Clobetasol propionate derivative and preparation method thereof

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a compound clobetasol propionate derivative and a preparation method thereof. The compound clobetasol propionate derivative has a structure as shown in a general formula (I). The clobetasol propionate derivative is prepared by carrying out esterification reaction on 11-site hydroxyl of clobetasol propionate and acid, the reaction condition is simple, the yield is higher, the clobetasol propionate derivative is easy to separate and purify, and the fat solubility of the clobetasol propionate subjected to structure optimization is improved. The invention provides possibility for subsequent activity test, and provides a novel method for structural modification of the compound. Hectogram-level preparation can be conveniently realized in a laboratory, and the method is suitable for large-scale production. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and relates to a new compound clobetasol propionate derivative and a preparation method thereof. The compound clobetasol propionate derivative has a structure shown in the general formula (I), and is prepared by esterifying the 11-hydroxyl group of clobetasol propionate with an acid, and the fat solubility of the clobetasol propionate after structural optimization is improved. Background Art

[0002] According to the literature, super-potent topical corticosteroids are the mainstay of treatment for psoriasis and atopic dermatitis, either alone or in combination with topical vitamin D analogs. Psoriasis is a common, genetically influenced skin disease with a relatively high prevalence in the general population. Chronic psoriasis is the most common form of psoriasis, accounting for 65-86% of cases. [1] Corticosteroids, vitamin D analogs, and simple moisturizers are the most commonly used topical medications for patients. Atopic dermatitis (AD) is a chronic, relapsing inflammatory skin disease. Corticosteroids, topical calcineurin inhibitors, and moisturizers are the most common treatments for mild to moderate AD. [2] Among the corticosteroids used to treat psoriasis and atopic dermatitis, clobetasol propionate is the most commonly used [3] .

[0003] Clobetasol propionate, also known as 17-propionate flumethasone, clobetasol propionate, is an odorless, white to cream-colored crystalline powder with a solubility of 2 micrograms / mL in water. It is a synthetic, potent (Class I) fluorinated topical corticosteroid and one of the most widely used FDA-approved prescription drugs on the market. [4] Developed in the early 1970s, it is a potent analog of prednisolone, an oxidized prodrug form of cortisone.

[0004] Clobetasol propionate has primary glucocorticoid activity, by promoting the induction of phospholipase A2 inhibitory protein, thereby controlling the release of the inflammatory precursor arachidonic acid from membrane phospholipids through the enzyme, and it also has slight activity at the mineralocorticoid receptor [5] .

[0005] In addition, clobetasol propionate is also being explored for the treatment of a variety of skin diseases, such as vitiligo, psoriasis, eczema, and autoimmune cell-mediated diseases. [6] In recent years, studies have shown that topical corticosteroids are effective for alopecia areata. However, clinical studies have shown that many patients will suffer from irreversible visual field defects and visual impairment after long-term use of corticosteroids. However, 0.05% clobetasol propionate will not cause increased intraocular pressure when used at a dose of <9.8g / week and can be used to treat alopecia areata in patients with glaucoma.[7] .

[0006] Human cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5 metabolize most drugs and have high similarities in structure and substrate preference. CYP3A4 is mainly expressed in the liver, while CYP3A5 is upregulated in cancer, leading to drug resistance. Therefore, selective inhibitors of CYP3A5 are essential to validate it as a therapeutic target. Clobetasol propionate has been shown to be a potent and selective CYP3A5 inhibitor. It can be seen that clobetasol propionate has great therapeutic prospects.

[0007] Studies have shown that although clobetasol propionate is effective for a variety of skin diseases, it has poor water and alcohol solubility and is sensitive to photodegradation. Although it shows potential clinical value, the FDA limits the continued use of the drug to a maximum of 2 weeks due to systemic absorption after topical application, which promotes secondary adverse reactions. [8] Therefore, it is of great significance to develop and study clobetasol propionate derivatives to improve the therapeutic effect, minimize toxicity and avoid secondary adverse reactions after medication.

[0008] Based on the current state of the art, the inventors of this application intend to provide a new compound clobetasol propionate derivative and a preparation method thereof. The present invention prepares a new compound clobetasol propionate derivative by esterifying the 11-hydroxyl group of clobetasol propionate with an acid, and the fat solubility of the clobetasol propionate after structural optimization is improved.

[0009]

[0010] [1]GORDON KB,RUDERMAN E M.The treatment of psoriasis and psoriaticarthritis:an interdisciplinary approach[J].J Am Acad Dermatol,2006,54(3Suppl2):S85-91.

[0011] [2] CALLEN J, CHAMLIN S, EICHENFIELD LF, et al. A systematic review of the safety of topical therapies for atopic dermatitis[J]. Br J Dermatol, 2007, 156(2): 203-21.

[0012] [3]FELDMAN S R,FLEISCHER A B,JR.,COOPER J Z.New topical treatmentschange the pattern of treatment of psoriasis:dermatologists remain theprimary providers of this care[J].IntJ Dermatol,2000,39(1):41-4.

[0013] [4]PEARCE D J,SPENCER L,HU J,et al.Class I topical corticosteroid useby psoriasis patients in an academic practice[J].Journal of DermatologicalTreatment,2004,15(4):235-8.

[0014] [5]RHEN T,CIDLOWSKI J A.Antiinflammatory action of glucocorticoids--new mechanisms for old drugs[J].N Engl J Med,2005,353(16):1711-23.

[0015] [6]UVA L,MIGUEL D,PINHEIRO C,et al.Mechanisms of Action of TopicalCorticosteroids in Psoriasis[J].International Journal of Endocrinology,2012,2012:561018.

[0016] [7]NOMIYAMA T,KATOH N.Clobetasol propionate 0.05%under occlusion foralopecia areata:Clinical effect and influence on intraocular pressure[J]Australas J Dermatol,2021,62(2):e262-e4.

[0017] [8] PANONNUMMAL R, JAYAKUMAR R, SABITHA M. Comparative anti-psoriaticefficacy studies of clobetasol loaded chitin nanogel and marketed cream[J]. Eur J Pharm Sci, 2017, 96: 193-206. Summary of the invention

[0018] The purpose of the present invention is to provide a new compound clobetasol propionate derivative and a preparation method thereof based on the current state of the prior art. The present invention prepares a new compound clobetasol propionate derivative by esterifying the 11-hydroxyl group of clobetasol propionate with an acid, and the fat solubility of the clobetasol propionate after structural optimization is improved. The preparation method of the present invention is characterized in that the reaction conditions are simple and a large amount of preparation can be carried out.

[0019] The present invention provides a clobetasol propionate derivative represented by a general formula (I), wherein the compound represented by the general formula (I) has the following structure:

[0020]

[0021] Wherein, R is selected from 4-fluoro-3-methylbenzoyl, 2-(trifluoromethyl)benzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3-ethylbenzoyl, 6-methoxy-2-naphthoyl, 3-methoxybenzoyl, 4-((trifluoromethyl)thio)benzoyl.

[0022] Specifically,

[0023] The compounds represented by the general formula (I) of the present invention have the structures shown in I-1 to I-10:

[0024]

[0025] The structures shown in the above compounds Ⅰ-1 to Ⅰ-10 have the following names respectively:

[0026] (I-1) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-fluoro-3-methylbenzoate

[0027] (I-2) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-2-(trifluoromethyl)benzoate

[0028] (I-3) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-2,4-dimethylbenzoate

[0029] (I-4) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-ethylbenzoate

[0030] (I-5) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3,4-dichlorobenzoate

[0031] (I-6) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3,4-difluorobenzoate

[0032] (I-7) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3-ethynylbenzoate

[0033] (I-8) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-6-methoxy-2-naphthoate

[0034] (I-9) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3-methoxybenzoate

[0035] (I-10) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-((trifluoromethyl)thio)benzoate

[0036] The compounds represented by the general formula (I) of the present invention are prepared according to the following technical route. In the following examples, the clobetasol propionate derivatives are represented by Arabic numerals according to the numbers in the structural formula.

[0037]

[0038] The above-mentioned synthetic route comprises the following synthetic steps:

[0039] Compound 1 is dissolved in N,N-dimethylformamide, dichloromethane or tetrahydrofuran, and then carboxylic acid, condensation agent dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and catalyst 4-(dimethylamino)pyridine, triethylamine or pyridine are added in sequence. The mixture is reacted at room temperature for 24-48 hours, filtered and dried, and purified by column chromatography to obtain compound 2.

[0040] The method for preparing clobetasol propionate derivatives of the present invention has simple operation and high yield, and the reagents used are all commonly used reagents, and the method is suitable for large-scale preparation.

[0041] The present invention provides a compound clobetasol propionate derivative and a preparation method thereof. The clobetasol propionate derivative is prepared by an esterification reaction of the 11-hydroxyl group of clobetasol propionate with an acid, and the reaction conditions are simple, the yield is high, and it is easy to separate and purify. The reagents used are all common reagents, and the fat solubility of clobetasol propionate after structural optimization is improved. The present invention provides the possibility for subsequent activity testing and provides a new method for structural modification of the compound. It is convenient to achieve 100-gram-level preparation in the laboratory, which is suitable for large-scale production. DETAILED DESCRIPTION

[0042] Example 1: Synthesis of compounds I-1 to I-10

[0043] To a solution of compound 1 (10.5 mmol, 1.0 eq) in dichloromethane (50 mL) were added carboxylic acid (21.0 mmol, 2.0 eq), N,N'-dicyclohexylcarbodiimide (11 g, 5.0 eq) and 4-(dimethylamino)pyridine (3.85 g, 3.0 eq). After reacting at room temperature for 24 h, the white solid was removed by filtration, the filtrate was dried by rotary evaporation, and the target compounds Ⅰ-1 to Ⅰ-10 were purified by a silica gel column with PE:EA=3:1.

[0044] The physicochemical data of the target molecule synthesized according to the above method are as follows:

[0045] (I-1) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-fluoro-3-methylbenzoate

[0046] White solid (5.75 g, 91%). 1 H NMR (400MHz, DMSO-d6) δ8.01-7.78(m,3H),7.28(d,J=10.1Hz,1H),6.04(d,J=20 .6Hz,1H),5.57(d,J=8.1Hz,1H),5.46-5.38(m,1H),4.24-4.13(m,3H),2.42-2. 35(m,2H),2.27-2.18(m,1H),1.88(d,J=8.8Hz,2H),1.74-1.68(m,2H),1.64-1. 57(m,3H),1.48(s,3H),1.30-1.25(m,6H),1.03-1.00(m,3H),0.94-0.85(m,3H).

[0047] (I-2) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-2-(trifluoromethyl)benzoate

[0048] White solid (4.29 g, 64%). 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.5Hz,1H),7.87(t,J=8.1Hz,2H),6.86(d,J=10.1Hz,1H),6.3 2(d,J=10.2Hz,1H),6.07(s,1H),5.56(d,J=9.6Hz,2H),4.34(d,J=15.7Hz,1H),4.16(d,J=15.4H z,1H),2.41(s,2H),2.10(d,J=7.9Hz,1H),1.91(d,J=14.0Hz,3H),1.71(d,J=12.5Hz,2H),1.60( d,J=13.0Hz,2H),1.44(d,J=28.8Hz,2H),1.30-1.24(m,6H),1.02(t,J=7.8Hz,5H),0.93(s,2H).

[0049] (I-3) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-2,4-dimethylbenzoate

[0050] White solid (4.40 g, 70%). 1H NMR (400MHz, DMSO-d6) δ7.28(d,J=10.1Hz,1H),6.23(dd,J=10.2,1.9Hz,1H),6.02(d,J=1.7Hz,1H),5.57 (d,J=8.0Hz,1H),5.42(dd,J=4.4,1.7Hz,1H),4.20(t,J=5.6Hz,4H),2.63(td,J=13.5,5.7Hz,1H),2.46- 2.19(m,6H),2.05(q,J=8.0Hz,1H),1.86(t,J=10.0Hz,4H),1.71(dd,J=12.6,4.1Hz,1H),1.65-1.56(m,2 H),1.48(s,4H),1.38(dd,J=12.7,4.9Hz,1H),1.26(d,J=7.3Hz,4H),1.01(t,J=7.4Hz,4H),0.85(s,3H).

[0051] (I-4) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-ethylbenzoate

[0052] White solid (4.65 g, 74%). 1 H NMR (400MHz, DMSO-d6) δ7.98(d,J=7.9Hz,1H),7.40(d,J=7.9Hz,1H),6.87(d,J=10.2Hz,1H),6 .27(d,J=10.1Hz,1H),6.07(s,1H),5.56(d,J=8.4Hz,3H),4.29(d,J=15.7Hz,1H),4.11(d,J=15 .7Hz,1H),2.68(q,J=7.3Hz,2H),1.98(s,1H),1.70(d,J=10.0Hz,3H),1.62-1.58(m,3H),1.49 (s,3H),1.32(s,2H),1.27(d,J=8.4Hz,4H),1.23-1.18(m,6H),1.04-1.00(m,4H),0.86(s,2H).

[0053] (I-5) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3,4-dichlorobenzoate

[0054] White solid (5.43 g, 81%). 1 H NMR(400MHz, DMSO-d6)δ8.21-8.16(m,1H),8.02(dd,J=8.4,1.9Hz,1H),7.87-7.82(m,1H),6.88(d,J=10.1Hz,1H), 6.26(dd,J=10.2,1.9Hz,1H),6.06(s,1H),5.61-5.55(m,1H),4.27(d,J=15.7Hz,1H),4.14(d,J=15.8Hz,1H),3.02 -2.87(m,1H),2.61(td,J=13.6,5.8Hz,1H),2.45-2.32(m,4H),2.09(q,J=7.8Hz,1H),2.03-1.89(m,3H),1.83(d,J =14.5Hz,1H),1.44(dt,J=12.3,6.3Hz,1H),1.32-1.26(m,6H),1.22-1.15(m,1H),1.03-0.97(m,3H),0.85(s,3H).

[0055] (I-6) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3,4-difluorobenzoate

[0056] White solid (5.09 g, 80%). 1H NMR (400MHz, DMSO-d6) δ8.08(td,J=8.5,7.5,4.4Hz,1H),7.96(d,J=8.3Hz,1H),7.65(q,J=8.9Hz,1H),6.88(d,J=10.1Hz,1H), 6.26(dd,J=10.1,1.9Hz,1H),6.06(s,1H),5.56(d,J=9.1Hz,1H),4.28(d,J=15.8Hz,1H),4.13(d,J=15.7Hz,1H),3.05-2.87(m, 1H),2.60(td,J=13.4,5.4Hz,1H),2.44-2.34(m,3H),2.09(q,J=7.8Hz,1H),1.98-1.91(m,2H),1.82(d,J=14.4Hz,1H),1.70(d, J=12.2Hz,1H),1.64-1.55(m,1H),1.48-1.40(m,1H),1.35-1.23(m,6H),1.23-1.11(m,2H),1.00(t,J=7.5Hz,3H),0.85(s,2H).

[0057] (I-7) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3-ethynylbenzoate

[0058] White solid (4.06 g, 65%). 1H NMR (400MHz, DMSO-d6) δ8.10-8.04(m,2H),7.79(d,J=7.6Hz,1H),7.59(t,J=7.8Hz,1H),6.88(d,J=10.1Hz,1H),6.26(dd,J=10.3,1 .9Hz,1H),6.06(s,1H),5.63-5.53(m,1H),4.37(s,1H),4.28(d,J=15.7Hz,1H),4.13(d,J=15.7Hz,1H),3.00-2.84(m,1H),2.62(dt ,J=13.3,6.7Hz,1H),2.40(dt,J=14.9,7.3Hz,3H),2.09(q,J=7.8Hz,1H),1.96-1.90(m,2H),1.83(d,J=14.5Hz,1H),1.70(d,J=12. 1Hz,1H),1.65-1.54(m,1H),1.48-1.40(m,1H),1.33-1.25(m,6H),1.15(td,J=7.1,0.7Hz,2H),1.00(t,J=7.5Hz,3H),0.86(s,2H).

[0059] (I-8) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-6-methoxy-2-naphthoate

[0060] White solid (4.10 g, 60%). 1H NMR(400MHz,DMSO-d6)δ7.96(d,J-1.7Hz,1H),7.90(d,J-8.0Hz,1H),7.82(dd,J-16.9,8.8Hz,3H),7 .55(dd,J-8.5,1.7Hz,1H),7.34(d,J-2.6Hz,2H),7.19(dd,J-8.9,2.5Hz,2H),4.28-4.17(m,2H),3. 88(s,3H),3.15-3.09(m,1H),1.81(t,J-16.9Hz,6H),1.70(dd,J-12.4,3.3Hz,2H),1.62(d,J-14.6H z,2H),1.33(s,6H),1.20-1.14(m,3H),1.00-0.94(m,2H),0.88-0.83(m,1H),0.68(d,J-11.2Hz,2H).

[0061] (I-9) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-3-methoxybenzoate

[0062] White solid (5.23 g, 83%). 1H NMR (400MHz, DMSO-d6) δ7.66(dt,J=7.7,1.2Hz,1H),7.57-7.45(m,2H),7.29(ddd,J=8.3,2.7,1.0Hz,1H),6.88(d,J=10.1Hz,1H),6.28(dd,J=10.2,1 .9Hz,1H),6.07(t,J=1.6Hz,1H),5.58(dd,J=13.3,7.7Hz,1H),4.31(d,J= 15.7Hz,1H),4.13(d,J=15.7Hz,1H),3.82(s,3H),2.91(dtd,J=29.6,11.6, 4.7Hz,1H),2.70-2.59(m,1H),2.41(d,J=8.0Hz,2H),2.11(q,J=7.8Hz,1H ),1.97(dt,J=11.5,7.2Hz,2H),1.82(d,J=14.4Hz,1H),1.72(dd,J=12.4,4 .0Hz,2H),1.61(dd,J=13.1,4.2Hz,2H),1.53-1.41(m,2H),1.33(s,2H),1. 28(d,J=7.3Hz,2H),1.24-1.16(m,2H),1.02(t,J=7.5Hz,3H),0.88(s,2H).

[0063] (I-10) (8S,9R,10S,11S,13S,14S,16S,17R)-17-(2-chloroacetyl)-9-fluoro-10,13,16-trimethyl-3-oxo-17-(propionyloxy)-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopentadienyl[α]phenanthren-11-yl-4-((trifluoromethyl)thio)benzoate

[0064] White solid (5.63 g, 80%). 1H NMR(400MHz,DMSO-d6)δ8.18(dd,J=8.5,2.2Hz,2H),7.89(dd,J=8.4,2.2Hz,2H),6.90(dd,J=10.1,2.3Hz,1H),6.26(dt,J=10.2,2.1Hz,1H),6.06(s,1H),5.64-5.50(m,1H),4.28(dd,J=15.7,2.3Hz,1H),4.13(dd,J=15.8,2.3Hz,1H),2.89(d,J=31.2Hz,1H),2.63(d,J=20.2Hz,1H),2.40(dt,J=14.3,4.5Hz,3H),2.09(q,J=7.8Hz,1H),1.98(dq,J=17.9,9.4,7.2Hz,3H),1.86(d,J=14.4Hz,1H),1.65(dd,J=43.1,12.8Hz,1H),1.50-1.41(m,1H),1.29(dd,J=17.8,4.7Hz,6H),1.22-1.15(m,1H),1.00(td,J=7.5,2.1Hz,3H),0.86(s,3H)。

Claims

1. A clobetasol propionate derivative compound represented by general formula (I), in, R is selected from 4-fluoro-3-methylbenzoyl, 2-(trifluoromethyl)benzoyl, 2,4-dimethylbenzoyl, 4-ethylbenzoyl, 3,4-dichlorobenzoyl, 3,4-difluorobenzoyl, 3-ethylbenzoyl, 6-methoxy-2-naphthoyl, 3-methoxybenzoyl, 4-((trifluoromethyl)thio)benzoyl.

2. The clobetasol propionate derivative compound of general formula (I) according to claim 1, characterized in that: The compound represented by the general formula (I) has the structures shown in I-1 to I-10:

3. A method for synthesizing a clobetasol propionate derivative compound, characterized in that: According to the following synthetic route: Compound 1 is dissolved in an organic solvent, and then carboxylic acid, a condensing agent and a catalyst are added in sequence, reacted at room temperature for 24-48 hours, filtered and dried, and purified by column chromatography to obtain compound 2.

4. The preparation method according to claim 3, characterized in that: The organic solvent is N,N-dimethylformamide, dichloromethane or tetrahydrofuran.

5. The preparation method according to claim 3, characterized in that: The carboxylic acid is selected from 4-fluoro-3-methylbenzoic acid, 2-(trifluoromethyl)benzoic acid, 2,4-dimethylbenzoic acid, 4-ethylbenzoic acid, 3,4-dichlorobenzoic acid, 3,4-difluorobenzoic acid, 3-ethylbenzoic acid, 6-methoxy-2-naphthoic acid, 3-methoxybenzoic acid or 4-((trifluoromethyl)thio)benzoic acid.

6. The preparation method according to claim 3, characterized in that: The condensing agent is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-(3-dimethylaminopropyl)carbodiimide or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride.

7. The method for preparing the drug according to claim 5, characterized in that: The catalyst is selected from 4-(dimethylamino)pyridine, triethylamine or pyridine.

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