopted in manufacturing facilities worldwide.

Author Response File: Author Response.pdf

Reviewer 2 Report

The review provided by Gerasimov and co-worker is indubitably interesting and provides much useful information that can be managed not only related to the specific target discussed. Is appreciates the attention devoted to the safety issue, and the ability to summarize much important information in a few phrases. Schemes are clearly drawn.

Here the corrections that need to be inserted.

Line 198: extra space between “in” and “interrogation”

Line 221 and 230.  Concerning stereochemistry. The authors have used the expression “chiral carbon atom”. It is  better to modify and use stereogenic center or sterocenter : adjacent stereocenter. Modify similarly, in all document.

Line 252 SN2

Line 260 L-(+)-lactic

Line 264 chiral epoxy carbon : Use steregenic epoxide.

Line 271 and 272. L-lactic and D-lactic

Line 452. Unfortunately, in scheme 17, the epoxide was indicated as 62, but in scheme 18, it indicates again the starting material for preparing 62 as 62. From this point, all numerations for compounds need to be carefully revised.

Line 542 SN2

Line 609. Scheme 24. H2

Line 705. Scheme 28. Two nitrogen atoms are missing. In 92 and 93. Under 96, ET3N

Line  720. Scheme 29. The transformation 100 to 101 is correct? (The Ac group how is obtained?)

 Line 811. Lanthanum(III) BINOL complex.

Line 1017. Scheme 42. The Co(Salen) drawn is incorrect (see Co(salen) that is commercially available. The position of tBu groups is uncorrected.

Line 1158. M3SOI?M is Me?

Line 1561. A conclusion is missing.

 

Author Response

We thank Reviewer 1 for his positive and constructive comments

We have corrected all typos and terminology inconsistencies pointed out by the reviewer (lactic acid, SN2 etc)

We have adopted "stereogenic center" or "stereocenter" instead of "chiral carbon atom" as suggested.

We have corrected the numbering of all structures and Schemes and assigned numbers to structures that previously did not have one.

We have corrected errors in some structures with respect to protecting group identity (Bz instead of Ac), position of substituents (tBu group in salen complex), missing atom labels (N) and formula format (eg subscript numbers in Et3N, H2).

In addition we have added an "Introduction" paragraph at the beginning with additional references and a "Conclusion" paragraph at the end.

We thank Reviewer 1 for the valid points raised and help in improving our manuscript.

Author Response File: Author Response.pdf

Reviewer 3 Report

This review by Moschona et al. is a nicely written scientific chronicle concentrating on the success stories of the use of epoxide chemistry in the synthesis of approved medicines and drug candidates enabling the development of robust and efficient syntheses at large scale. It is also an excellent “textbook” for young scientist to train them into the differences of research lab chemistry and industrial chemistry, as well as to exemplify that even big pharma collaborations may be employed for the effective and economic production of a safe drug.

Overall, the case studies described therein are nicely and concisely presented with good use of referencing. However, there is a serious numbering problem of the schemes and the compounds and other some small suggestions/corrections should be taken into consideration by the authors.

1. There is no introduction. The Abstract should be brief and self-contained followed by a slightly more detailed introduction with the scope of the review and the sections to follow. A concluding remark would also add to the structure of the manuscript, in wrapping it all up.
2. Please, Check font and size of section titles under the abstract.
3. Please, check SN2 throughout the text to be written in the same way.
4. Compound 14 in line 158 or Sharpless catalyst in scheme 6???
5. line 323….. “route to CCR1 (Scheme 6)…..” should this be Scheme 11???
6. A compound 62 is in both Scheme 17 and 18 and it is not the same. One is an epoxide and the second is a diol. Please, renumber and correct the text accordingly.
7. Schemes 22-24 have no numbering of the compounds and the text is only descriptive which makes it more difficult to follow.
8. Line 757 “From this effort was born….” Wrong syntax
9. Scheme 30 – compounds 10 and 11 have wrong numbers, they are different to the 10 and 11 previously presented. Please renumber.
10. Scheme 32-33 – is 103 recemic??? Then the 103d appears without showing the a,b,c although they are described in the text. Please, amend accordingly
11. Scheme 38 and text underneath – what is the purpose of the * next to the compound numbers?? To distinguish them from what??
12. Scheme 39: compound 116 leads to compound ???? please add number to intermediate in this route.
13. I believe I did not see compound 163
14. Line 1274. scheme 36 should be scheme 52???
15. line 1459: scheme 39 is scheme 59

Author Response

We thank Reviewer 2 for his constructive comments and recognition of the educational value of this review

We have corrected all typos and terminology inconsistencies pointed out by the reviewer

We have corrected the numbering of all structures and Schemes and assigned numbers to structures that previously did not have one and corrected errors in some structures and

In addition we have added an "Introduction" paragraph at the beginning with additional references and a "Conclusion" paragraph at the end.

Overall we believe we have addressed successfully all points raised.

We thank Reviewer 2 for the valid comments, time,  effort and support in improving our manuscript.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Updated manuscript looks much better and fits  to my previous remarks, although authors refuse to remove names of drugs from the Keywords. I still support my position in order to do this. Two keywords 'epoxides' and ‘drug’ are sufficient to find this paper by the readers via databases.

Finally, I understand well that in the industrial issues the term "telescoped" is in use but for the organic chemists who dealing in the frame of academic and basic research is not very common.Therefore, I stand by my opinion in this case. Indeed, the terms "merge" or "condensed" are not very adequate, but it is better to clarify (or use instead) this expression by terms e.g. ‘multistep’, ‘one-pot’ or more vividly  ‘stepwise synthesis without isolation of intermediate products’ which will be better understood for wider audience.

Author Response

Updated manuscript looks much better and fits  to my previous remarks, although authors refuse to remove names of drugs from the Keywords. I still support my position in order to do this. Two keywords 'epoxides' and ‘drug’ are sufficient to find this paper by the readers via databases.

We have removed the names of the drugs from the keywords as requested.

 

Finally, I understand well that in the industrial issues the term "telescoped" is in use but for the organic chemists who dealing in the frame of academic and basic research is not very common.Therefore, I stand by my opinion in this case. Indeed, the terms "merge" or "condensed" are not very adequate, but it is better to clarify (or use instead) this expression by terms e.g. ‘multistep’, ‘one-pot’ or more vividly  ‘stepwise synthesis without isolation of intermediate products’ which will be better understood for wider audience.

We agree with the Reviewer that for educational purposes it is perhaps best to explain the process terms used in the article so wider audiences get familiar with industry idioms. Initially we considered adding an explanation for the terms "telescoped" and "one pot" next to the first instances they appear in the text but this disrupted the flow of the discussion and found it counterproductive. Finally we opted to include definitions of these in the introduction (lines 39-46) so the concepts are registered early on without need to be repeated later. We think this addresses  adequately the point made by the Reviewer.

Once again we would like to thank Reviewer 1 for the time and effort in reviewing our manuscript and for the improvements made thanks to the valid points raised.

Yours Faithfully

and on behalf of the authoring team

Gerry Rassias