Process development for substituted resorcinol production from cyclohexane-1,3-diones

Abstract

The invention provides a scalable and low cost process for synthesis of different high value 4-alkyl resorcinols such as 3-(2,4-dihydroxyphenyl)propanoic acid, 3-(2,4- dihydroxy-5-methylphenyl)-2-methylpropanoic acid, 4-methyl resorcinol, 4-isopropyl resorcinol and 4-hexyl resorcinol from their corresponding cyclohexane-1,3-diones. The present invention also provides a process for preparing cyclohexane-1,3-diones which is the starting materials for the synthesis of resorcinols.

Description

[0001] PROCESS DEVELOPMENT FOR SUBSTITUTED RESORCINOL PRODUCTION FROM CYCLOHEXANE-1 ,3-DIONES

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to the process development in synthesis of resorcinol compounds.

[0004] The present invention particularly relates to a process for the synthesis of resorcinol analogues using substituted cyclohexane-1 ,3-dione compounds, as precursors.

[0005] The present invention further relates to a first approach for scalable production of high cost 4-alkyl resorcinol compounds from corresponding substituted cyclohexane-

[0006] I ,3-diones.

[0007] The present invention more particularly relates to the synthesis of substituted resorcinol compounds from substituted cyclohexane-1 ,3-dione compounds.

[0008] BACKGROUND OF THE INVENTION

[0009] Substituted phenols are ubiquitous structural motifs of various compounds and are widely applied in the preparation of high-value pharmaceuticals, cosmeceuticals, agrochemicals, polymers, biologically active compounds, as well as other fine and bulk chemicals [(a). J. H. P. Tyman, Synthetic and Natural Phenols, Elsevier, New York, 1996; b). Z. Rappoport, The Chemistry of Phenols, Wiley-VCH, Weinheim, 2003; c). P. M. Dewick, Medicinal Natural Products: A Biosynthetic Approach, Wiley- VCH, Weinheim, 2011 ; d). S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54, 3451 ]. Resorcinol was reported for the production of tires through rubber industry, specific hair colour dyes [M. Shah, W. Tolgyesi, and A. Britt, 1972, 23, 853- 861] and also used in cosemetic industry [a. IPCS, IOMC, WHO (2006) Concise International Chemical Assessment Document 47: Resorcinol. Availible online: http: / / www.who.int / ipcs / publications / cicad / cicad71.pdf; b). R.H. Lindsay,

[0010] J.B. Hill, E. Gaitan, R.C. Cooksey, and R.L. Jolley, J. Toxicol. Environ. Health, 1992, 37(4), 467-481 ; c). R. Divi, and D. Doergel, National Center for Toxicological Research, 1994], It is used for the dermatological treatment. Routes and modes of administration of resorcinol and their relationship to potential manifestations of thyroid gland toxicity in animals and man [F. Welsch, International Journal of Toxicology, 2008, 27(1 ), 59- 63]. Resorcinol derivatives are described in many publications, including Collington et al., PCT Patent Application WO 00 / 56702; Hu et al., U.S. Pat. No. 6,132,740; Shinomiya et al., U.S. Pat. No. 5,880,314; LaGrange et al., U.S. Pat. No. 5,468,472; Bradley et al., European Patent Appli cation EP 1 134 207; Hiroaki et al., Japanese Patent Application JP11 -255638 A2; Japanese published patent applications JP 2001 -010925, JP2000-327557 and Tori hara et al., U.S. Pat. No. 4,959,393. Among resorcinol, 4-alkyl substituted resorcinols have drawn much attention and intense research activity because of their profound pharmacological potential. Perviously people have synthesized these 4-alkyl substituted resorcinol by using various approaches. 4-Methyl resorcinol is a known chemical which is used in certain medicinal applications and as a reagent for carbohydrates. It is also of potential utility in the production of plastic resins [C. Yue, L. Baojie, M.Pengfei, CN 111285954 A 20200616, 2020]. Gessen, Jean Pierre et al. has prepared 4-methyl resorcinol taking phenol as substrate using H2O2 / SbFs in the presence of hydrogen fluoride [ Gessen, Jean Pierre et al., Journal of the Chemical Society, Chemical Communications, 1980, 23, 1128-9]. In 2009, Woong Hee Lee et al. synthesized 4-methyl resorcinol by using dinitrotoluene and trinitrotoluene under microwave irradiation in the presence of acid [W. H. Lee, J. S. Kim and S. C. Kim, Bull. Korean Chem. Soc., 2009, 30,12], 4-Methyl resorcinol is synthesized via reduction of 2,4-dihydroxybenzyaldehyde by using Pd / C catalyzed and other reducing sources [(a)M. Shoham, R. Viswanathan, US 2018 / 0021277 Al; (b) T. Hamish et al. WO 2020 / 000065 A2], Brown, J. P. et al. has prepared 4- isopropylresorcinol from 1 ,4-dimethoxyacetophenone via hydrogenation followed by demethylation. In another report, Meyer and Bernhauer synthesized 4- isopropylresorcinol by the condensation of resorcinol and isopropyl alcohol in presence of sulphuric acid [(a). Brown, J. P. et al. .Journal of the Chemical Society., 1951 , 2019-20; b). Monatsh., 1929, 53, 721], Langle, W. D. et al. prepared 2,4- dihydroxybenzenepropanoic acid through condensation of [3- P-chloro-propionitrile with polyhydroxyphenols in the presence of Lewis acid [ W. D. Langle, and Adams, Roger; J. Am. Chem. Soc, 1922, 44, 23, 20-30]. 4-Hexyl resorcinol is prepared by acylation of alkyloic acid in the presence of zinc chloride catalyst followed by hydrogenation [(a)S. W.Wilken, H. J. Schmidt, J. Wilken, A. K.Conradsen, US 2006 / 0129002 Al; (b) M. Ingale, S. Mistry, P. Kadia, K. Patel, Mangrolia, M. Patel, C. Pansuriya]. The major industrial approach for the synthesis of 4-hexyl resorcinol through the condensation of resorcinol and hexanoic acid by using zinc catalyst and finally reduced in acidic condition [SUDARSHAN CHEMICAL INDUSTRIES LTD], 4- Alkyl substituted resorcinol has wide application in the area of skin-care [(a) M. Xavier and M. Chunyu, 3066492 A1 20181123, 2018; (b) T. Shivanand, PCT Int. AppL WO 2020212958 A1 20201022, 2020], depigmentation [(a)D.Christell, D. A. Lise, B. Alexander, F. Francois and C. Guillaume, WO 2018197808 A1 20181101 , 2018; (b) R. Karan, IN 201711009865 A 20180928, 2018], anti-ageing and skin- whiteing [W. Zhenghui, CN 110448475 A 20191115, 2019] and hair dyeing [S., Stephane and R. Christophe, WO 2012 / 084473A I PCT / EP2011 / 071744], It also acts as tyrosinase inhibitor [ (a) K. Satoshi, W. Takashi, W. Hiroyuki, K. Takehiro, S. Hayato, K. Hirohisa, O.Yoshino, O. Yuka and S. Daishin, JP 2017057148 A 20170323, 2017; (b) H. Ichiro, M. Sayaka, T. Masahisa and T. Yoshihiro, WO 2014092166 A1 20140619, 2014], 4-Hexylresorcinol used as antibiotic adjuvant [ Y. A Nikolaev, A. V. Tutel'yan, N. G. Loiko, J. Buck, S. V. Sidorenko, I. Lazareva, V. Gostev, O. Y. Manzen'yuk, I. G. Shemyakin and R. A. Abramovich, PLoS One, 2020, 15, e0239147].

[0011] There are number synthetic approaches published in recent years for cyclohexane-

[0012] I ,3-diones compounds [(a). S. E. Leonard, K. G. Reddie, and K. S. Carroll, ACS Chem. Biol., 2009, 4, 783; b). E.K Ryu, K. M Kim, H. R. Kim, J. H. Song, J. N. Kim,

[0013] J. S. Kim, WO / 1994 / 003443; c) T. Ishikawa, R. Kadoya, M. Arai, H. Takahash, Y. Kaisi, T. Mizuta, K. Yoshikai, and S. Satio, J. Org. Chern., 2001 , 66, 8000-8009; d). T. Ishikawa, K. Kudo, K. Kuroyabu, S. Uchida, T. Kudoh, and S. Saito, J. Org. Chem., 2008, 73, 7498-7508]. The vast application of cyclohexane-1 ,3-dione derivatives make it more popular for its synthesis [(a). D. A. Somers, W. B. Parker, D. L. Wyse, J. W. Gronwald, B. G. Gengenbach, U.S. Pat. No. 5,162,602; b). M. D. Johnson, C. L. Dunne, D. W. Kidder, M. Hudetz, EP19970953744; c). M. Sawaki, I. Iwataki, Y. Hirono, H. Ishikawa, U.S. Pat. No. 3,950,420)].

[0014] Recently, a very simple and convenient approach for different substituted cyclohexane-1 ,3-diones derivatives synthesis and their scale-up production have been reported [(a). P. Das, D. Sharma, B. Singh, Pat. No. WO2011 / 117881 , PCT / IN2011 / 000180, US 8,916,723 B2; b). D. Sharma, Bandana, A. K. Shil, B. Singh, and P. Das, Synlett., 2012, 23, 1199-1204)].

[0015] All the earlier processes existing in the art have been developed for the production of 4-alkyl resorcinol compounds from unsubstituted resorcinol following a costly and complicated reagent system. In few cases, number of steps are involved with poor yield and difficult to scale-up therefore, the production cost is very high. The present invention provides the first-ever scalable aromatization process for the production of 4-alkyl resorcinol compounds from corresponding cyclohexane-1 ,3-diones, prepared through as precursor molecules. Moreover, the overall process is milder, easy to scale-up, high yielding and cost-effective approach.

[0016] Cyclohexane-1 ,3-dione derivatives could be a very interesting building block for the synthesis of substituted resorcinol compounds by its aromatization. Keeping this concept in mind, an economic and scalable process for the synthesis of substituted resorcinol or polyphenols from their corresponding cyclohexane-1 ,3-diones have been developed.

[0017] OBJECTIVES OF THE INVENTION

[0018] The main objective of the present invention is to develop a low cost and scalable direct process for the synthesis of substituted resorcinol compounds from their corresponding cyclohexane-1 ,3-diones.

[0019] Another objective of the present invention is the development of synthetic methodology for conversion of substituted cyclohexane-1 ,3-diones to their corresponding resorcinol compounds with high yield and selectivity.

[0020] Yet another objective of the present invention is to provide a process for preparing the substituted cyclohexane-1 ,3-dione compounds in acid form, to be used as starting material for the synthesis of corresponding resorcinol compounds.

[0021] Yet another objective of the present invention is to develop an economic and scalable approaches for the synthesis of different substituted high value resorcinol compounds.

[0022] SUMMARY OF THE INVENTION Accordingly, the present invention provides a process for preparing the 4-alkyl resorcinol compound of Formula I, wherein R is selected from the group consisting of and -CH3, R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting of hydrogen, S, O, N, alkyl and aryl, comprising the steps of; (i) oxidative aromatization of substituted cyclohexane-1 ,3-dione of Formula II wherein R is selected from the group consisting of and -CH3; R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting of hydrogen, S, O, N, alkyl and aryl, by treating with iodine and DMSO in presence of a solvent at refluxing conditions for 3-8 hours; (ii) after completion of the reaction, the reaction mixture is treated with saturated solution of sodium thiosulfate and extracting with ethyl acetate to obtain 4- alkyl resorcinol compound of Formula I; and

[0023] (iii) purifying the product by extraction or column chromatography.

[0024] In an embodiment of the present invention, the yield of the 4-alkyl resorcinol compound is 50-60% by the above mentioned process.

[0025] In an embodiment of the present invention, the resorcinol compound of Formula I is selected from the group consisting of,

[0026] In another embodiment of the present invention, the solvent used for oxidative aromatization is selected from the group consisting of DMC, propylene carbonate, diethyl carbonate or a combination thereof.

[0027] In an embodiment of the present invention, the molar proportion of iodine used is in the range of 0.10-0.30 molar equivalents.

[0028] In an embodiment of the present invention, the temperature for oxidative aromatization is 100-120 °C.

[0029] The present invention provides a 4-alkyl resorcinol compound 2

[0030] The present invention provides a process for preparing the cyclohexane-1 ,3-dione of

[0031] Formula II’ wherein R is selected from the group consisting of ; R1, R2, R3and R4are independently selected from the group consisting of hydrogen, alkyl and aryl, comprising the steps of: i. treating acetone and an acrylate of formula III, , wherein R1and R2are selected from the group consisting of hydrogen, alkyl and aryl; R7is selected from the group constituting of methyl, ethyl, secondary and tertiary alkyl, with NaH base in presence of toluene as a solvent at a temperature in the range of -10 to 60 °C for 3-4 hours to obtain a reaction mass; ii. acidifying the reaction mass with HCL (1 N) and extracting with ethyl acetate to obtain a reaction crude; and iii. treating the reaction crude with 0.66 N H2SO4 solution at 60-80 °C for 5-8 hrs to obtain the cyclohexane-1 , 3-dione product of Formula II.

[0032] The present invention provides a cyclohexane-1 ,3-dione compound of formula 1 a, The present invention provides a cyclohexane-1 ,3-dione compound of formula 1 a,

[0033] In another embodiment of the present invention, said alkyl / aryl substituted resorcinol compounds are useful for skin care, anti-microbial, anti-fungal, anti-bacterial, antiviral, depigmenting agent, UV-protectant, cosmeceutical, health care etc. products.

[0034] DETAILED DESCRIPTION OF THE INVENTION

[0035] Present invention provides a process for preparing alkyl / aryl substituted resorcinol by oxidative aromatization of substituted cyclohexane-1 ,3-dione compounds with iodine and DMSO in DMC solvent condition.

[0036] The 4-alkyl resorcinol compound of Formula I, wherein R is selected from the group consisting of and -CH3, R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting of hydrogen, S, O, N, alkyl and aryl, is produced from the oxidative aromatization of substituted cyclohexane-1 ,3-dione of Formula II wherein R is selected from the group consisting of and -CH3; R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting of hydrogen, S, O, N, alkyl and aryl.

[0037] The substituted resorcinol compounds produced are of General formula I to V provided below: wherein R1, R2, R3, R4, X and Y are as defined above.

[0038] Present invention provides a method for the synthesis of the following substituted resorcinol compounds 1 -5 following a simple, highly selective and high yielding economic approaches.

[0039]

[0040] EXAMPLES

[0041] The following examples are given by way of illustration and therefore should not construe to limit the scope of the present invention. EXPERIMENTAL

[0042] All reagents and solvents were purchased from reputed commercial sources (Sigma- Aldrich, CDH and Merck India Ltd). Reactions were monitored by TLC plates coated with 0.2 mm silica gel 60 F254. TLC plates were visualized by UV irradiation (254 nm) and iodine spray. The products were purified by column chromatography employing silica gel of 60-120 mesh size (Merck). The1H and13C NMR spectra were recorded at 298 K with Bruker AM-300 spectrometer; using TMS as internal reference standard in MeOD-d4 and DMSO-d6. HRMS were conducted with UHR-QTOF (ultra- high resolution Q-time of flight). The coupling constants (J) are reported in hertz (Hz) and the following abbreviations are used to designate signal multiplicity: s = singlet; d = doublet; t = triplet; m = multiplet; br = broad.

[0043] EXAMPLE 1

[0044] Synthesis of 3-(2,4-dioxocyclohexyl)propanoic acid (1a):

[0045] A mixture of acetone (172.41 mmol, lequiv.), ethyl acrylate (206.89 mmol, 1.2 equiv.) and NaH (137.92 mmol, 0.8 equiv.) in toluene solvent were placed in round bottom flask at -10 °C to room temperature at nitrogen atmosphere for 3-4 hrs. After that the reaction mixture was acidified with HCL (1 N) and extracted with ethyl acetate. The extracted reaction crude was further treated with 0.66 N H2SO4 solution at 60-80 °C for 5-6 hrs. Progress of the reaction monitored by TLC. After completion of the reaction the mixture was extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (60:40) to obtain the desired product as a white solid with 55% yield.

[0046] EXAMPLE 2

[0047] Synthesis of 2-methyl-3-(5-methyl-2,4-dioxocyclohexyl)propanoic acid (2a):

[0048] Mixtures of acetone (172.41 mmol, l equiv,), tert-butylbut-2-enoate (396.54mmol, 2.3 equiv) and NaH (344.82mmol, 2 equiv) in toluene solvent were placed in round bottom flask at -10 °C to room temperature at nitrogen atmosphere for 3-4 hrs. After that the reaction mixture was acidified with HCL (1 N) and extracted with ethyl acetate. The extracted reaction crude was further treated with 0.66 N H2SO4 solution at 60-80 °C for 7-8 hrs. Progress of the reaction monitored by TLC. After completion of reaction, the reaction mixture was extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (50:50) solvents to obtain the desired product in 50% yield as a white semi-solid.

[0049] EXAMPLE 3

[0050] Synthesis of 3-(2,4-dihydroxyphenyl)propanoic acid (1)

[0051] A mixture of 3-(2,4-dioxocyclohexyl) propanoic acid 1a (27.17 mmol, 1.0 equiv.), dimethyl sulphoxide (135.86 mmol, 5.0 equiv.) and iodine (5.43 mmol, 0.2 equiv.) in DMC (25 mL) were placed in round bottom flask for reflux at 120 °C for 7-8 hrs. After completion of reaction, the saturated solution of sodium thiosulfate (20-25 mL) was added to the reaction mixture and extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (70:30) to obtain the desired product 1 as pale yellow solid with 55% yield.

[0052] 1H NMR (MeOD-d4, 600 MHz, 5, ppm): 11.99 (s, br, 1 H), 9.15 (s, 1 H), 8.97 (s, 1 H), 6.80-6.81 (d, 2H), 6.27 (s, 1 H), 6.11 -6.13 (d, 1 H), 2.62-2.64 (m, 2H), 2.39-2.41 (m, 2H);13C NMR (MeOD-d4, 150 MHz) 5, 174.74, 157.00, 156.23, 130.42, 177.80, 106.34, 102.84, 34.63, 25.37. MS-ESI: calcd for C9H10O4 [M + H]+183.0652 found 183.032.

[0053] EXAMPLE 4

[0054] Synthesis of 3-(2,4-dihydroxy-5-methylphenyl)-2-methylpropanoic acid (2):

[0055] A mixture of 2-methyl-3-(5-methyl-2,4-dioxocyclohexyl) propanoic acid (23.58 mmol, 1.0 equiv.), dimethyl sulphoxide (117.92 mmol, 5.0 equiv.) and iodine (4.71 mmol, 0.2 equiv.) in DMC (25ml) were placed in round bottom flask for reflux at 120 °C (6-7 hrs). After completion of reaction the saturated solution of sodium thiosulfate (20- 25ml) was added to the reaction mixture and extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SO4 and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (70:30) to obtain the desired product (solid) with 40% yield.

[0056] EXAMPLE 5

[0057] Synthesis of 4-methylbenzene-1,3-diol / 4-methyl resorcinol (3)

[0058] A mixture of 4-methylcyclohexane-1 ,3-dione (39.68 mmol, 1.0 equiv.), dimethyl sulphoxide (198.4 mmol, 5.0 equiv.) and iodine (4.76 mmol, 0.12 equiv.) in DMC (25ml) were placed in round bottom flask for reflux at 120°C (3-4 hrs). After completion of reaction the saturated solution of sodium thiosulfate (20-25ml) was added to the reaction mixture and extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (80:20) to obtain the desired product as creamy solid with 45% yield.1H NMR (MeOD-d4, 600 MHz, 6, ppm): 6.82-6.81 (d, 1 H), 6.26-6.25 (d, 1 H), 6.19- 6.17 (m, 1 H), 2.06 (s, 3H);13C NMR (MeOD-d4, 150 MHz) 5, 159.7, 159.6, 134.4, 119.0, 109.8, 105.7, 17.9. MS-ESI: calcd for C7H8O2 [M + H]+125.0597 found 125.413.

[0059] EXAMPLE 6

[0060] Synthesis of 4-isopropylbenzene-1,3-diol / 4-siopropyl resorcinol (4):

[0061] A mixture of 4-isopropylcyclohexane-1 ,3-dione (32.89 mmol, 1.0 equiv.), dimethyl sulphoxide (164.47 mmol, 5.0 equiv.) and iodine (6.58 mmol, 0.2 equiv.) in DMC (25 ml) were placed in round bottom flask for reflux at 120 °C (5-6 hrs). After completion of reaction the saturated solution of sodium thiosulfate (20-25ml) was added to the reaction mixture and extracted with ethyl acetate (10 X 3 times) and treated with chilled NaOH (0.1 N, 50ml) solution. The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (80:20) to obtain the desired product as off white solid with 60% yield.

[0062] 1H NMR (MeOD-d4, 600 MHz, 5, ppm): 6.82-6.81 (d, 1 H), 6.26-6.25 (d, 1 H), 6.19- 6.17 (m, 1 H), 2.06 (s, 3H);13C NMR (MeOD-d4, 150 MHz) 5, 159.7, 159.6, 134.4, 119.0, 109.8, 105.7, 17.9. MS-ESI: calcd for C9H12O2 [M + H]+153.0910 found 153.246.

[0063] EXAMPLE 7

[0064] Synthesis of 4-hexylbenzene-1,3-diol / 4-hexyl resorcinol (5)

[0065] A mixture of 4-hexylcyclohexane-1 ,3-dione (25.51 mmol, 1.0 equiv.), dimethyl sulphoxide (127.55mmol, 5.0 equiv.), LiCI (30.61 mmol, 1.2 equiv.) and iodine (5.10 mmol, 0.20 equiv.) in DMC (25 ml) were placed in round bottom flask for reflux at 120 °C (3-4 hrs). After completion of reaction the saturated solution of sodium thiosulfate (20-25ml) was added to the reaction mixture and extracted with ethyl acetate (10 X 3 times). The combined organic layer was washed with water and dried over Na2SCU and vacuum evaporated. The viscous liquid obtained which was purified by column chromatography on silica gel (mesh 60-120) using the mixture of hexane: EtOAc (80:20) to obtain the desired product as white solid with 45% yield.

[0066] 1H NMR (DMSO-d6, 600 MHz, 5, ppm): 8.98 (s, 1 H), 8.90 (s, 1 H), 6.77-6.75 (d, 1 H), 6.25-6.24 (d, 1 H), 6.12-6.10 (m, 1 H), 2.39-2.36 (t, 2H), 1.45-1.43 (t, 2H), 1.45-1.43 (t, 2H), 1.28-1.26 (m, 6H), 0.86-0.84 (t, 3H);13C NMR (DMSO-d6, 150 MHz) 5, 156.5, 156.1 , 130.3, 119.3, 106.2, 102.8, 31.7, 30.2, 29.4, 29.0, 22.6, 14.4. MS-ESI: calcd for C12H18O2 [M + H]+195.1380 found 195.4187.

[0067] ADVANTAGES OF THE INVENTION

[0068] • A simple protocol for the preparation of different substituted resorcinol compounds from their corresponding cyclohexane-1 ,3-diones following oxidative aromatization using low-cost reagent system.

[0069] • A simple process for the preparation of 3-(2,4-dioxocyclohexyl) propanoic acid (DPPacid) (compound 1 ) following an economic approach from its corresponding cyclohexane-1 ,3-dione compound as a new molecule claimed and developed by the same inventors.

[0070] The invention utilizes inexpensive and abundantly available chemicals as feed-stock material for different substituted cyclohexane-1 ,3-diones and their corresponding 4-alkyl resorcinol production. The process is easy for purification to achieve high yield of the products.

[0071] • First scalable approach for 4-alkyl resorcinol production from its corresponding cyclohexane-1 ,3-diones.

[0072] • 4-Methyl, isopropyl and propanoic acid substituted resorcinols are highly demanding chemicals and > 50-100 industries are world-wide manufacturing these chemicals for different applications and the prices are very high. Herein, first time we have applied our own earlier patented process for 4-alkyl cyclohexane- 1 , 3-diones synthesis (WO2011 / 117881 , PCT / IN2011 / 000180, US 8,916,723 B2) as a feedstock chemical for their easy conversion to corresponding high value 4- alkyl resorcinols production, as a new application.

[0073] • A simple, scalable, cost-effective and high yielding route has been developed for the preparation of 4-alkyl resorcinol compounds.

Claims

WE CLAIM1 . A process for preparing the 4-alkyl resorcinol compound of Formula I,wherein R is selected from the group consisting ofand -CH3, R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting of hydrogen, S, O, N, alkyl and aryl, comprising the steps of;(i) oxidative aromatization of substituted cyclohexane-1 ,3-dione of Formula IIIIwherein R is selected from the group consisting ofand -CH3; R1, R2, R3, R4, R5and R6are independently selected from the group consisting of hydrogen, alkyl and aryl; X is selected from the group consisting of carboxylic, carbonyl, hydroxyl, sulphur and amine; and Y is selected from the group consisting ofhydrogen, S, O, N, alkyl and aryl, by treating with iodine and DMSO in presence of a solvent at refluxing conditions for 3-8 hours;(ii) after completion of the reaction treating the reaction product with saturated solution of sodium thiosulfate and extracting with ethyl acetate to obtain 4-alkyl resorcinol compound of Formula I; and(iii) purifying the product by extraction or column chromatography.

2. The process as claimed in claim 1 , wherein the yield is 50-60%.

3. The process as claimed in claim 1 , wherein the resorcinol compound of Formula I is selected from the group consisting of,4. The process as claimed in claim 1 , wherein the solvent used for oxidative aromatization is selected from the group consisting of DMC, propylene carbonate, diethyl carbonate or a combination thereof.

5. The process as claimed in claim 1 , wherein the molar proportion of iodine is in the range of 0.10-0.30 molar equivalents.

6. The process as claimed in claim 1 , wherein the process is carried out in the presence of a lithium halide selected from LiCI and LiBr in the range of 1.0-1.5 equivalents.

7. The process as claimed in claim 1 , wherein the temperature for oxidative aromatization is 100-120 °C.

8. A 4-alkyl resorcinol compound 29. A process for preparing the cyclohexane-1 ,3-dione of Formula II’wherein R is selected from the group consisting of; R1, R2, R3and R4are independently selected from the group consisting of hydrogen, alkyl and aryl, comprising the steps of: i. treating acetone and an acrylate of formula III,wherein R1and R2are selected from the group consisting of hydrogen, alkyl and aryl; R7is selected from the group constituting of methyl, ethyl, secondary and tertiary alkyl, with NaH base in presence of toluene as a solvent at a temperature in the range of -10 to 60 °C for 3-4 hours to obtain a reaction mass; ii. acidifying the reaction mass with HCL (1 N) and extracting with ethyl acetate to obtain a reaction crude; and iii. treating the reaction crude with 0.66 N H2SO4 solution at 60-80 °C for 5-8 hrs to obtain the cyclohexane-1 , 3-dione product of Formula II’.

10. A cyclohexane-1 ,3-dione compound of Formula II’ selected from the compound of formula 1 a and 2a