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Synthesis of Ethyl 2-Amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and Ethyl 6-(Acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate

by
Andrii Yu. Myshastyi
1,2,
Sergiy V. Vlasov
1,2,
Hanna I. Severina
3,*,
Georgiy G. Yakovenko
2,4 and
Andrii R. Khairulin
2,4
1
Department of Supramolecular Chemistry, Educational Scientific Institute of High Technologies, Taras Shevchenko National University of Kyiv, Volodymyrska Str., 60, 01033 Kyiv, Ukraine
2
Enamine Ltd., 78 Winston Churchill Str., 02094 Kyiv, Ukraine
3
Department of Pharmaceutical Chemistry, National University of Pharmacy, 53 H. Skovorody Str., 61002 Kharkiv, Ukraine
4
Chemistry and Biology Scientific Production Center, Faculty of Chemistry, Taras Shevchenko National University of Kyiv, Volodymyrska Str., 60, 01033 Kyiv, Ukraine
*
Author to whom correspondence should be addressed.
Molbank 2026, 2026(2), M2144; https://doi.org/10.3390/M2144
Submission received: 30 January 2026 / Revised: 24 February 2026 / Accepted: 27 February 2026 / Published: 4 March 2026
(This article belongs to the Section Organic Synthesis and Biosynthesis)
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Abstract

An effective one-step synthetic procedure for preparation of hydroxylated analogues of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate as novel promising multifunctional building blocks for drug discovery based on the Gewald procedure was developed.

Graphical Abstract

1. Introduction

Since the discovery of an effective procedure to synthesize 2-aminothiophene by Karl Gewald [1,2], it remains useful and opens up new horizons for drug discovery. This reaction made a variety of 2-aminothiophene-3-carboxylic acid derivatives available; among them, the simplest but by no means the least useful is ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate I, which is the product of the Gewald reaction of cyclohexanone with ethyl cyanoacetate. According to Reaxsys, this molecule is cited in 933 documents and 2661 reactions as the starting compound. In the period 2020–2026, 94 papers were published mentioning this compound. Many of them are about the discovery of new biologically active substances like anticancer [3,4,5], antibacterial [3,6,7,8,9], anti-inflammatory [10,11,12], anthelmintic [13], anti-plasmodia [14] and multitarget anti-Alzheimer agents [15,16]. This derivative of 2-aminothiophene is also a precursor for the preparation of antivirals [17], α-glucosidase inhibitors [18], and antimalarial agents [19].
The popularity of ethyl 2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate is explained by its structure; as a matter of fact, cyclohexane is a structural fragment of many useful drugs [20,21,22,23,24,25,26] (Figure 1).
For many of these drugs, metabolic transformations were studied, and it was found that they undergo hydroxylation of the cyclohexane ring [27,28,29,30].
Among good examples of the metabolite application of cyclohexane hydroxylation in drug discovery is the introduction of paliperidone to the pharmaceutical market (Figure 2) [31,32,33]. This compound was first identified as metabolite of risperidone with an almost identical pharmacological profile. That gave an opportunity to introduce paliperidone palmitate under the brand name Invega Sustenna ® as an alternative to risperidone with the possible development of long-acting injectable dosage forms [34,35].
In view of the importance of aminoester I as a building block for biologically active compounds and much information about the hydroxylation of the cyclohexane ring as a key metabolic transformation for cyclohexane-containing xenobiotics, we focused our efforts on the preparation of previously unknown hydroxylated analogues 3a and 3b, with either a free or acetylated hydroxyl group (Figure 3).

2. Results and Discussion

We tested the Gewald protocol of synthesis, similarly to the reported for more active malononitrile [36,37], with 4-hydroxycyclohexanone in ethanol, applying morpholine as the catalyst suitable to be extracted with water during the isolation procedure (Scheme 1). According to LC-MS monitoring, the product was formed to a high extent. The main challenging task was the isolation of the product as, unlike its cyclohexyl analog I, 3a did not precipitate from the reaction mixture even upon cooling. We performed the extraction of water-soluble ethanol and morpholine.
For purification of the product 3a, simple flash chromatography was enough for isolation of the pure product. For acetylated product 3b, an additional chromatographic purification round was needed. The oily 3b product obtained was additionally crystallized from acetonitrile.
The products 3 were isolated in 56% for 3a and 33% for 3b yields; the set of analytical data confirmed their purity, and the structure was recorded.
In the 1H NMR spectrum of 3a (see Supplementary Materials), the signal of the amino group is observed at 7.18 ppm, and the carboethoxy group displays two signals: the methyl group at 1.22 ppm and the methylene group at 4.12 ppm. The signal of the secondary OH group for compound 3a is observed at 3.83 ppm and it has the splitting pattern, which confirms its proximity to the CH group at position 6 with the signal at 4.77 ppm. The compound 3b has a very similar pattern of signals in the 1H NMR spectrum, but the signal of OH is not observed, while the signal of the CH group at position 6 is shifted to 5.01 ppm.

3. Materials and Methods

All solvents were purified according to the standard procedures. All starting materials were obtained from Enamine Ltd. (Enamine Ltd., Kyiv, Ukraine) and used without additional purification. Analytical TLC was performed using ALUGRAM Xtra SIL G UV254, (Macherey-Nagel GmbH, Duren, Germany). Column chromatography was performed using Kieselgel Merck 60 (230–400 mesh) (Merck KGaA, Darmstadt, Germany) as the stationary phase. 1H and 13C NMR spectra were recorded at 500 MHz or 400 MHz, and 126 MHz or 101 MHz, respectively. LC-MS spectra were obtained on the Shimadzu 10-AV LC (Shimadzu Corporation, Kyoto, Japan), Gilson-215 (Gilson, Inc., Middleton, WI, USA), equipped with autosampler, with the following detectors: UV (215 and 254 nm), electrospray ionization mass spectrometer (API 150EX) (Agilent, Santa Clara, CA, USA), ELS detectors. HRMS spectra were acquired with the Agilent 6200 Series TOF (Agilent, Melbourne, Australia) and 6500 Series Q-TOF LC/MS System. IR spectra were taken on an IR5 FTIR spectrometer (Edinburgh Instruments, Livingston, Scotland, UK). AI was used for the preparation of the graphic abstract.
The starting of 4-oxocyclohexyl acetate 1b was achieved by the reported procedures from 4-hydroxycyclohexanone and acetyl chloride [38,39].
Preparation of ethyl 2-amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 3a.
To the stirred mixture of 20 mL (0.175 mol) of 4-hydroxycyclohexanone, 20 mL (0.175 mol) of ethyl cyanoacetate, 5.6 g (0.175 mol) of sulfur and 20 mL of ethanol in a conical 1000 mL flask, 20 mL of morpholine was added. The reaction mixture was stirred at 60 °C till the sulfur powder was dissolved and additionally for 2 h at the same temperature. The reaction mixture was left with stirring overnight for 10 h at ambient temperature. The reaction mixture was quenched with 700 mL of water, which was then removed. The oily mass was washed with 500 mL of water three times. The oily residue was dissolved in the minimal amount of ethyl acetate, and the organic extract was dried over anhydrous sodium sulfate and filtered through the 100 mm pad of silica on the 500 mL Schott filter funnel. Ethyl acetate was used as the eluent. The obtained ethyl acetate solution of the product was evaporated at reduced pressure till crystallization occurred. The yellow mass solid was additionally dried at 60 °C in the oven.
Yellow crystalline powder, yield 56%. m.p. 98 °C.
1H NMR (500 MHz, DMSO-d6) δ: 7.18 (m, J = 9.6 Hz, 2H), 4.77 (d, J = 4.0 Hz, 1H), 4.12 (dtt, J = 9.7, 4.8, 2.7 Hz, 2H), 3.83 (br.s, 1H), 2.75 (dt, J = 17.7, 5.3 Hz, 1H), 2.62 (dd, J = 15.5, 5.0 Hz, 1H), 2.53 (q, J = 8.9, 8.1 Hz, 1H), 2.31–2.20 (m, 1H), 1.79 (dd, J = 12.6, 6.2 Hz, 1H), 1.59–1.44 (m, 1H), 1.22 (td, J = 7.1, 2.0 Hz, 3H).
13C NMR (101 MHz, DMSO-d6) δ: 165.4 (C=O), 163.7 (C), 131.1 (C), 113.6 (C), 102.7 (C), 65.9 (CH), 59.0 (CH2), 33.6 (CH2), 31.5 (CH2), 25.1 (CH2), 14.8 (CH3).
LCMS, positive mode, m/z: 241.0 [M + H]+.
HRMS (ESI): calcd. for C11H15NO3S [M + H]+: 241.0773; found: 241.0763.
IR (ATR, neat), ν, cm−1: 356, 375, 391, 430, 457, 491, 517, 556, 634, 677, 751, 778, 828, 881, 957, 981, 1009, 1030, 1069, 1119, 1148, 1195, 1214, 1267, 1295, 1338, 1365, 1384, 1413, 1439, 1482, 1588, 1639, 2840.88 VW; 2893.91 W; 2928, 2951, 2978, 3083, 3170, 3306, 3417.
Preparation of ethyl 6-(acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate 3b.
The preparation was similar to the previous one, but for isolation of the individual product, additional chromatography for the ethyl acetate extract was needed. First, it was filtered through the 100 mm pad of silica on the 500 mL Schott filter funnel and eluted with ethyl acetate–hexane 1:2 mixed eluent. The second purification round was performed on 2000 mL Schott filter funnel (1500 mL of silica gel) and elution of the desired compounds was successful with (ethyl acetate–hexane 1:5). The product was additionally crystallized from dry acetonitrile. The formed crystals were filtered off and dried at 60 °C in the oven.
Yellow crystalline powder, yield 33%. m.p. 119 °C.
1H NMR (500 MHz, DMSO-d6) δ: 7.24 (m, J = 9.6 Hz, 2H), 5.01 (dtd, J = 8.7, 5.4, 3.2 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.79 (dd, J = 16.1, 5.0 Hz, 1H), 2.68 (q, J = 5.7 Hz, 2H), 2.45 (d, J = 6.1 Hz, 1H), 1.98 (s, 3H), 1.90–1.76 (m, 2H), 1.23 (t, J = 7.1 Hz, 3H).
13C NMR (126 MHz, DMSO-d6) δ: 170.4 (C=O), 165.3 (C=O), 163.9 (C), 131.1 (C), 112.3 (C), 102.6 (C), 69.3 (CH), 59.2 (CH2), 29.8 (CH2), 27.2 (CH2), 24.0 (CH2), 21.5 (CH3), 14.8 (CH3).
LCMS, positive mode, m/z: 283.1 [M + H]+.
HRMS (ESI): calcd. for C13H17NO4S [M + H]+: 283.0878; found: 283.0869.
IR (ATR, neat), ν, cm−1: 355, 375, 384, 419, 473, 490, 526, 550, 607, 627, 656, 741, 779, 832, 882, 921, 970, 996, 1030, 1102, 1138, 1158, 1251, 1308, 1337, 1365, 1380, 1413, 1431, 1457, 1476, 1496, 1532, 1592, 1672, 1714, 2902, 2932, 2977, 3169, 3265, 3309, 3427.

Supplementary Materials

The following supporting information can be downloaded online: LCMS, 1H, 13C NMR, DEPT, HRMS, IR spectra, of ethyl 2-aminothiophen-3-carboxylates 3a and 3b.

Author Contributions

Conceptualization, A.Y.M., S.V.V. and A.R.K.; Methodology, A.Y.M. and G.G.Y.; Software, H.I.S.; Validation, A.Y.M. and S.V.V.; Formal Analysis, A.R.K.; Investigation, A.Y.M.; Resources, A.Y.M., G.G.Y. and A.R.K.; Data Curation, A.Y.M. and S.V.V.; and Writing—Original Draft Preparation, A.Y.M. and H.I.S.; Writing—Review and Editing, A.Y.M. and H.I.S.; Visualization, A.Y.M. and G.G.Y.; Supervision, S.V.V.; Project Administration, S.V.V.; Funding Acquisition, G.G.Y. and A.R.K. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

Data is contained within the article or the Supplementary Material.

Acknowledgments

All the authors and contributors are truly grateful to Enamine Ltd. company for the research opportunities and analytical data like 1H, 13C NMR, LC-MS, IR and HRMS spectra.

Conflicts of Interest

The authors Andrii Yu. Myshastyi, Sergiy V. Vlasov, Georgiy G. Yakovenko and Andrii R. Khairulin were employed by the company Enamine Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationship that could be considered a potential conflict of interest.

References

  1. Gewald, K.J. Heterocyclen aus CH-aciden nitrilen. IV. Addition von Schwefelkohlenstoff an Alkyliden Malonitrile. J. Prakt. Chem. 1966, 31, 205–213. [Google Scholar] [CrossRef]
  2. Sharma, J.; Champagne, P.A. Mechanisms of the Gewald synthesis of 2-aminothiophenes from elemental sulfur. J. Org. Chem. 2024, 89, 9609–9619. [Google Scholar] [CrossRef] [PubMed]
  3. Sultan, S.; Tawfik, S.S.; Selim, K.B.; Nasr, M.N.A. Design, Synthesis and molecular docking of new thieno[2,3-d]pyrimidin-4-one derivatives as dual EGFR and FGFR Inhibitors. Drug Dev. Res. 2025, 86, e70061. [Google Scholar] [CrossRef] [PubMed]
  4. Abdel-Rahman, S.A.; Nada, H.; Gabr, M.T. First-in-class dual inhibitors of MASTL and Aurora A kinase: Discovery of selective cyclohexa[b]thiophenes with potent anticancer activity. Eur. J. Med. Chem. 2025, 5, 117729. [Google Scholar] [CrossRef]
  5. Akhtar, A.; Chaudhari, T.Y.; Inam, A. Design and Synthesis of Tetrahydrobenzo[4,5]Thieno[2,3-d]Pyrimidine-Sulfonamide Derivatives Using p-Phenylenediamine as a Linker. Synthesis 2025, 57, 2880–2892. [Google Scholar] [CrossRef]
  6. Mohamed, M.F.A.; Soliman, A.M.; Alshazly, O.; Nafady, A.; Soomro, R.A. Design, synthesis, molecular docking, and antibacterial activity of novel amide-linked tetrahydrobenzothienopyrimidinone derivatives as potential DNA gyrase and topoisomerase IV inhibitors. Med. Chem. Res. 2025, 34, 172–182. [Google Scholar] [CrossRef]
  7. Chandrakanth, M.; Mishra, S.; Gayathri, K.; Katreddy, R.R.; Ranganathan, S.; Arya, G.A.; Gondru, R.; Rajasekaran, S.; Banothu, J. Fused thiophene—Benzimidazole conjugates targeting EGFR: Design, synthesis, anticancer evaluation and their mechanistic insights. Eur. J. Med. Chem. 2026, 303, 118435. [Google Scholar] [CrossRef] [PubMed]
  8. da Cruz, R.M.D.; Zelli, R.; Benshain, S.; da Cruz, R.M.D.; Siqueira-Júnior, J.P.; Décout, J.L.; Mingeot-Leclercq, M.P.; Mendonça-Junior, F.J.B. Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors. Chem. Med. Chem. 2020, 15, 716–725. [Google Scholar] [CrossRef] [PubMed]
  9. Magoulas, G.E.; Kalopetridou, L.; Ćirić, A.; Kritsi, E.; Kouka, P.; Zoumpoulakis, P.; Chondrogianni, N.; Soković, M.; Prousis, K.C.; Calogeropoulou, T. Synthesis, biological evaluation and QSAR studies of new thieno[2,3-d]pyrimidin-4(3H)-one derivatives as antimicrobial and antifungal agents. Bioorg. Chem. 2021, 106, 104509. [Google Scholar] [CrossRef]
  10. Mak, K.K.; Shiming, Z.; Epemolu, O.; Dinkova-Kostova, A.T.; Wells, G.; Gazaryan, I.G.; Sakirolla, R.; Mohd, Z.; Pichika, M.R. Synthesis and Anti-Inflammatory Activity of 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-Derived NRF2 Activators. ChemistryOpen 2022, 11, e202200181. [Google Scholar] [CrossRef]
  11. Abdelkhalek, A.S.; Kothayer, H.; Rezq, S.; Orabi, K.Y.; Romero, D.G.; El-Sabbagh, O.I. Synthesis of new multitarget-directed ligands containing thienopyrimidine nucleus for inhibition of 15-lipoxygenase, cyclooxygenases, and pro-inflammatory cytokines. Eur. J. Med. Chem. 2023, 256, 115443. [Google Scholar] [CrossRef]
  12. Elsayed, S.; Abdelkhalek, A.S.; Rezq, S.; Abu Kull, M.E.; Romero, D.G.; Kothayer, H. Magic shotgun approach to anti-inflammatory pharmacotherapy: Synthesis of novel thienopyrimidine monomers/heterodimer as dual COX-2 and 15-LOX inhibitors endowed with potent antioxidant activity. Eur. J. Med. Chem. 2023, 260, 115724. [Google Scholar] [CrossRef]
  13. Islam, F.; Doshi, A.; Robles, A.J.; Quadery, T.M.; Zhang, X.; Zhou, X.; Hamel, E.; Mooberry, S.L.; Gangjee, A. Design, Synthesis, and Biological Evaluation of 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidines as Microtubule Targeting Agents. Molecules 2022, 27, 321. [Google Scholar] [CrossRef] [PubMed]
  14. Pal, K.; Raza, M.K.; Legac, J.; Ataur Rahman, M.; Manzoor, S.; Rosenthal, P.J.; Hoda, N. Design, synthesis, crystal structure and anti-plasmodial evaluation of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives. RSC Med. Chem. 2021, 12, 970–981. [Google Scholar] [CrossRef] [PubMed]
  15. Eissa, K.I.; Kamel, M.M.; Mohamed, L.W.; Galal, M.A.; Kassab, A.E. Design, synthesis, and biological evaluation of thienopyrimidine and thienotriazine derivatives as multitarget anti-Alzheimer agents. Drug Dev. Res. 2022, 83, 1394–1407. [Google Scholar] [CrossRef] [PubMed]
  16. Eissa, K.I.; Kamel, M.M.; Mohamed, L.W.; Doghish, A.S.; Alnajjar, R.; Al-Karmalawy, A.A.; Kassab, A.E. Design, synthesis, and biological evaluation of thienopyrimidine derivatives as multifunctional agents against Alzheimer’s disease. Drug Dev. Res. 2023, 84, 937–961. [Google Scholar] [CrossRef]
  17. He, T.; Edwards, T.C.; Majima, R.; Jung, E.; Kankanala, J.; Xie, J.; Geraghty, R.J.; Wang, Z. Repurposing N-hydroxy thienopyrimidine-2,4-diones (HtPD) as inhibitors of human cytomegalovirus pUL89 endonuclease: Synthesis and biological characterization. Bioorg. Chem. 2022, 129, 106198. [Google Scholar] [CrossRef] [PubMed]
  18. Wang, K.M.; Ge, Y.X.; Zhang, J.; Chen, Y.T.; Zhang, N.Y.; Gu, J.S.; Fang, L.; Zhang, X.L.; Zhang, J.; Jiang, C.S. New cycloalkyl[b]thiophenylnicotinamide-based α-glucosidase inhibitors as promising anti-diabetic agents: Synthesis, in silico study, in vitro and in vivo evaluations. Bioorg. Med. Chem. Lett. 2023, 79, 129069. [Google Scholar] [CrossRef]
  19. Pal, K.; Raza, M.K.; Legac, J.; Rahman, A.; Manzoor, S.; Bhattacharjee, S.; Rosenthal, P.J.; Hoda, N. Identification, in-vitro anti-plasmodial assessment and docking studies of series of tetrahydrobenzothieno[2,3-d]pyrimidine-acetamide molecular hybrids as potential antimalarial agents. Eur. J. Med. Chem. 2023, 248, 115055. [Google Scholar] [CrossRef] [PubMed]
  20. Everett, J.A. Use of oral antidiabetic agents during breastfeeding. J. Hum. Lact. 1997, 13, 319–321. [Google Scholar] [CrossRef]
  21. Christophersen, P.; Dyhring, T. The shortcoming of using glibenclamide in exploratory clinical headache provocation studies. Cephalalgia 2023, 43, 3331024231219475. [Google Scholar] [CrossRef] [PubMed]
  22. Chen, H.; Lin, Y.; Zhao, Z.; Lin, T.; Lin, Q.; Chen, X.; Wu, W.; Zeng, G.; Wu, S.; Liu, N.; et al. Efficacy and safety of venlafaxine hydrochloride combined with tandospirone citrate for patients with vascular depression accompanied by somatic symptoms: An open-labeled randomized control trial. CNS Neurosci. Ther. 2024, 30, e14650. [Google Scholar] [CrossRef] [PubMed]
  23. Gibuła-Tarłowska, E.; Wiszniewska, A.; Turyk, M.; Szymczyk, P.; Kotlińska, J.H.; Kędzierska, E. Ketamine—From an Anesthetic to a Psychiatric Drug: Mechanisms of Action, Clinical Applications and Potential Risks. Molecules 2025, 30, 2824. [Google Scholar] [CrossRef] [PubMed]
  24. Rusciano, D. Molecular Mechanisms and Therapeutic Potential of Gabapentin with a Focus on Topical Formulations to Treat Ocular Surface Diseases. Pharmaceuticals 2024, 17, 623. [Google Scholar] [CrossRef]
  25. Blanco, J.R.; Ochoa-Callejero, L. Off-label use of maraviroc in clinical practice. Expert Rev. Anti Infect. Ther. 2016, 14, 5–8. [Google Scholar] [CrossRef]
  26. Javed, A.; Arthur, H.; Curtis, L.; Hansen, L.; Pappa, S. Practical Guidance on the Use of Lurasidone for the Treatment of Adults with Schizophrenia. Neurol. Ther. 2019, 8, 215–230. [Google Scholar] [CrossRef]
  27. Tseng, E.; Fate, G.D.; Walker, G.S.; Goosen, T.C.; Obach, R.S. Biosynthesis and Identification of Metabolites of Maraviroc and Their Use in Experiments to Delineate the Relative Contributions of Cytochrome P4503A4 versus 3A5. Drug Metab. Dispos. 2018, 46, 493–502. [Google Scholar] [CrossRef]
  28. El-Haj, B.M.; Ahmed, S.B.M.; Garawi, M.A.; Ali, H.S. Linking Aromatic Hydroxy Metabolic Functionalization of Drug Molecules to Structure and Pharmacologic Activity. Molecules 2018, 23, 2119. [Google Scholar] [CrossRef] [PubMed]
  29. El-Haj, B.M.; Ahmed, S.B.M. Metabolic-Hydroxy and Carboxy Functionalization of Alkyl Moieties in Drug Molecules: Prediction of Structure Influence and Pharmacologic Activity. Molecules 2020, 25, 1937. [Google Scholar] [CrossRef] [PubMed]
  30. Enders, J.; Strickland, E.C.; McIntire, G.L. Determination of the relative prevalence of lurasidone metabolites in urine using untargeted HRMS. Spectrosc. Suppl. 2019, 17, 8–15. [Google Scholar]
  31. Dopheide, J.A. Paliperidone: An improvement over risperidone? Am. J. Health Syst. Pharm. 2008, 65, 401. [Google Scholar] [CrossRef] [PubMed]
  32. Hodkinson, A.; Heneghan, C.; Mahtani, K.R.; Kontopantelis, E.; Panagioti, M. Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: A meta-analysis involving individual participant data and clinical study reports. BMC Med. 2021, 19, 195. [Google Scholar] [CrossRef] [PubMed]
  33. Corena-McLeod, M. Comparative Pharmacology of Risperidone and Paliperidone. Drugs in R&D 2015, 15, 163–174. [Google Scholar] [CrossRef]
  34. Tost, M.; González-Rodríguez, A.; Aguayo, R.; Álvarez, A.; Montalvo, I.; Barbero, J.D.; Gabernet, R.; Izquierdo, E.; Merodio, I.; Monreal, J.A.; et al. Switching from risperidone to paliperidone palmitate in schizophrenia: Changes in social functioning and cognitive performance. Prog. Neuropsychopharmacol. Biol. Psychiatry 2023, 120, 110619. [Google Scholar] [CrossRef]
  35. Morris, M.T.; Tarpada, S.P. Long-Acting Injectable Paliperidone Palmitate: A Review of Efficacy and Safety. Psychopharmacol. Bull. 2017, 47, 42–52. [Google Scholar] [CrossRef]
  36. Xie, H.X.; Zhang, J.; Li, Y.; Zhang, J.H.; Liu, S.K.; Zhang, J.; Zheng, H.; Hao, G.Z.; Zhu, K.K.; Jiang, C.S. Novel tetrahydrobenzo[b]thiophen-2-yl)urea derivatives as novel α-glucosidase inhibitors: Synthesis, kinetics study, molecular docking, and in vivo anti-hyperglycemic evaluation. Bioorg. Chem. 2021, 115, 105236. [Google Scholar] [CrossRef]
  37. Feroci, M.; Casadei, M.A.; Orsini, M.; Palombi, L.; Inesi, A. Cyanomethyl anion/carbon dioxide system: An electrogenerated carboxylating reagent. Synthesis of carbamates under mild and safe conditions. J. Org. Chem. 2003, 68, 1548–1551. [Google Scholar] [CrossRef] [PubMed]
  38. Kleinpeter, E.; Heydenreich, M.; Koch, A.; Linker, T. Synthesis and NMR spectroscopic conformational analysis of esters of 4-hydroxy-cyclohexanone—The more polar the molecule the more stable the axial conformer. Tetrahedron 2012, 68, 2363–2373. [Google Scholar] [CrossRef]
  39. Tian, Y.; Chen, Z.; Liu, S.; Wu, F.; Cao, W.; Pang, D.W.; Xiong, H. “Dual-Key-and-Lock” NIR-II NSCyanines Enable High-Contrast Activatable Phototheranostics in Extrahepatic Diseases. Angew. Chem. Int. Ed. Engl. 2023, 62, e202309768. [Google Scholar] [CrossRef] [PubMed]
Molbank 2026 m2144 g001
Figure 1. Modern medicines with cyclohexane ring.
Figure 1. Modern medicines with cyclohexane ring.
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Molbank 2026 m2144 g002
Figure 2. Transformation of risperidone to paliperidone.
Figure 2. Transformation of risperidone to paliperidone.
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Figure 3. The target compounds with a hydroxylated cyclohexane ring.
Figure 3. The target compounds with a hydroxylated cyclohexane ring.
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Scheme 1. Synthesis of the target hydroxylated derivatives 3a and 3b.
Scheme 1. Synthesis of the target hydroxylated derivatives 3a and 3b.
Molbank 2026 m2144 sch001
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Myshastyi, A.Y.; Vlasov, S.V.; Severina, H.I.; Yakovenko, G.G.; Khairulin, A.R. Synthesis of Ethyl 2-Amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and Ethyl 6-(Acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate. Molbank 2026, 2026, M2144. https://doi.org/10.3390/M2144

AMA Style

Myshastyi AY, Vlasov SV, Severina HI, Yakovenko GG, Khairulin AR. Synthesis of Ethyl 2-Amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and Ethyl 6-(Acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate. Molbank. 2026; 2026(2):M2144. https://doi.org/10.3390/M2144

Chicago/Turabian Style

Myshastyi, Andrii Yu., Sergiy V. Vlasov, Hanna I. Severina, Georgiy G. Yakovenko, and Andrii R. Khairulin. 2026. "Synthesis of Ethyl 2-Amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and Ethyl 6-(Acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate" Molbank 2026, no. 2: M2144. https://doi.org/10.3390/M2144

APA Style

Myshastyi, A. Y., Vlasov, S. V., Severina, H. I., Yakovenko, G. G., & Khairulin, A. R. (2026). Synthesis of Ethyl 2-Amino-6-hydroxy-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate and Ethyl 6-(Acetyloxy)-2-amino-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylate. Molbank, 2026(2), M2144. https://doi.org/10.3390/M2144

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