Chemistry:Tropine

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Tropine is a derivative of tropane containing a hydroxyl group at the third carbon. It is also called 3-tropanol.[1] It is a poisonous white hygroscopic crystalline powder.[2] It is a heterocyclic alcohol and an amine.[2]

Tropine is a central building block of many chemicals active in the nervous system, including tropane alkaloids. Some of these compounds, such as long-acting muscarinic antagonists are used as medicines because of these effects.[3]

Occurrence

Tropine is a natural product found in the plants of deadly nightshade (Atropa belladonna) and devil's trumpet (Datura stramonium).[4]

Chemistry

Synthesis

It can be prepared by hydrolysis of atropine[5] or other solanaceous alkaloids.[2][6]

In the laboratory it is made by the reduction of tropinone:[7] Patent:[8][9]

Derivatives

List of derivatives that can be made from tropine:

  1. AHN 1-055 HCl: [202646-03-5][10][11] Patent:[12] Selfsame as JHW-007 (N-butyl group). This benzhydrol aromatic entity is the same as for flunamine & vanoxerine.
  2. Atropine[13]
  3. Atromepine[14][15]
  4. Benztropine[16][17]
  5. Bemesetron[18][19]
  6. Butropium bromide (Coliopan®)[20][21]
  7. Ciclotropium (wrong stereochemistry if employing this method)[22]
  8. Clobenztropine[23][24][25][26]
  9. Decitropine [1242-69-9][27]
  10. Deptropine[28][29]
  11. Fentonium[30][31]
  12. Flutropium bromide (wrong stereoisomer using this method of synthesis).[32]
  13. Homatropine[33]
  14. PG-9 [156143-26-9] Maleate salt: [155649-00-6] Synthesis:[34][35] Pharmacol:[36][37][38]
  15. Methoxytropacin HCl: [74051-44-8]
  16. Pudafensine[39] (by Mitsunobu inversion chemistry)
  17. SM-21 (other codenames covered too)[35][40]
  18. SM-25 is the ester between tropine and clofibric acid.[40]
  19. Tropacine[41][42][43]
  20. Tropacocaine (by Mitsunobu inversion chemistry)[5]
  21. Tropanserin[44][45]
  22. Tropatepine[46]
  23. Tropine benzilate ("BAT")
  24. Tropirine[47][48]
  25. Tropodifene[49]
  26. Xenytropium[50]
  27. Zepastine[51]
  28. 3-Perfluorophenoxytropane (PC14575207)[52]
  29. Tropine p-chlorophenoxyacetate [6658-61-3][53] (c.f. Meclofenoxate).

See also

References

  1. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named hand
  2. ↑ 2.0 2.1 2.2 Cite error: Invalid <ref> tag; no text was provided for refs named merriam-webster
  3. ↑ Ping, Yu; Li, Xiaodong; You, Wenjing; Li, Guoqiang; Yang, Mengquan; Wei, Wenping; Zhou, Zhihua; Xiao, Youli (10 June 2019). "Production of the Plant-Derived Tropine and Pseudotropine in Yeast". ACS Synthetic Biology 8 (6): 1257–1262. doi:10.1021/acssynbio.9b00152. PMID 31181154. 
  4. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named pubchem
  5. ↑ 5.0 5.1 "[2008-09-10 Cocaine analog in two steps from native plant material"]. https://www.seanmichaelragan.com/html/%5B2008-09-10%5D_Cocaine_analog_in_two_steps_from_native_plant_material.shtml. 
  6. ↑ "Bildung von Tropin aus Tropidin und die Synthese des Atropins". Berichte der deutschen chemischen Gesellschaft 35 (1): 1159–1162. January 1902. doi:10.1002/cber.190203501191. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cber.190203501191. 
  7. ↑ "Stereochemistry of the reduction of tropinone". Tetrahedron 6 (4): 319–330. January 1959. doi:10.1016/0040-4020(59)80012-0. https://linkinghub.elsevier.com/retrieve/pii/0040402059800120. 
  8. ↑ Rolf Sachse & Albert Schaupp, U.S. Patent 6,005,110 (1999 to Pfleger R Chemische Fabrik GmbH).
  9. ↑ Van de Kamp, Sletzinger, U.S. Patent 2,366,760 (1945 to Merck & Co.)
  10. ↑ Newman, Amy Hauck; Allen, Andrew C.; Izenwasser, Sari; Katz, Jonathan L. (1994). "Novel 3.alpha.-(Diphenylmethoxy)tropane Analogs: Potent Dopamine Uptake Inhibitors without Cocaine-like Behavioral Profiles". Journal of Medicinal Chemistry. 37 (15): 2258–2261. doi:10.1021/jm00041a002.
  11. ↑ Newman, Amy Hauck; Kline, Richard H.; Allen, Andrew C.; Izenwasser, Sari; George, Clifford; Katz, Jonathan L. (1995). "Novel 4'-Substituted and 4',4-Disubstituted 3.alpha.-(Diphenylmethoxy)tropane Analogs as Potent and Selective Dopamine Uptake Inhibitors". Journal of Medicinal Chemistry. 38 (20): 3933–3940. doi:10.1021/jm00020a006.
  12. ↑ Amy Hauck Newman, U.S. Patent 5,792,775 (1998 to US Department of Health and Human Services).
  13. ↑ Al-Badr, A. A., Muhtadi, F. J. (1985). "Analytical Profiles of Drug Substances". Atropine. Vol. 14. Elsevier. pp. 325–389. doi:10.1016/S0099-5428(08)60585-7.
  14. ↑ Melone, Gaetano; Vecchi, Alberto; Pagani, Giuseppe; Testa, Emilio (1960). "Notes- Tropine DL-α-Methyltropate (Methylatropine) and Its Optical Antipodes". The Journal of Organic Chemistry. 25 (5): 859–861. doi:10.1021/jo01075a624.
  15. ↑ Scarselli, Veniero; Cignarella, Giorgio; Maffii, Giulio (1964). "Structural Changes and Anticholinergic Activity in a Class of Tropic and α-Methyltropic Acid Derivatives". Journal of Medicinal Chemistry. 7 (2): 237–238. doi:10.1021/jm00332a026.
  16. ↑ Richard P. Phillips, U.S. Patent 2,595,405 (1952 to Merck a Co).
  17. ↑ Weijlard John, U.S. Patent 2,706,198 (1952 to Merck & Co Inc).
  18. ↑ "MDL-72222". Drugs of the Future 10 (10): 820. 1985. doi:10.1358/dof.1985.010.10.61916. ISSN 0377-8282. http://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=2&p_RefId=61916&p_IsPs=N. Retrieved 8 December 2025. 
  19. ↑ John Richard Fozard, Maurice Ward Gittos, EP0067770 (1982 to Merrell Dow France Et Cie).
  20. ↑ Tanaka, Satoru; Wakabayashi, Tsuneo; Hashimoto, Kazunori; Toyoshima, Shoji (1972). "Studies on Diphenyl Ether Derivatives. III. : Synthesis and Spasmolytic Screening of New Quaternary Salts of Tropine Tropates". YAKUGAKU ZASSHI. 92 (4): 510–513. doi:10.1248/yakushi1947.92.4_510.
  21. ↑ DE1950378 idem Satoru Tanaka, Kazunori Hasimoto, US3696110 (1972 to Gisai Kk).
  22. ↑ DE2026661 idem R Bauer, W Schulz, W Sirrenberg, G Walther US3743735 (1973 to Boehringer Sohn Ingelheim).
  23. ↑ Fromer Stephen, FR1249205 (1961).
  24. ↑ Stephen Fromer, U.S. Patent 2,799,680 (1957).
  25. ↑ Dr Stephan Fromer, DE1020634 (1957 to Schenley Lab Inc).
  26. ↑ Cyril H. Meld, U.S. Patent 2,782,200 (1957 to Schenley Labora).
  27. ↑ Dr August Franciscus Harms, DE1152410 (1963 to Koninklijke Pharma Fab Nv).
  28. ↑ "The Effect of Alkyl-Substitution in Drugs--V. Synthesis and Chemical Properties of Some Dibenzo [a,d1,4-cycloheptadienyl Ethers"]. Journal of Medicinal and Pharmaceutical Chemistry 4 (2): 335–349. September 1961. doi:10.1021/jm50018a008. https://pubs.acs.org/doi/abs/10.1021/jm50018a008. 
  29. ↑ Harms August Franciscus, U.S. Patent 3,119,829 (1964 to Koninklijke Pharmaceutische Fabrieken NV).
  30. ↑ Teotino, U.M . et al, Eur. J. Med. Chem .-Chim. Ther ., 1968, 3, 453 (synth, pharmacol)
  31. ↑ , GB1026640 idem Davide Della Bella, Uberto Teotino, US3436458 (1969 to Whitefin Holding Sa).
  32. ↑ DE2540633 idem Rolf Banholzer, Rudolf Bauer, Alex Heusner, Werner Schulz, U.S. Patent 4,042,700 (1977 to Boehringer Ingelheim Gmbh).
  33. ↑ Chemnitius, F. (1927). "Zur Darstellung des Homatropins". Journal für Praktische Chemie. 17 (1): 142–146. ISSN 0021-8383. doi:10.1002/prac.19271170105.
  34. ↑ "Presynaptic Cholinergic Modulators as Potent Cognition Enhancers and Analgesic Drugs. 1. Tropic and 2-Phenylpropionic Acid Esters". Journal of Medicinal Chemistry 37 (11): 1704–1711. May 1994. doi:10.1021/jm00037a022. https://pubs.acs.org/doi/abs/10.1021/jm00037a022. 
  35. ↑ 35.0 35.1 <225::AID-CHIR1>3.0.CO;2-G "Synthesis and enantioselectivity of the enantiomers of PG9 and SM21, new potent analgesic and cognition-enhancing drugs". Chirality 8 (3): 225–233. 1996. doi:10.1002/(SICI)1520-636X(1996)8:3<225::AID-CHIR1>3.0.CO;2-G. https://onlinelibrary.wiley.com/doi/10.1002/(SICI)1520-636X(1996)8:3<225::AID-CHIR1>3.0.CO;2-G. 
  36. ↑ Ghelardini, Carla; Galeotti, Nicoletta; Bartolini, Alessandro; Furukawa, Shoei; Nitta, Atsumi; Manetti, Dina; Gualtieri, Fulvio (1998). "Memory Facilitation and Stimulation of Endogenous Nerve Growth Factor Synthesis by the Acetylcholine Releaser PG-9". The Japanese Journal of Pharmacology. 78 (3): 245–251. doi:10.1254/jjp.78.245. ISSN 0021-5198.
  37. ↑ Ghelardini C, Galeotti N, Gualtieri F, Marchese V, Bellucci C, Bartolini A. Antinociceptive and antiamnesic properties of the presynaptic cholinergic amplifier PG-9. J Pharmacol Exp Ther. 1998;284(3):806-16. PMID: 9495837.
  38. ↑ Ghelardini, C., Galeotti, N., Romanelli, M. N., Gualtieri, F., Bartolini, A. (March 2000). "Pharmacological Characterization of the Novel ACh Releaser α‐tropanyl 2‐(4‐bromophenyl)propionate (PG‐9)". CNS Drug Reviews. 6 (1): 63–78. doi:10.1111/j.1527-3458.2000.tb00138.x.
  39. ↑ Dan Peters, et al. WO2011092061 (to NTG Nordic Transport Group AS).
  40. ↑ 40.0 40.1 Alessandro Bartolini, et al. WO1994001435 (Abiogen Pharma SRL).
  41. ↑ Basel Gesellschaft Fuer Chemis [ch], CH202181 (1939 to Ciba), C.A. 33, 89228(1939).
  42. ↑ Friess, S.L.; Reber, L.J.; Thommesen, W.C.; Greenbaum, L.J.; Standaert, F.G.; Hudak, W.V. (1960). "Toxicologic properties and stereochemical configuration in derivatives of the tropanol series". Toxicology and Applied Pharmacology. 2 (5): 574–588. ISSN 0041-008X. doi:10.1016/0041-008X(60)90024-7.
  43. ↑ XU, Rong; SIM, Meng-Kwoon; GO, Mei-Lin (1998). "Synthesis, Antimuscarinic Activity and Quantitative Structure-Activity Relationship (QSAR) of Tropinyl and Piperidinyl Esters". CHEMICAL & PHARMACEUTICAL BULLETIN. 46 (2): 231–241. doi:10.1248/cpb.46.231.
  44. ↑ J. R. Fozard and M. W. Gittos, US4563465 (1986 to Merrell Dow Pharmaceuticals Inc.)
  45. ↑ Fozard John Richard; Gittos Maurice Ward +, GB2131420 (1984 to Merrell Toraude & Co +); CA, 101,230355
  46. ↑ DE1952206 idem J Boissier, R Ratouis, US3725415 (1973 to Ind Pour La Fab Antibiotiques).
  47. ↑ Harms, A. F., Chim. Ther., 1968, 3, 277.
  48. ↑ van der Stelt C, Hofman PS, Funcke AB, Nauta WT. Synthesis and pharmacological properties of some 5H-benzo(4,5)cyclohepta(1,2-b)pyridine derivatives. Arzneimittelforschung. 1968 Jun;18(6):756-8. PMID: 4387811.
  49. ↑ Fedosowa; Magidson Zhurnal Obshchei Khimii, 1956 , vol. 26, p. 3475, 3477; engl. Ausg. S. 3867, 3868.
  50. ↑ Laszlo Gyermek, U.S. Patent 2,833,773 (1958).
  51. ↑ Abraham Weber, Jacques Jean Frossard, U.S. Patent 3,700,663 (1972 to Mead Johnson & Co).
  52. ↑ Grover C. Helsley, Larry Davis, Gordon E. Olsen, U.S. Patent 4,861,889 (1989 to Hoechst-Roussel Pharmaceuticals, Inc.).
  53. ↑ "[Pharmacological properties of some p-chlorophenoxyacetic acid derivatives]" (in Russian). Farmakologiia I Toksikologiia 38 (2): 154–9. 1975. PMID 1227878. 



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