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Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones



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(S)-4-(2,4-Dihydroxyphenyl)-N-(1-phenylethyl)piperidine-1-carboxamide (1)

In a………………….. to yield crude 1 (3.51 kg, 77%, 97.7 A% purity). Recrystallization: In a 100 L double jacketed reactor were charged crude 1 (3.51 kg, 10.31 mol, 1.0 equiv), iPrOH (27.0 L, 7.5 vol), AcOH (74.1 g), and water (27.0 L, 7.5 vol). The suspension was warmed to reflux and turned to a solution after 30 min of reflux. Heating was stopped, and the reaction medium was allowed to cool to 23 °C over 20 h. The suspension was filtered through a 25 μm filter medium; the cake was washed with a mixture of water (3.6 L) and AcOH (7.3 g) and the solid collected and dried under vacuum at 45 °C for 48 h to yield 1 (2.86 kg, 81%, 98.5 A% purity).
1H NMR (400 MHz, DMSO-d6): δ 9.11 (s, 1H), 8.96 (s, 1H), 7.30–7.31 (m, 4), 7.19–7.20 (m, 1H), 6.79 (d, J = 8.3 Hz, 2H), 6.7 (d, J = 7.9 Hz, 2H), 6.28 (d, J = 2.4 Hz, 1H), 6.16 (dd, J = 8.3, 2.4 Hz, 1H), 4.85–4.87 (m, 1 H), 4.13 (d, J = 12.9 Hz, 2H), 2.85 (t, J = 11.9 Hz, 1H), 2.70 (t, J = 12.7 Hz, 2H), 1.64 (d, J = 12.1 Hz, 2H), 1.40–1.41 (m, 5H).
13C NMR (101 MHz, DMSO-d6) δ 156.6, 156.0, 155.2, 146.3, 127.9, 126.7, 126.1, 125.9, 122.5, 106.0, 102.4, 49.3, 44.4, 34.7, 31.8, 31.7, 22.9;
mp: 200–201 °C;
HRMS (m/z, ES+) for C20H25N2O3 (M + H)+ calcd. 341.1865, measd. 341.1859.

Process Development and Good Manufacturing Practice Production of a Tyrosinase Inhibitor via Titanium-Mediated Coupling between Unprotected Resorcinols and Ketones

Nestlé Skin Health R&D, 2400 Route des colles BP 87, 06902 Sophia-Antipolis Cedex, France
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.7b00036

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Thibaud Gerfaud

Thibaud Gerfaud

Team Leader Process Chemistry

Nestlé Skin Health Logo

Boiteau Jean-Guy

Boiteau Jean-Guy

Head of Process Research & Development

Nestlé Skin Health

Nestlé Skin Health Logo


Abstract Image

A concise and economically attractive process for the synthesis of a novel tyrosinase inhibitor has been developed and implemented on a multikilogram scale under GMP. A major achievement to the success of the process is the development of a direct coupling between free resorcinol and ketone. First developed under basic conditions, this coupling has been turned to a novel titanium(IV) mediated process allowing good selectivity, easy isolation, and high atom efficiency. Other key steps feature an alkene reduction by palladium catalyzed transfer hydrogenation and a urea formation using N,N′-disuccinimidyl carbonate as the carbonyl source. This route allowed us to produce kilogram batches of the candidate to support preclinical and clinical studies.


Boiteau, J.-G.; Bouquet, K.; Talano, S.; Millois-Barbuis, C. Patent WO 2010/063774 A1, 2010.



Cas 1228342-28-6
MF C20 H24 N2 O3,
MW  340.42
1-Piperidinecarboxamide, 4-(2,4-dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-
  • 4-(2,4-Dihydroxyphenyl)-N-[(1S)-1-phenylethyl]-1-piperidinecarboxamide
  • 4-(2,4-Dihydroxyphenyl)piperidine-1-carboxylic acid N-((S)-1-phenylethyl)amide
Inventors Jean-Guy Boiteau , Karine Bouquet , Sandrine Talano , Barbuis Corinne Millois
Applicant Galderma Research & Development

Hyperpigmentation disorders such as melasma are characterized by an increase in melanin synthesis which accumulates in the epidermis and is responsible for a darkening of the skin. Melanogenesis occurs in the basal layer of the epidermis into specific organelles of the melanocytes called melanosomes.

A detailed analysis of the biosynthetic pathway reveals that tyrosinase is a key enzyme in melanogenesis and is responsible for the oxidation of tyrosine into DOPA (3,4-dihydroxyphenylalanine) and DOPA quinone.

It is a melanogenesis inhibitor working through the inhibition of tyrosinase (IC50 = 0.1 μM on normal human epidermal melanocytes) currently under development at Nestlé Skin Health R&D for the topical treatment of hyperpigmentation disorders. REF 1-5

WO 2010063774

Novel 4- (azacycloalkyl)benzene-l ,3-diol compounds as tyrosinase inhibitors, process for the preparation thereof and use thereof in human medicine and in cosmetics

The invention relates to novel 4- (azacycloalkyl) benzene-1, 3-diol compounds as industrial and useful products. It also relates to the process for the preparation thereof and to the use thereof, as tyrosinase inhibitors, in pharmaceutical or cosmetic compositions for use in the treatment or prevention of pigmentary disorders.

Skin pigmentation, in particular human skin pigmentation, is the result of melanin synthesis by dendritic cells, melanocytes. Melanocytes contain organelles called melanosomes which transfer melanin into the upper layers of keratinocytes which are then transported to the surface of the skin through differentiation of the epidermis (Gilchrest BA, Park HY, Eller MS, Yaar M, Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol 1996; 63: 1-10; Hearing VJ, Tsukamoto K, Enzymatic control of pigmentation in mammals. FASEB J 1991; 5: 2902-2909) .

Among the enzymes of melanogenesis, tyrosinase is a key enzyme which catalyses the first two steps of melanin synthesis. Homozygous mutations of tyrosinase cause oculocutaneous albinism type I characterized by a complete lack of melanin synthesis (Toyofuku K, Wada I, Spritz RA, Hearing VJ, The molecular basis of oculocutaneous albinism type 1 (OCAl) : sorting failure and degradation of mutant tyrosinases results in a lack of pigmentation. Biochem J 2001; 355: 259-269) .

In order to treat pigmentation disorders resulting from an increase in melanin production, for which there is no treatment that meets all the expectations of patients and dermatologists, it is important to develop new therapeutic approaches.

Most of the skin-lightening compounds that are already known are phenols or hydroquinone derivatives.

These compounds inhibit tyrosinase, but the majority of them are cytotoxic to melanocytes owing to the formation of quinones. There is a risk of this toxic effect causing a permanent depigmentation of the skin. The obtaining of compounds that can inhibit melanogenesis while at the same time being very weakly cytotoxic or devoid of toxicity to melanocytes is most particularly sought.

Among the compounds already described in the literature, patent application WO 99/15148 discloses the use of 4-cycloalkyl resorcinols as depigmenting agents .

Patent FR2704428 discloses the use of 4-halo-resorcinols as depigmenting agents.

Patent applications WO 2006/097224 and WO 2006/097223 disclose the use of 4-cycloalkylmethyl resorcinols as depigmenting agents.

Patent application WO 2005/085169 discloses the use of alkyl 3- (2, 4-dihydroxyphenyl) propionate as a depigmenting agent.

Patent application WO 2004/017936 discloses the use of 3- (2, 4-dihydroxyphenyl) acrylamide as a depigmenting agent.

Patent application WO 2004/052330 discloses the use of 4- [ 1, 3] dithian-2-ylresorcinols as depigmenting agents .

More particularly, patent EP0341664 discloses the use of 4-alkyl resorcinols as depigmenting agents, among which 4-n-butyl resorcinol, also known as rucinol, is part of the composition of a depigmenting cream sold under the name Iklen®.

The applicant has now discovered, unexpectedly and surprisingly, that novel compounds of 4- (azacycloalkyl) benzene-1, 3-diol structure have a very good tyrosinase enzyme-inhibiting activity and a very low cytotoxicity. Furthermore, these compounds have a tyrosinase enzyme-inhibiting activity that is greater than that of rucinol while at the same time being less cytotoxic with respect to melanocytes than rucinol.

These compounds find uses in human medicine, in particular in dermatology, and in the cosmetics field.

FR 2939135


  1. Briganti, S.; Camera, E.; Picardo, M. Pigm. Cell Res. 2003, 16, 101, DOI: 10.1034/j.1600-0749.2003.00029.x

  2. 2.

    Brenner, M.; Hearing, V. J. Photochem. Photobiol. 2008, 84, 539, DOI: 10.1111/j.1751-1097.2007.00226.x

  3. 3.

    (a) Schallreuter, K. U.; Kothari, S.; Chavan, B.; Spencer, J. D. Exp. Dermatol. 2008, 17, 395, DOI: 10.1111/j.1600-0625.2007.00675.x

    (b) Cooksey, C. J.; Garratt, P. J.;Land, E. J.; Pavel, S.; Ramsden, C. A.; Riley, P. A.; Smit, N. P.J. Biol. Chem. 1997, 272, 26226, DOI: 10.1074/jbc.272.42.26226

    (c) Stratford, M. R. L.; Ramsden, C. A.; Riley, P. A.Bioorg. Med. Chem. 2013, 21, 1166, DOI: 10.1016/j.bmc.2012.12.031

  4. 4.

    Chang, T. S. Int. J. Mol. Sci. 2009, 10, 2440, DOI: 10.3390/ijms10062440

  5. 5.

    Hypopigmentation effect have already been demonstrated for resorcinols; see:

    (a) Kim, D. S.; Kim, S. Y.;Park, S. H.; Choi, Y. G.; Kwon, S. B.; Kim, M. K.; Na, J. I.; Youn, S. W.; Park, K. C. Biol. Pharm. Bull. 2005,28, 2216, DOI: 10.1248/bpb.28.2216

    (b) Khemis, A.; Kaiafa, A.;Queille-Roussel, C.; Duteil, L.; Ortonne, J. P. Br. J. Dermatol.2007, 156, 997, DOI: 10.1111/j.1365-2133.2007.07814.x



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DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries...... , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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