32222-06-3

Basic information

• Product Name: Calcitriol
• Synonyms: VITAMIN D3, 1ALPHA,25-DIHYDROXY;(5z,7e)-(1s,3r)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol;9,10-SECOCHOLESTA-5Z,7E,10(19)-TRIENE-1ALPHA,3BETA,25-TRIOL;1,25-(OH)2-D3;(1ALPHA,3BETA,5Z,7E)-9,10-SECOCHOLESTA-5,7,10(19)-TRIENE-1,3,25-TRIOL;1ALPHA,25-DIHYDROXYCHOLECALCIFEROL;1ALPHA,25-DIHYDROXYVITAMIN D3;1ALPHA,25-DIHYDROXY-VITAMIN D8
• CAS NO: 32222-06-3
• Molecular Formula: C27H44O3
• Molecular Weight: 416.64
• EINECS: 250-963-8
• Product Categories: Miscellaneous Biochemicals;Vitamin D3 analogs;API;Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Isolabel;reagent;standard substance;Inhibitors
• Mol File: 32222-06-3.mol
• Article Data: 56

Chemical Properties

• Melting Point: 119-1210C
• Boiling Point: 474.91°C (rough estimate)
• Flash Point: 14 °C
• Appearance: white crystalline powder
• Density: 1.0362 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.4700 (estimate)
• Storage Temp.: 2-8°C
• Solubility: Do you have solubility information on this product that you woul
• PKA: 14.43±0.40(Predicted)
• Stability: Air and Light Sensitive
• Merck: 14,1644
• BRN: 7559394
• CAS DataBase Reference: Calcitriol(CAS DataBase Reference)
• NIST Chemistry Reference: Calcitriol(32222-06-3)
• EPA Substance Registry System: Calcitriol(32222-06-3)

Safety Data

• Hazard Codes: T+,Xn,F
• Statements: 26/27/28-63-36/37/38-20/21/22-11
• Safety Statements: 36/37/39-45-36-26-16-7
• RIDADR: UN 2811 6.1/PG 1
• WGK Germany: 3
• RTECS: FZ4645000
• F: 8-10-19
• HazardClass: 6.1(a)
• PackingGroup: I
• Hazardous Substances Data: 32222-06-3(Hazardous Substances Data)

Usage

Introduction

Calcitriol (1,25-dihydroxylcholecaldiferol) is a steroid hormone with three hydroxyl groups, which is an active metabolite and the most effective form of vitamin D. It is produced primarily in the kidney when the blood calcium level and parathyroid hormone are low. Calcitriol promotes the calcium and phosphorus absorption in the intestine, reabsorption in the kidneys. Along with parathyroid hormone, it regulates bone growth for building and keeping strong bones. Calcitriol is used to treat and prevent low levels of calcium and bone disease in patients whose kidneys or parathyroid glands are not working normally, to treat secondary hyperparathyroidism and metabolic bone disease in people with kidney disease. Calcitriol may also be chemopreventive for colon and prostate cancers as it induces cell cycle arrest, cell differentiation, and apoptosis.

References

https://pubchem.ncbi.nlm.nih.gov https://medlineplus.gov http://flexikon.doccheck.com/en/Calcitriol https://en.wikipedia.org/wiki/Calcitriol https://www.webmd.com

Description

Different sources of media describe the Description of 32222-06-3 differently. You can refer to the following data:
1. Calcitriol is the active form of vitamin D and is also a kind of hormones in the body. It plays an important role in the regulation of calcium and phosphorus concentration. It can increase the blood calcium level by increasing the intestinal absorption of calcium and can also increase the release of the bone calcium release for increasing the blood calcium levels. This study was first conducted and reported by Michael F. Holick in 1971. The basic principle of action model of calcitriol in many cases is through binding with the vitamin D receptor (the VDR), e.g., the ligand-receptor complex forming between calcitriol and its receptor in the intestinal epithelial cells cytoplasm can be transferred to the nucleus for being as the transcriptional factor in promoting the expression of calcium-binding protein. The increased level of calcium-binding proteins can help the cell to actively transport of more calcium ions, thereby increasing the calcium absorption level. Calcium absorption while maintaining electrical neutrality also requires transporting anions, mainly the absorption of inorganic phosphate ions, so calcitriol also promote the absorption of phosphorus. Clinically, this drug can be used in the treatment of hypocalcemia, hypoparathyroidism (adult), osteomalacia, rickets (infants), chronic kidney disease, renal osteodystrophy, osteoporosis, as well as the prevention of glucocorticoid induced osteoporosis. Calcitriol-dimensional molecular structure The above information is edited by the lookchem of Dai Xiongfeng.
2. Calcitriol is synthesized from 7-dehydro cholesterol in humans via a non-enzymatic photochemical reaction with 290-310 nm UV light in the skin. Hydroxylation of the resulting cholecalciferol in the liver produces 25-hydroxy vitamin D3, the principal circulating form of vitamin D. A second, tightly regulated hydroxylation in the kidney produces calcitriol. Plasma calcitriol levels range from 10-70 pg/ml and are influenced by numerous dietary and hormonal factors. The main physiologic effects of calcitriol are to increase the absorption of calcium at the level of the intestinal epithelium, and to increase the mineralization of bone via the direct stimulation of osteoblasts.

Chemical Properties

White Crystalline Powder

Originator

Rocaltrol,Roche,US,1978

Uses

Different sources of media describe the Uses of 32222-06-3 differently. You can refer to the following data:
1. The biologically active form of vitamin D3. Calcium regulator; vitamin (antirachitic); antihyperparathyroid; antineoplastic; antipsoriatic
2. Calcitriol (1α,25-dihydroxy Vitamin D3) is synthesized from 7-dehydrocholesterol in humans via a non-enzymatic photochemical reaction with 290-310 nm UV light in the skin. Hydroxylation of the resulting cholecalciferol in the liver produces 25-hydroxy Vitamin D3, the principal circulating form of Vitamin D. A second, tightly regulated hydroxylation in the kidney produces calcitriol. Plasma calcitriol levels range from 10-70 pg/ml and are influenced by numerous dietary and hormonal factors. The main physiologic effects of calcitriol are to increase the absorption of calcium at the level of the intestinal epithelium, and to increase the mineralization of bone via the direct stimulation of osteoblasts.[Cayman Chemical]
3. Calcium regulator, anti-psoriatic
4. Vitamin medicines; it can be used for treating the renal bone malnutrition of patients with chronic renal failure;

Definition

ChEBI: A hydroxycalciol that is calcidiol in which the pro-S hydrogen of calcidiol is replaced by a hydroxy group. It is the active form of vitamin D3, produced fom calciol via hydoxylation in the li er to form calcidiol, which is subsequently oxidised in the kidney to give calcitriol.

Manufacturing Process

1α,25-Dihydroxyprecholecalciferol: A solution of 1α,25- diacetoxyprecholecalciferol (0.712 g, 1.42 mmols), potassium hydroxide (2.0 g, 35.6 mmols) and methanol (40 ml) was stirred at room temperature under argon for 30 hours. The reaction mixture was concentrated under reduced pressure. Water (50 ml) was added to the residue and the mixture was extracted with methylene chloride (3 x 100 ml). The combined organic extracts were washed with saturated sodium chloride solution (3 x 50 ml), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 0.619 g of 1alpha,25-dihydroxyprecholecalciferol as a thick oil.1α,25-Dihydroxycholecalciferol: A solution of 1α,25-dihydroxyprecholecalciferol [0.619 g in dioxane (30 ml)] was heated under reflux for 30 minutes under an atmosphere of argon. The reaction mixture was concentrated under reduced pressure and the residue was purified with a Waters Associates liquid chromatograph model 202 using a 8 foot * 3/8 inch Porasil A column and a 5:1 mixture of ethyl acetate-n-hexane as the eluent to give 0.474 g (80% yield based on 1α,25-diacetoxyprecholecalciferol) of pure 1α,25- dihydroxycholecalciferol. Recrystallization from methyl formate afforded 0.340 g of 1α,25-dihydroxcholecalciferol as colorless crystals, MP 113°-114°C.

Brand name

Calcijex (Abbott); Rocaltrol (Roche.

Therapeutic Function

Calcium regulator

General Description

1α,25-Dihydroxyvitamin D3, also referred as calcitriol, is a calcitrophic hormone. It is the most biologically active metabolite of vitamin D produced in proximal tubular cells in the kidney.

Biological Activity

Active metabolite of vitamin D 3 that activates the vitamin D receptor (VDR). Displays calcemic actions; stimulates intestinal and renal Ca 2+ absorption and regulates bone Ca 2+ turnover. Exhibits antitumor activity; inhibits in vivo and in vitro cell proliferation in a wide range of cells including breast, prostate, colon, skin and brain carcinomas and myeloid leukemia cells.

Biochem/physiol Actions

Biologically active form of vitamin D3 in calcium absorption and deposition. 1α,25-Dihydroxyvitamin D3 has widespread effects on cellular differentiation and proliferation, and can modulate immune responsiveness, and central nervous system function. Recent studies suggest that 1α,25-dihydroxyvitamin D3 acts as a chemopreventive agent against several malignancies including cancers of the prostate and colon and shows synergy with other anticancer compounds.

Clinical Use

Vitamin D analogue: Promotes intestinal calcium absorption Suppresses PTH production and release

Veterinary Drugs and Treatments

Calcitriol may be potentially beneficial in the adjunctive treatment of chronic renal disease in dogs and cats but its use is somewhat controversial, particularly the decision on how soon in the course of chronic renal insufficiency it should employed. It may also be of benefit in treating some types of dermatopathies (primary idiopathic seborrhea).

Drug interactions

Potentially hazardous interactions with other drugs Antiepileptics: the effects of vitamin D may be reduced in patients taking barbiturates or anticonvulsants. Diuretics: increased risk of hypercalcaemia with thiazides. Sevelamer: absorption may be impaired by sevelamer

Metabolism

During transport in the blood at physiological concentrations, calcitriol is mostly bound to a specific vitamin D binding protein (DBP), but also, to a lesser degree, to lipoproteins and albumin. At higher blood calcitriol concentrations, DBP appears to become saturated, and increased binding to lipoproteins and albumin occurs. Calcitriol is inactivated in both the kidney and the intestine, through the formation of a number of intermediates including the formation of the 1,24,25-trihydroxy derivatives. It is excreted in the bile and faeces and is subject to enterohepatic circulation.

InChI:InChI=1/C27H44O3/c1-18(8-6-14-26(3,4)30)23-12-13-24-20(9-7-15-27(23,24)5)10-11-21-16-22(28)17-25(29)19(21)2/h10-11,18,22-25,28-30H,2,6-9,12-17H2,1,3-5H3/b20-10+,21-11-/t18-,22-,23-,24?,25+,27-/m1/s1

Synthetic route

[2H]-Pre-1,25-D3 (57102-09-7) → calcitriol (32222-06-3)

Conditions	Yield
at 80℃;	100%
In acetone at 80.3℃; for 3h;	26 mg
at 70℃; for 2h;
In hexane; ethyl acetate at 65℃;	182 mg
In acetone at 80.3℃; Rate constant; Equilibrium constant; Thermodynamic data; var. temp.; kinetics, E(a), ΔG(excit.), ΔH(excit.), ΔS(excit.);

C30H52O3Si → calcitriol (32222-06-3)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere;	100%

(1R,3aS,7aR)-1-((R)-5-Methoxymethoxy-1,5-dimethyl-hexyl)-7a-methyl-4-[2-[(3S,5R)-2-methylene-3,5-bis-triisopropylsilanyloxy-cyclohex-(Z)-ylidene]-eth-(E)-ylidene]-octahydro-indene (873567-12-5) → calcitriol (32222-06-3)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 2h;	95%

C45H86O3Si3 → 2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3 + 1α,25-dihydroxy-2-methylene-19-nor-vitamin D3 + calcitriol (32222-06-3)

Conditions	Yield
With AG 50W-X4 resin In methanol; benzene at 20℃; for 19h;	A 95% B n/a C n/a

C51H98O3Si3 → calcitriol (32222-06-3)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 24h;	81%

1α-[(triethylsilyl)oxy]-24-(tert-butoxycarbonyl)-25,26,27-trisnorvitamin D3 triethylsilyl ether → calcitriol (32222-06-3)

Conditions	Yield
Stage #1: 1α-[(triethylsilyl)oxy]-24-(tert-butoxycarbonyl)-25,26,27-trisnorvitamin D3 triethylsilyl ether With methyllithium In diethyl ether at 0℃; for 0.5h; Stage #2: With tetrabutyl ammonium fluoride In tetrahydrofuran for 0.75h; Darkness;	81%

methyllithium (917-54-4) + 1α-Hydroxy-25-oxo-27-norvitamin D3 (77531-53-4) → calcitriol (32222-06-3)

Conditions	Yield
In diethyl ether at -78℃; for 0.333333h;	80%

(1S),3(R)-9,10-secocholesta-5(E),7(E),10(19)-triene-1,3,25-triol (73837-24-8) → calcitriol (32222-06-3)

Conditions	Yield
With 9-acetylanthracene In ethanol Inert atmosphere; UV-irradiation; Cooling with ice;	78%
With 9-acetylanthracene In methanol at 0℃; for 2h; Irradiation;	66%

(1S),3(R)-bis<(tert-butyldimethylsilyl)oxy>-9,10-secocholesta-5(Z),7(E),10(19)-trien-25-ol (140710-96-9) → calcitriol (32222-06-3)

Conditions	Yield
With n-BuNF In tetrahydrofuran at 45℃; for 4h;	71%
With tetrabutyl ammonium fluoride In tetrahydrofuran for 24h; Ambient temperature; in the dark; Yield given;
With camphor-10-sulfonic acid In methanol at 20℃; for 12h; desilylation;

(1R,3R)-5-{(Z)-2-[(1R,3aR,7aR)-1-((R)-5-Hydroxy-1,5-dimethyl-hexyl)-7a-methyl-2,3,3a,6,7,7a-hexahydro-1H-inden-4-yl]-vinyl}-4-methyl-cyclohex-4-ene-1,3-diol → calcitriol (32222-06-3)

Conditions	Yield
In acetone at 80℃; for 4h;	70%

7,8-cis-1α,25-dihydroxyvitamin D3 (157809-60-4) → calcitriol (32222-06-3)

Conditions	Yield
With 9-acetylanthracene In d(4)-methanol for 1.5h; Irradiation;	67%

(1R,3aR,7aR)-4-{(E)-2-[(1S,3S,5S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-methylene-bicyclo[3.1.0]hex-1-yl]-vinyl}-1-((R)-5-hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ol (135446-94-5) → calcitriol (32222-06-3)

Conditions	Yield
With toluene-4-sulfonic acid In 1,4-dioxane; water	64%

(R)-1-[(1S,3S,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohexyl]-2-[(1R,3aS,7aR)-1-[(R)-5-(tert-butyl-dimethyl-silanyloxy)-1,5-dimethyl-hexyl]-7a-methyl-octahydro-inden-(4E)-ylidene]-ethanol (130759-99-8) → calcitriol (32222-06-3) + (1R,3S,5R)-5-{(E)-2-[(1R,7aR)-1-((R)-5-Hydroxy-1,5-dimethyl-hexyl)-7a-methyl-2,3,5,6,7,7a-hexahydro-1H-inden-4-yl]-vinyl}-4-methylene-cyclohexane-1,3-diol (130760-01-9)

Conditions	Yield
With hydrogen fluoride; silica gel; copper(II) sulfate 1) C6H6, 50 deg C, 1.5h, 2) MeOH, THF, r.t., 5h; Yield given. Multistep reaction;	A n/a B 57%
With hydrogen fluoride; silica gel; copper(II) sulfate 1) C6H6, 50 deg C, 1.5h, 2) MeOH, THF, r.t., 5h; Yield given. Multistep reaction;	A 33% B n/a

(1S,6R)-1-hydroxy-6-(1,3-benzodithiol-2-yloxy)-25-tetrahydropyranyloxy-3,5-cyclovitamin D3 (161003-71-0) → calcitriol (32222-06-3)

Conditions	Yield
With phosphomolybdic acid hydrate In 1,4-dioxane; water at 30℃; for 3h;	30%

1α,3β,25-trihydroxycholesta-5,7-diene (61954-91-4) → calcitriol (32222-06-3)

Conditions	Yield
Stage #1: 1α,3β,25-trihydroxycholesta-5,7-diene In 1,4-dioxane High-pressure mercury lamp; Stage #2: at 100℃; Photomicroreactor; thermalmicroreactor;	8%
(i) EtOH, (UV-irradiation), (ii) (heating); Multistep reaction;
Multi-step reaction with 2 steps 1: tBuOMe / 0.92 h / -45 °C / Irradiation 2: 182 mg / ethyl acetate; hexane / 65 °C View Scheme
Multi-step reaction with 3 steps 1: 6 mg / tBuOMe / 0.92 h / -45 °C / Irradiation 2: 25 mg / tBuOMe, fluorenone / -5 °C / Irradiation 3: 182 mg / ethyl acetate; hexane / 65 °C View Scheme

(1R,3aR,7aR)-1-{(1R)-1,5-dimethyl-5-[(trimethylsilyl)oxy]hexyl}-7a-methyloctahydro-4H-inden-4-one (81506-41-4) + [(2Z)-2-[(3S,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide (81522-68-1) → calcitriol (32222-06-3)

Conditions	Yield
With n-butyllithium 1.) THF, n-hexane, -78 deg C, 5 min, 2.) THF, n-hexane, -78 deg C, 2 h; Yield given. Multistep reaction;

<1R-<1α(R*),3aβ,4α<(E)-(1S*,3S*,5R*)>,7aα>>-octahydro-4-hydroxy-4-<2-(3-hydroxy-2-methylenebicyclo<3.1.0>hexan-1-yl)ethenyl>-α,α,ε-tetramethyl-1H-indene-pentanol (135041-06-4) → calcitriol (32222-06-3)

Conditions	Yield
With toluene-4-sulfonic acid 1.) dioxan, water; 2.) t-butylmethyl ether, irradiation; Yield given. Multistep reaction;
With tert-butyl methyl ether; 9-acetoxyanthracene; toluene-4-sulfonic acid 1.) dioxane, H2O, 75 deg C, 4 h, 2.) irradiation, 1 h; Yield given. Multistep reaction;

anti-3-(tertbutyldimethylsiloxy)-5-(tert-butyldiphenylsiloxy)-1-octen-7-yne (138924-21-7) + (E)-(20R)-de-A,B-8-(bromomethylene)cholestan-25-ol (143705-63-9) → calcitriol (32222-06-3)

Conditions	Yield
With tris(dibenzylideneacetone)dipalladium(0) chloroform complex; tetrabutyl ammonium fluoride; thiamine diphosphate; triethylamine 1.) toluene, reflux, 2 h, 2.) THF, RT, 30 h; Yield given. Multistep reaction;

(3bR,5aR,6R,8aR,10S)-10-((3S,5R)-3,5-Dihydroxy-2-methyl-cyclohex-1-enyl)-6-((R)-5-hydroxy-1,5-dimethyl-hexyl)-5a-methyl-2-phenyl-4,5,5a,6,7,8,8a,10-octahydro-3bH-2,3a,10a-triaza-dicyclopenta[a,f]naphthalene-1,3-dione (86307-44-0) → calcitriol (32222-06-3) + [2H]-Pre-1,25-D3 (57102-09-7)

Conditions	Yield
With potassium hydroxide In methanol; water at 85℃; for 70h;	A 51 mg B 9 mg

(3-bromo-1,1-dimethylpropoxy)triethylsilane (87417-12-7) + 1α,3β-bis<(triethylsilyl)oxy>-20(S)-<<(p-tolylsulfonyl)oxy>methyl>-9,10-secopregna-5(Z),7(E),10(19)-triene (87417-31-0) → calcitriol (32222-06-3)

Conditions	Yield
With copper(l) iodide; tetrabutyl ammonium fluoride; magnesium Yield given. Multistep reaction;

3β-tert-butyldimethylsilyl-1α-tert-butyldimethylsilyloxy-25-trimethylsilyloxy-19-norvitamin D3 (599165-21-6) → calcitriol (32222-06-3)

Conditions	Yield
With tetrabutyl ammonium fluoride In tetrahydrofuran at 25℃; Yield given;
With tetrabutyl ammonium fluoride In tetrahydrofuran
With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 24h;	68.3 mg

1-Oxo-25-hydroxyprevitamin D3 (66760-28-9) → calcitriol (32222-06-3) + [2H]-Pre-1,25-D3 (57102-09-7)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In tetrahydrofuran for 2h; Ambient temperature;	A 2.4 mg B 11.4 mg

((5Z,7E,1S,3R)-1,25-Dihydroxy-9,10-seco-5,7,10(19)-cholestatrien-3-yl)-β-D-glucopyranosid → calcitriol (32222-06-3)

Conditions	Yield
With β-glucosidase In water for 24h; Ambient temperature; formation of aglycone;

2-{(1S,5R)-5-(tert-Butyl-dimethyl-silanyloxy)-3-[2-[(1R,3aS,7aR)-1-((R)-1,5-dimethyl-5-trimethylsilanyloxy-hexyl)-7a-methyl-octahydro-inden-(4E)-ylidene]-eth-(Z)-ylidene]-2-methylene-cyclohexyloxy}-tetrahydro-pyran → calcitriol (32222-06-3)

Conditions	Yield
With camphor-10-sulfonic acid In methanol; water at 30℃; for 6h;

vitamin D3 (67-97-0) → 2alpha,25-Dihydroxyvitamin D3 + calcitriol (32222-06-3) + calcidiol (19356-17-3)

Conditions	Yield
With Pseudonocardia autotrophica 100U-19 cells In ethanol at 30℃; for 72h;	A 35 mg B n/a C n/a

de-A,B-25-[(methoxymethyl)oxy]-cholestan-8-one (873567-08-9) → calcitriol (32222-06-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: t-BuLi / diethyl ether; pentane / 0.5 h / -78 °C 1.2: ZnBr2 / tetrahydrofuran; diethyl ether; pentane / -78 - -10 °C 1.3: 75 percent / Et3N / (Ph3P)4Pd / tetrahydrofuran; diethyl ether; pentane / -40 - 20 °C 2.1: 95 percent / n-Bu4NF / tetrahydrofuran / 2 h / 20 °C View Scheme

Grundmann's alcohol (33813-99-9) → calcitriol (32222-06-3)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: 95 percent / (trifluoromethyl)methyldioxirane / CH2Cl2 / 2 h / -20 °C 2.1: 96 percent / i-Pr2NEt; DMAP / CH2Cl2 / 24 h / 20 °C 3.1: HMDS / tetrahydrofuran / 2 h / -60 °C 3.2: 60 percent / tetrahydrofuran / 17 h / -60 - -5 °C 4.1: t-BuLi / diethyl ether; pentane / 0.5 h / -78 °C 4.2: ZnBr2 / tetrahydrofuran; diethyl ether; pentane / -78 - -10 °C 4.3: 75 percent / Et3N / (Ph3P)4Pd / tetrahydrofuran; diethyl ether; pentane / -40 - 20 °C 5.1: 95 percent / n-Bu4NF / tetrahydrofuran / 2 h / 20 °C View Scheme

(1R,3aR,7aR)-1-[(2R)-6-hydroxy-6-methylhept-2-yl]-7a-methyloctahydroinden-4-one (70550-73-1) → calcitriol (32222-06-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: 96 percent / i-Pr2NEt; DMAP / CH2Cl2 / 24 h / 20 °C 2.1: HMDS / tetrahydrofuran / 2 h / -60 °C 2.2: 60 percent / tetrahydrofuran / 17 h / -60 - -5 °C 3.1: t-BuLi / diethyl ether; pentane / 0.5 h / -78 °C 3.2: ZnBr2 / tetrahydrofuran; diethyl ether; pentane / -78 - -10 °C 3.3: 75 percent / Et3N / (Ph3P)4Pd / tetrahydrofuran; diethyl ether; pentane / -40 - 20 °C 4.1: 95 percent / n-Bu4NF / tetrahydrofuran / 2 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: 1.) sodium hexamethyldisilazide / 1.) THF, -60 deg C, 1 h, 2.) THF, RT, 30 min 2: 1.) (dba)3Pd2*CHCl3, TPP, Et3N, 2.) TBAF / 1.) toluene, reflux, 2 h, 2.) THF, RT, 30 h View Scheme
Multi-step reaction with 2 steps 1: 98 percent / CH2Cl2 / 18 h / Ambient temperature 2: 1.) n-BuLi / 1.) THF, n-hexane, -78 deg C, 5 min, 2.) THF, n-hexane, -78 deg C, 2 h View Scheme
Multi-step reaction with 3 steps 1: 98 percent / tetrahydrofuran / 25 °C 2: tetrahydrofuran / 1 h / -78 °C 3: (Bu)4NF / tetrahydrofuran / 25 °C View Scheme

(1R,6R,7R)-7-[(R)-6-(methoxymethoxy)-6-methylheptan-2-yl]-6-methylbicyclo[4.3.0]nonan-2-one (139619-80-0) → calcitriol (32222-06-3)

Conditions

Yield

Multi-step reaction with 3 steps 1.1: HMDS / tetrahydrofuran / 2 h / -60 °C 1.2: 60 percent / tetrahydrofuran / 17 h / -60 - -5 °C 2.1: t-BuLi / diethyl ether; pentane / 0.5 h / -78 °C 2.2: ZnBr2 / tetrahydrofuran; diethyl ether; pentane / -78 - -10 °C 2.3: 75 percent / Et3N / (Ph3P)4Pd / tetrahydrofuran; diethyl ether; pentane / -40 - 20 °C 3.1: 95 percent / n-Bu4NF / tetrahydrofuran / 2 h / 20 °C View Scheme

calcitriol (32222-06-3) + 4-<2-(6,7-dimethoxy-4-methyl-3-oxo-3,4-dihydroquinoxalyl)ethyl>-1,2,4-triazoline-3,5-dione (132788-52-4) → C42H59N5O8 (132788-59-1)

Conditions	Yield
In dichloromethane Ambient temperature;	100%

calcitriol (32222-06-3) + 6,7-Dimethoxy-4-methyl-3-oxo-3,4-dihydro-quinoxaline-2-carboxylic acid 4-(3,5-dioxo-3,5-dihydro-[1,2,4]triazol-4-yl)-benzyl ester (132788-51-3) → C48H61N5O10 (132788-58-0)

Conditions	Yield
Ambient temperature;	100%

calcitriol (32222-06-3) → 1-Oxo-25-hydroxyprevitamin D3 (66760-28-9)

Conditions	Yield
With Dess-Martin periodane In acetonitrile for 2h; Ambient temperature;	88%

calcitriol (32222-06-3) + tert-butyldimethylsilyl chloride (18162-48-6) → (1S),3(R)-bis<(tert-butyldimethylsilyl)oxy>-9,10-secocholesta-5(Z),7(E),10(19)-trien-25-ol (140710-96-9)

Conditions	Yield
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h;	80%

calcitriol (32222-06-3) + N-(benzo-15-crown-5)-1,2,4-triazole-3,5-dione → C43H63N3O10

Conditions	Yield
In ethyl acetate at 25℃;	45%

calcitriol (32222-06-3) → [2H]-Pre-1,25-D3 (57102-09-7)

Conditions	Yield
In acetone at 80.3℃; Equilibrium constant; var. temp.;
In benzene-d6 at 80℃; Rate constant;
Multi-step reaction with 2 steps 1: 88 percent / Dess-Martin reagent / acetonitrile / 2 h / Ambient temperature 2: 11.4 mg / sodium triacetoxyborohydride, AcOH / tetrahydrofuran / 2 h / Ambient temperature View Scheme

calcitriol (32222-06-3) → (4S,6R)-1-[(1R,3aS,7aR)-1-((R)-5-Hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-(4E)-ylidenemethyl]-2,2-dioxo-2,3,4,5,6,7-hexahydro-1H-2λ6-benzo[c]thiophene-4,6-diol (140710-95-8)

Conditions	Yield
With sulfur dioxide for 1h; Heating;
With sulfur dioxide In dichloromethane at -15℃; for 3h; Yield given;

calcitriol (32222-06-3) → 1α,25-dihydroxy-6,19-dihydro-6,19-epidioxyvitamin D3

Conditions	Yield
With oxygen; rose bengal In ethanol for 1.5h; Irradiation; Yield given;

Upstream product

• 130759-99-8 (R)-1-[(1S,3S,5R)-3,5-Bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohexyl]-2-[(1R,3aS,7aR)-1-[(R)-5-(tert-butyl-dimethyl-silanyloxy)-1,5-dimethyl-hexyl]-7a-methyl-octahydro-inden-(4E)-ylidene]-ethanol 
• 140710-96-9 (1S),3(R)-bis<(tert-butyldimethylsilyl)oxy>-9,10-secocholesta-5(Z),7(E),10(19)-trien-25-ol 
• 599165-21-6 3β-tert-butyldimethylsilyl-1α-tert-butyldimethylsilyloxy-25-trimethylsilyloxy-19-norvitamin D₃ 
• 126772-11-0 22-phenyl-sulfonyl-9,10-secocholesta-5,7,10(19)-triene-1α,3β,25-triol 
• 19356-17-3 calcidiol 
• 41294-56-8 1α-hydroxyvitamin D3 
• 126771-82-2 C₃₃H₄₄O₉S 
• 133856-07-2 1α,3β-dihydroxy-22-tosyloxy-23,24-bisnorchola-5,7-diene 
• 1384584-77-3 1α,3β-dihydroxy-25-trimethylsilyloxycholesta-5,7-diene 
• 81522-68-1 [(2Z)-2-[(3S,5R)-3,5-bis(tert-butyldimethylsilanyloxy)-2-methylenecyclohexylidene]ethyl]diphenylphosphine oxide 
• 53702-06-0 (1S,3aS,4S,7aS)-1-tert-Butoxy-7a-methyl-5-oxo-octahydro-indene-4-carboxylic acid 
• 132713-39-4 (1R,3aR,4R,7aR)-1-((R)-5-Hydroxy-1,5-dimethyl-hexyl)-7a-methyl-octahydro-inden-4-ol 
• 31944-51-1 (1S-cis)-(1,1-dimethylethoxy)-2,3,5,6,7,7a-hexahydro-7a-methyl-5-oxo-1H-indene-4-carboxylic acid 
• 87407-67-8 1α-hydroxy-3β-<(triethylsilyl)oxy>-20(S)-<<(p-tolylsulfonyl)oxy>methyl>-9,10-secopregna-5(E),7(E),10(19)-triene 

Downstream Products

• 73837-24-8 (1S),3(R)-9,10-secocholesta-5(E),7(E),10⁽¹⁹⁾-triene-1,3,25-triol 
• 81203-50-1 (3R,5S)-5-((R)-2-((1R,3αS,7αR,E)-4-((Z)-2-((3S,5R)-3,5-dihydroxy-2-methylenecyclohexylidene)ethylidene)-7α-methyloctahydro-1H-inden-1-yl)propyl)-3-hydroxy-3-methyldihydrofuran-2(3H)-one 
• 97903-37-2 24,25,26,27-tetranor-1,23-(OH)2D₃ 
• 76338-50-6 1α,25-dihydroxy-24-oxo-vitamin D3 
• 50648-94-7 (1alpha,24R,25)-trihydroxy-Vitamin D₃ 
• 128723-16-0 C₂₇H₄₁⁽²⁾H₃O₃ 
• 140710-96-9 (1S),3(R)-bis<(tert-butyldimethylsilyl)oxy>-9,10-secocholesta-5(Z),7(E),10(19)-trien-25-ol 
• 66760-28-9 1-Oxo-25-hydroxyprevitamin D₃ 
• 57102-09-7 [2H]-Pre-1,25-D₃ 

Relevant articles and documents

Synthesis of β-D-glucopyranosides of some hydroxylated vitamin-D compounds

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Preparation method of 25-hydroxyvitamin D3, 1alpha, 25-dihydroxyvitamin D3 and isotope internal standard compound thereof

The invention discloses a preparation method of 25-hydroxyvitamin D3 and 1alpha, 25-dihydroxyvitamin D3 and an isotope internal standard compound thereof. The preparation method comprises the following steps: a compound III is subjected to SO2 conjugate protection, O3 oxidation, NaBH4 reduction, iodination ring opening, conjugate addition with acrylate, and reaction with a methyl Grignard reagentor isotope labeled methyl Grignard reagent, a silicon protecting group is removed under the action of TBAF, and a product is obtained through ultraviolet irradiation configuration inversion under thecatalysis of 9-acetyl anthracene. The method is good in reaction selectivity, high in total yield, simple and convenient to operate and short in isotope introduction step, and the isotope utilizationrate is greatly increased.

Hydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and Mouse CYP27B1

CYP11A1 can hydroxylate vitamin D3 at carbons 17, 20, 22, and 23, producing a range of secosteroids which are biologically active with respect to their ability to inhibit proliferation and stimulate differentiation of various cell types, including cancer cells. As 1a-hydroxylation of the primary metabolite of CYP11A1 action, 20S-hydroxyvitamin D3 [20(OH)D3], greatly influences its properties, we examined the ability of both human and mouse CYP27B1 to 1a-hydroxylate six secosteroids generated by CYP11A1. Based on their kcat/Km values, all CYP11A1-derived metabolites are poor substrates for CYP27B1 from both species compared with 25-hydroxyvitamin D3. No hydroxylation of metabolites with a 17a-hydroxyl group was observed. 17a,20-Dihydroxyvitamin D3 acted as an inhibitor on human CYP27B1 but not the mouse enzyme. We also tested CYP27B1 activity on 20,24-, 20,25-, and 20,26-dihydroxyvitamin D3, which are products of CYP24A1 or CYP27A1 activity on 20(OH)D3. All three compounds were metabolized with higher catalytic efficiency (kcat/Km) by both mouse and human CYP27B1 than 25-hydroxyvitamin D3. CYP27B1 action on these new dihydroxy derivatives was confirmed to be 1ahydroxylation by mass spectrometry and nuclear magnetic resonance analyses. Both 1,20,25- and 1,20,26- trihydroxyvitamin D3 were tested for their ability to inhibit melanoma (SKMEL-188) colony formation, and were significantly more active than 20(OH)D3. This study shows that CYP11A1-derived secosteroids are 1ahydroxylated by both human and mouse CYP27B1 with low catalytic efficiency, and that the presence of a 17a-hydroxyl group completely blocks 1a-hydroxylation. In contrast, the secondary metabolites produced by subsequent hydroxylation of 20(OH)D3 at C24, C25, or C26 are very good substrates for CYP27B1.