112965-21-6

Basic information

• Product Name: Calcipotriene
• Synonyms: 5z,7e,22e,24s)--bet;9,10-secochola-5,7,10(19),22-tetraene-1,3,24-triol,24-cyclopropyl-,(1-alpha,3;dovonex;mc903;CALCIPOTRIOL,CALCIPOTRIENE;Calciptriol, MC-903, Daivonex, Dovonex, Psorcutan;9,10-Secochola-5,7,10(19),22-tetraene-1,3,24-triol, 24-cyclopropyl-, (1α,3β,5Z,7E,22E,24S)-;Calciptriol
• CAS NO: 112965-21-6
• Molecular Formula: C₂₇H₄₀O₃
• Molecular Weight: 412.6
• EINECS: 1806241-263-5
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labelled Compounds
• Mol File: 112965-21-6.mol
• Article Data: 10

Chemical Properties

• Melting Point: 166-168°C
• Boiling Point: 582 ºC at 760 mmHg
• Flash Point: 250.6 ºC
• Appearance: white crystalline solid
• Density: 1.12 g/cm³
• Vapor Pressure: 5.74E-16mmHg at 25°C
• Refractive Index: 1.579
• Storage Temp.: Desiccate at -20°C
• Solubility: DMSO: soluble15mg/mL, clear
• PKA: 14.29±0.20(Predicted)
• CAS DataBase Reference: Calcipotriene(CAS DataBase Reference)
• NIST Chemistry Reference: Calcipotriene(112965-21-6)
• EPA Substance Registry System: Calcipotriene(112965-21-6)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26
• RIDADR: UN 2811 6.1 / PGIII
• WGK Germany: 3
• Hazardous Substances Data: 112965-21-6(Hazardous Substances Data)

Usage

Description

Calcipotriene also known as Calcipotriol, is a topical vitaminD3 derivative effective in the treatment of psoriasis vulgaris. The drug acts by binding to vitamin D3 receptors in the skin keratinocytes, producing an elevation in cell differentiation and a reduction in cell proliferation. Although its efficacy is comparable to calcitriol, calcipotriol exhibits at least 100 times less effect on calcium metabolism in rats.

Chemical Properties

White Crystalline Solid

Originator

Leo Denmark (Denmark)

Uses

Calcipotriene is an antipsoriatic that is a vitamin D3 analogue with low calcemic activity. It works by regulating the production and growth of skin cells. In the United States, this drug was first marketed under the trade name Dovonex and is used mainly for the treatment of psoriasis. It is one of the most effective non glucocorticoid topical drugs for the treatment of localized psoriasis.This drug has many off-label applications that are alternative therapies for many dermatologic diseases.

Indications

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible.

Definition

ChEBI: Calcipotriol is a seco-cholestane that is 26,27-cyclo-9,10-secocholesta-5,7,10,22-tetraene carrying additional hydroxy substituents at positions 1, 3 and 24. It is used (as its hydrate) in combination with betamethasone dipropionate, a corticosteroid, for the topical treatment of plaque psoriasis in adult patients. It has a role as a drug allergen and an antipsoriatic. It is a member of cyclopropanes, a secondary alcohol, a triol, a hydroxy seco-steroid and a seco-cholestane.

Preparation

A convergent approach for the total synthesis of calcipotriol (brand name: Dovonex), a proven Vitamin D analog used for the treatment of psoriasis, and medicinally relevant synthetic analogs is described.A Synthesis of calcipotriol via a Key Electroreductive Cross-coupling ApproachCalcipotriol is currently the most successful VitD analog and is prescribed for the treatment of psoriasis, an autoimmune skin disease.

Manufacturing Process

(1S,3R)-Bis-(t-butyldimethylsilyloxy)-(20S)-formyl-9,10-secopregna(5E,7E,10 (19))triene (Calverley Tetrahedron 43.4609 (1967) and (cyclopropyl)(tri-phenylphoshoranylidene)ketone are stirred in dimethyl sulfoxide under nitrogen. The reaction mixture is then diluted at room temperature with ethyl acetate and washed with common salt solution. The organic phase is dried on sodium sulfate and filtered. After removal of the solvent, the residue is filtered with toluene through silica gel. Evaporation of the solvent and gradient chromatography (toluene/hexane (1:1)-toluene) of the residue on silica gel yield (5E,7E,22E),(1S,3R)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-one.(5E,7E,22E),(1S,3R)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10- secochola-5,7,10(19),22-tetraene-24-one in tetrahydrofuran and methanol are mixed with a 0.4 M methanol CeCl3·7H2O solution. Sodium borohydride is added by portions under nitrogen with ice cooling. The suspension is stirred with ice cooling and then put into ice/common salt solution. The aqueous phase is extracted with ethyl acetate, the organic phase is washed neutral with water and dried on sodium sulfate. Filtration and removal of the solvent yield oil. By chromatography on silica gel with ethyl acetate/hexane (1:9). The (5E,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol is obtained.(5E,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol is dissolved in toluene and after addition of anthracene and 1 drop of triethylamine it is radiated at room temperature with a high pressure mercury vapor lamp (Heraeus TQ 150) through Pyrex glass. The reaction mixture is concentrated by evaporation and the residue a mixture of (5Z,7E,22E),(1S,3R,24S)-1,3-bis-(t-butyldimethylsilyloxy)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene- 24-ol and anthracene - is directly reacted with tetrabutylammonium fluoride.(5Z,7E,22E),(1S,3R,24S)-1,3-Bis-(t-butyldimethylsilyloxy)-24-cyclopropyl- 9,10-secochola-5,7,10(19),22-tetraene-24-ol in tetrahydrofuran is kept with a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran under nitrogen. For working up, the cooled reaction mixture is poured into cold sodium bicarbonate solution and then extracted with ethyl acetate. After drying of the organic phase on sodium sulfate, filtration and evaporation of the solvent yields a resin-like residue. Chromatography on silica gel with ethyl acetate/hexane (2:1) yields (5Z,7E,22E),(1S,3R,24S)-24-cyclopropyl-9,10- secochola-5,7,10(19),22-tetraene-1,3,24-triol.

Brand name

Dovonex (Leo);Daivonex.

Therapeutic Function

Antipsoriatic

Biological Activity

Vitamin D 3 analog that displays minimal effects on calcium homeostasis. Regulates cell differentiation and proliferation; exhibits antiproliferative activity against human HL-60, HL60/MX2, MCF-7, T47D, SCC-25 and mouse WEHI-3 cancer cell lines.

Biochem/physiol Actions

Calcipotriol, a synthetic derivative of calcitriol or Vitamin D, is used in the treatment of psoriasis and marketed under the trade name Dovonex. It has comparable affinity with calcitriol (Vit. D) for the Vitamin D receptor (VDR), while being less than 1% as active as the calcitriol in regulating calcium metabolism. VDR belongs to the steroid/thyroid receptor superfamily, and is found on the cells of many different tissues including the thyroid, bone, kindney, and T cells of the immune system. Binding of calcipotriol to the VDR modulates the T cells gene transcription of cell differentiation and proliferation-related genes.

Pharmacology

Calcipotriene (Dovonex) enhances the effectiveness of ultraviolet B (UVB) but also increases photosensitivity in UVB-treated patients. Ultraviolet light, 6% salicylic acid, 12% lactic acid, hydrocortisone valerate 0.2% ointment, and tazarotene (Tazorac) gel degrade calcipotriene (Dovonex). Halobetasol ointment and 5% tar gel are compatible with Calcipotriene (Dovonex). A British study found calcipotriene (Dovonex) to be safe and effective in a pediatric population over the age of 3, although it is not approved by the FDA.

InChI:InChI=1/C27H40O3/c1-17(6-13-25(29)20-8-9-20)23-11-12-24-19(5-4-14-27(23,24)3)7-10-21-15-22(28)16-26(30)18(21)2/h6-7,10,13,17,20,22-26,28-30H,2,4-5,8-9,11-12,14-16H2,1,3H3/b13-6+,19-7+,21-10-/t17-,22-,23-,24?,25-,26+,27-/m1/s1

Synthetic route

(1S,3R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'(S)-cyclopropyl-3'-hydroxyprop-1'(E)-enyl)-9,10-secopregna-5(Z),7(E),10(19)-triene (112875-61-3) → calcipotriene (112965-21-6)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃;	87%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 60℃; for 0.833333h;	73%
With tetrabutyl ammonium fluoride In tetrahydrofuran at 40℃; for 2h;
With tetrabutyl ammonium fluoride In tetrahydrofuran at 60℃;
Stage #1: (1S,3R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'(S)-cyclopropyl-3'-hydroxyprop-1'(E)-enyl)-9,10-secopregna-5(Z),7(E),10(19)-triene With tetrabutyl ammonium fluoride In tetrahydrofuran at 60 - 65℃; for 2h; Stage #2: With water; sodium hydrogencarbonate In tetrahydrofuran; ethyl acetate for 0.25h;

Cyclopropyl methyl ketone (765-43-5) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 9 steps 1: 87 percent / bromine / methanol / 0.5 h / Ambient temperature 2: 84 percent 3: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 5: N-methylmorpholine N-oxide, selenium dioxide 6: imidazole / dimethylformamide 7: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 8: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 9: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 7 steps 1: 87 percent / bromine / methanol / 0.5 h / Ambient temperature 2: 84 percent 3: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 4: dimethylsulfoxide / 4 h / 105 °C 5: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 6: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 7: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

2-bromo-1-cyclopropylethan-1-one (69267-75-0) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 8 steps 1: 84 percent 2: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 4: N-methylmorpholine N-oxide, selenium dioxide 5: imidazole / dimethylformamide 6: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 7: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 8: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 6 steps 1: 84 percent 2: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 3: dimethylsulfoxide / 4 h / 105 °C 4: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 5: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 6: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

1-cyclopropyl-2-(triphenyl-λ5-phosphanylidene)ethan-1-one (7691-76-1) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 6 steps 2: N-methylmorpholine N-oxide, selenium dioxide 3: imidazole / dimethylformamide 4: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 5: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 6: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 4 steps 1: dimethylsulfoxide / 4 h / 105 °C 2: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 3: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 4: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

3(R)-(tert-butyldimethylsilyloxy)-20(S)-formyl-9,10-secopregna-5(Z),7(E),10(19)-triene (112828-12-3) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 6 steps 2: N-methylmorpholine N-oxide, selenium dioxide 3: imidazole / dimethylformamide 4: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 5: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 6: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(S)-3-[(1R,3aS,7aR)-7a-Methyl-1-((E)-(1R,4R)-1,4,5-trimethyl-hex-2-enyl)-octahydro-inden-(4E)-ylidenemethyl]-2,2-dioxo-2,3,4,5,6,7-hexahydro-1H-2λ6-benzo[c]thiophen-5-ol (87680-65-7) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 9 steps 1: 42 percent / imidazole / dimethylformamide / 1.5 h / 20 °C 2: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 3: NaHCO3 / aq. ethanol / Heating 5: N-methylmorpholine N-oxide, selenium dioxide 6: imidazole / dimethylformamide 7: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 8: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 9: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 9 steps 1: 52 percent / imidazole / dimethylformamide / 1.5 h / 20 °C 2: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 3: NaHCO3 / aq. ethanol / Heating 5: N-methylmorpholine N-oxide, selenium dioxide 6: imidazole / dimethylformamide 7: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 8: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 9: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

20(R),3(R)-(tert-butyldimethylsilyloxy)-20-(3'-cyclopropyl-3'-oxoprop-1'(E)-enyl)-9,10-secopregna-5(Z),7(E),10(19)-triene (112849-18-0) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 5 steps 1: N-methylmorpholine N-oxide, selenium dioxide 2: imidazole / dimethylformamide 3: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 4: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 5: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(E)-(R)-4-{(1R,3aS,7aR)-4-[2-[(R)-5-(tert-Butyl-dimethyl-silanyloxy)-3-hydroxy-2-methylene-cyclohex-(E)-ylidene]-eth-(E)-ylidene]-7a-methyl-octahydro-inden-1-yl}-1-cyclopropyl-pent-2-en-1-one → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: imidazole / dimethylformamide 2: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 3: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 4: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(2-cyclopropyl-2-oxoethyl) (triphenyl)phosphonium bromide (112849-15-7) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 3: N-methylmorpholine N-oxide, selenium dioxide 4: imidazole / dimethylformamide 5: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 6: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 7: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 5 steps 1: 86 percent / 2N sodium hydroxide / H2O; CH2Cl2 2: dimethylsulfoxide / 4 h / 105 °C 3: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 4: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 5: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(7Z)-Vitamin D2 (247900-07-8) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 10 steps 1: liq. SO2 / 0.5 h / Heating 2: 42 percent / imidazole / dimethylformamide / 1.5 h / 20 °C 3: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 4: NaHCO3 / aq. ethanol / Heating 6: N-methylmorpholine N-oxide, selenium dioxide 7: imidazole / dimethylformamide 8: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 9: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 10: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme
Multi-step reaction with 10 steps 1: liq. SO2 / 0.5 h / Heating 2: 52 percent / imidazole / dimethylformamide / 1.5 h / 20 °C 3: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 4: NaHCO3 / aq. ethanol / Heating 6: N-methylmorpholine N-oxide, selenium dioxide 7: imidazole / dimethylformamide 8: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 9: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 10: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

3(S)-tert-butyldimethylsilyloxy-20(S)-formyl-9,10-secoprega-5,7(E),10(19)-triene (87407-47-4) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: NaHCO3 / aq. ethanol / Heating 3: N-methylmorpholine N-oxide, selenium dioxide 4: imidazole / dimethylformamide 5: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 6: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 7: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

3(S)-tert-butyldimethylsilyloxy-20(S)-formyl-9,10-secoprega-5,7(E),10(19)-triene (87422-13-7) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 7 steps 1: NaHCO3 / aq. ethanol / Heating 3: N-methylmorpholine N-oxide, selenium dioxide 4: imidazole / dimethylformamide 5: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 6: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 7: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(3S,6R)-(tert-butyldimethylsilyloxy)-9,10-seco-ergosta-5,7(E),10(19),22(E)-tetraene SO2 adduct (87417-26-3) → calcipotriene (112965-21-6)

Conditions

Yield

Multi-step reaction with 8 steps 1: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 2: NaHCO3 / aq. ethanol / Heating 4: N-methylmorpholine N-oxide, selenium dioxide 5: imidazole / dimethylformamide 6: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 7: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 8: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(3S,6S)-(tert-butyldimethylsilyloxy)-9,10-seco-ergosta-5,7(E),10(19),22(E)-tetraene SO2-adduct (87417-26-3, 87417-27-4) → calcipotriene (112965-21-6)

Conditions

Yield

Multi-step reaction with 8 steps 1: 1.) ozone 2.) PPh3 / 1.) CH2Cl2, MeOH, -60 deg C 2.) CH2Cl2, MeOH, -60 to 0 deg C 2: NaHCO3 / aq. ethanol / Heating 4: N-methylmorpholine N-oxide, selenium dioxide 5: imidazole / dimethylformamide 6: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 7: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 8: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(1S,3R,3'S)-bis(tert-butyldimethylsilyloxy)-20(R)-(3'-cyclopropyl-3'-hydroxyprop-1'(E)-enyl)-9,10-secopregna-5(E),7(E),10(19)-triene (112849-27-1) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 2: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

1(S),3(R)-bis(tert-butyldimethylsilyloxy)-20(R)-(3’-cyclopropyl-3’-oxypropyl-1’(E)-enyl)-9,10-secopregna-5(E),7(E),10(19)-triene (112849-17-9) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 33 percent / NaBH4, CeCl3*6H2O / methanol / further reag.: (S)-BINAL-H 2: anthracene, triethylamine / toluene / 1 h / 20 °C / Irradiation 3: 73 percent / tetrabutylammonium fluoride / tetrahydrofuran / 0.83 h / 60 °C View Scheme

(5Z,7E,22E)-(1S,3R,24R)-24-acetoxy-26,27-cyclo-9,10-secocholesta-5,7,10(19),22-tetraene-1,3-diol → 20(R)-(3'(R)-cyclopropyl-3'-hydroxyprop-1'(E)-enyl)-1(S),3(R)-dihydroxy-9,10-secopregna-5(Z),7(E),10(19)-triene (112827-99-3) + calcipotriene (112965-21-6)

Conditions	Yield
With silica gel In hexane; dichloromethane for 24h; Product distribution / selectivity;

PRI-2201 + phenylboronic acid (98-80-6) → C33H43BO3 (934338-46-2) + calcipotriene (112965-21-6)

Conditions	Yield
In acetone for 3h; Purification / work up;

PRI-2205 (113082-99-8) → calcipotriene (112965-21-6)

Conditions	Yield
With 9-acetylanthracene In acetone at 10℃; Product distribution / selectivity; UV-irradiation;

C27H40O3 (934338-38-2) → (5Z,7E,22E,24R)-24-cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-1β,3β,24-triol + calcipotriene (112965-21-6)

Conditions	Yield
With 9-acetylanthracene In acetone at 10℃; Product distribution / selectivity; UV-irradiation;

C35H60O2Si2 (590366-68-0) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: bis(cyclohexanyl)borane; diethylzinc; (2R)-3-exo-(dimethylamino)isoborneol / hexane / -20 - 0 °C 1.2: 0 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C View Scheme

[(2Z)-2-[(3S,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide (81522-68-1) → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: n-hexyllithium / -78 °C 2.1: bis(cyclohexanyl)borane; diethylzinc; (2R)-3-exo-(dimethylamino)isoborneol / hexane / -20 - 0 °C 2.2: 0 °C 3.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 20 °C View Scheme

tert-butyl[(1S)-1-cyclopropyl-2-[(R)-4-methylbenzenesulfinyl]ethoxy]dimethylsilane → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 2,4,6-trimethyl-pyridine; trifluoroacetic anhydride / acetonitrile / 0.17 h / 30 °C / Inert atmosphere 1.2: 0.08 h 2.1: dichloromethane / 0.17 h / -50 °C / Inert atmosphere 3.1: N-ethyl-N,N-diisopropylamine / water; acetonitrile 4.1: hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide / isopropyl alcohol / 20 - 30 °C 5.1: potassium hexamethylsilazane / tetrahydrofuran / 2 h / -50 °C / Inert atmosphere 6.1: triethylamine; anthracene / toluene / 1.5 h / 20 °C / UV-irradiation 6.2: 1 h / 60 °C View Scheme
Multi-step reaction with 6 steps 1.1: 2,4,6-trimethyl-pyridine; trifluoroacetic anhydride / acetonitrile / 0.17 h / 30 °C / Inert atmosphere 1.2: 0.08 h 2.1: dichloromethane / 0.17 h / -50 °C / Inert atmosphere 3.1: lithium diisopropyl amide / tetrahydrofuran; N,N-dimethyl-formamide / 0.08 h 3.2: 2 h / 30 °C 4.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 0 - 20 °C 5.1: lithium diisopropyl amide / tetrahydrofuran / 2 h / -30 °C / Inert atmosphere 6.1: triethylamine; anthracene / toluene / 1.5 h / 20 °C / UV-irradiation 6.2: 1 h / 60 °C View Scheme

(1S,2R)-1-cyclopropyl-2-(p-tolylsulfoxy)-O-methoxy methyl ether → calcipotriene (112965-21-6)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: potassium carbonate; acetic anhydride / acetonitrile / 0.5 h / 50 °C / Inert atmosphere 1.2: 0.17 h 2.1: triethylamine / acetonitrile / 0.5 h / 0 °C / Inert atmosphere 3.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 3.2: 2 h / 30 °C 4.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 0 - 20 °C 5.1: sodium hexamethyldisilazane / diethyl ether / 3 h / -80 °C / Inert atmosphere 6.1: triethylamine; anthracene / toluene / 1.5 h / UV-irradiation 6.2: 1 h / 60 °C 6.3: 3 h / 20 °C View Scheme

(S)-2-{[(benzyloxy)carbonyl]oxy}-2-cyclopropylethan-1-ol → calcipotriene (112965-21-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 0.5 h / -30 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 3.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 2 h / 20 - 50 °C 4.1: lithium hexamethyldisilazane / tetrahydrofuran; 1,4-dioxane / 2 h / -20 °C / Inert atmosphere 5.1: triethylamine; anthracene / toluene / 1.5 h / UV-irradiation 5.2: 1 h / 60 °C 5.3: 3 h / 20 °C / 760.05 Torr View Scheme

(S)-2-[(tert-butyldimethylsilyl)oxy]-2-cyclopropylethan-1-ol → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: dichloromethane / 0.17 h / -50 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine / water; acetonitrile 3.1: hexaammonium heptamolybdate tetrahydrate; dihydrogen peroxide / isopropyl alcohol / 20 - 30 °C 4.1: potassium hexamethylsilazane / tetrahydrofuran / 2 h / -50 °C / Inert atmosphere 5.1: triethylamine; anthracene / toluene / 1.5 h / 20 °C / UV-irradiation 5.2: 1 h / 60 °C View Scheme
Multi-step reaction with 5 steps 1.1: dichloromethane / 0.17 h / -50 °C / Inert atmosphere 2.1: lithium diisopropyl amide / tetrahydrofuran; N,N-dimethyl-formamide / 0.08 h 2.2: 2 h / 30 °C 3.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 0 - 20 °C 4.1: lithium diisopropyl amide / tetrahydrofuran / 2 h / -30 °C / Inert atmosphere 5.1: triethylamine; anthracene / toluene / 1.5 h / 20 °C / UV-irradiation 5.2: 1 h / 60 °C View Scheme

(S)-2-cyclopropyl-2-(methoxymethoxy)ethan-1-ol → calcipotriene (112965-21-6)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: triethylamine / acetonitrile / 0.5 h / 0 °C / Inert atmosphere 2.1: sodium hydride / mineral oil; N,N-dimethyl-formamide / 0.08 h / Inert atmosphere 2.2: 2 h / 30 °C 3.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 0 - 20 °C 4.1: sodium hexamethyldisilazane / diethyl ether / 3 h / -80 °C / Inert atmosphere 5.1: triethylamine; anthracene / toluene / 1.5 h / UV-irradiation 5.2: 1 h / 60 °C 5.3: 3 h / 20 °C View Scheme

(1S)-2-{[(benzyloxy)carbonyl]oxy}-2-cyclopropylethyl trifluoromethanesulfonate → calcipotriene (112965-21-6)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C 2.1: 3-chloro-benzenecarboperoxoic acid / acetonitrile / 2 h / 20 - 50 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran; 1,4-dioxane / 2 h / -20 °C / Inert atmosphere 4.1: triethylamine; anthracene / toluene / 1.5 h / UV-irradiation 4.2: 1 h / 60 °C 4.3: 3 h / 20 °C / 760.05 Torr View Scheme

all-cis-6,9,12-octadecatrienoic acid (506-26-3) + calcipotriene (112965-21-6) → calcipotriol 24-γ-linolenoate + calcipotriol bis(γ-linolenoate)

Conditions	Yield
With 4-(dimethylamino)pypiridine; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;

(9Z,12Z,15Z)-octadeca-9-12,15-trienoic acid (463-40-1) + calcipotriene (112965-21-6) → calcipotriol 24-linolenoate + calcipotriol dilinolenoate

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;

(9Z,12Z,15Z)-octadeca-9-12,15-trienoic acid (463-40-1) + calcipotriene (112965-21-6) → calcipotriol mono-linoleic ester

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 3h;

calcipotriene (112965-21-6) → calcipotriol monohydrate

Conditions	Yield
With water In ethyl acetate
With ammonia; water at 25 - 40℃; for 12 - 50h; pH=> 7; Product distribution / selectivity;

calcipotriene (112965-21-6) → calci-dioxole (1201658-10-7)

Conditions	Yield
With oxygen; methylene blue In methanol at 20℃; Photolysis;

calcipotriene (112965-21-6) → calci-Cl

Conditions	Yield
With hydrogenchloride; oxygen In ethanol at 20℃;

Upstream product

• 615251-52-0 (1S)-1-[(t-butyl)dimethylsilyloxy]-1-cyclopropyl-2-[(2'-benzothiazolyl)sulfonyl]ethane 
• 615251-51-9 2-{[(1S)-2-[(tert-butyldimethylsilyl)oxy]-2-cyclopropylethyl]sulfanyl}-1,3-benzothiazole 
• 615251-47-3 toluene-4-sulfonic acid (S)-2-(tert-butyl-dimethyl-silanyloxy)-2-cyclopropyl-ethyl ester 
• 81522-68-1 [(2Z)-2-[(3S,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide 
• 590366-68-0 C₃₅H₆₀O₂Si₂ 

Downstream Products

• 147657-22-5 calcipotriol monohydrate 
• 1201658-10-7 calci-dioxole 

Relevant articles and documents

Calcipotriol intermediate compound and preparation method thereof

The invention discloses a calcipotriol intermediate compound and a preparation method thereof. The structure of the compound is represented by general formula I shown in the description. In the general formula I, R1 is selected from a carbobenzoxy group (Cbz), a trimethylsilyl group (TMS), a triethylsilyl group (TES), a t-butyldimethylsilyl group (TBDMS), a triisopropylsilyl group (TIPS), a t-butyl-diphenylsilyl group (TBDPS) or a methoxymethyl group (MOM); and R2 is one of groups shown in the description.

EPIMERIZATION BY STEREOSELECTIVE SYNTHESIS OF VITAMIN D ANALOGUES

A method for epimerization process of C-24 ketones to desired C-24 alcohol by stereo selective reduction using chiral borane reducing agents in the presence of chiral auxillary such as (R)-2-methyl-CBS-oxazaborolidine for the preparation of calcipotriene intermedites and its process to calcipotriene.

Method for preparing analogue of vitamin D

A method for preparing analogues of C1,C24-dihydroxy-vitamin D is disclosed. Especially the method for preparing calcipotriol and tacalcitol from a starting material of Vitamin D2 is disclosed here. Calcipotriol (compound 1(a)) and tacalcitol (compound 1(b)) can be synthesized by the method of the present invention. Moreover, only nine steps are needed for the synthesis of calcipotriol using the method. Likewise, only ten steps are needed for the synthesis of tacalcitol by the present method. Hence, the present method, with less process steps and higher yields, represents an improvement over the conventional methods.