DE4336429C1 - Process for the preparation of intermediates in vitamin D or vitamin D derivative syntheses - Google Patents

Process for the preparation of intermediates in vitamin D or vitamin D derivative syntheses

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DE4336429C1
DE4336429C1 DE19934336429 DE4336429A DE4336429C1 DE 4336429 C1 DE4336429 C1 DE 4336429C1 DE 19934336429 DE19934336429 DE 19934336429 DE 4336429 A DE4336429 A DE 4336429A DE 4336429 C1 DE4336429 C1 DE 4336429C1
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general formula
vitamin
intermediates
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nickel
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Andreas Dr Steinmeyer
Dirk Prof Dr Walter
Reinald Dr Fischer
Bruno Dr Sc Nat Schoenecker
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/62—Unsaturated compounds containing ether groups, groups, groups, or groups containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation

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Abstract

The invention relates to processes for the preparation of intermediates of the general formula I, which are very suitable for preparing vitamin D or vitamin D derivatives. The process comprises the substitution of an aliphatic iodide (general formula II) by an optionally substituted C3 or C4 building block. This building block (synthon) is an organonickel compound of the general formula III. <IMAGE>

Description

Die Erfindung betrifft Verfahren zur Herstellung von Zwischenprodukten innerhalb der Vitamin D- oder Vitamin D-Derivat-Synthesen.The invention relates to processes for the production of intermediates within the Vitamin D or vitamin D derivative syntheses.

Innerhalb des Standes der Technik werden Zwischenstufen für die Vitamin-D- Synthese bereits beschrieben, so in EP 0 078 704 B1, EP 227 826 B1 und US-PS 4 847 012. Es werden mehrere verschiedene Synthesewege aufgezeigt.Intermediate stages for the vitamin D Synthesis already described, so in EP 0 078 704 B1, EP 227 826 B1 and US-PS 4,847,012. Several different synthetic routes are shown.

Es wurde nun gefunden, daß Verbindungen der allgemeinen Formel IIt has now been found that compounds of the general formula I

worinwherein

R¹, R² Wasserstoff oder eine Schutzgruppe,
R³, R⁴ und R⁵ Wasserstoff oder eine niedrige Alkylgruppe und
n = 0 oder 1R¹, R² are hydrogen or a protective group,
R³, R⁴ and R⁵ are hydrogen or a lower alkyl group and
n = 0 or 1

bedeuten, leicht und in hoher Ausbeute hergestellt werden können.mean can be produced easily and in high yield.

Setzt man die gut zugänglichen Verbindungen der allgemeinen Formel IIIf you put the easily accessible compounds of general formula II

worin R¹ und R² die o. g. Bedeutung besitzen, mit Nickelalactonen der allgemeinen Formel IIIwherein R¹ and R² are the above. Have meaning  with nickel alactones of the general formula III

worin n, R³ und R⁴ die o. g. Bedeutung besitzen und (bipy) für 2 Pycidinringe steht, um, so erhält man die trans Vitamin D-Derivate der allgemeinen Formel I.where n, R³ and R⁴ the above. Have meaning and (bipy) for 2 pycidin rings, um, so the trans vitamin D derivatives of the general formula I are obtained

Die Umsetzungen von quasi aliphatischen Jodverbindungen mit Nickelalactonen sind aus der Steroid-Chemie bekannt. Innerhalb von J. Organo Met. Chem. 427 (1992), 395, wird die Seitenkettenverlängerung einer Jodverbindung mit einem nickelorganischen Propionsäurederivat beschrieben. Die Synthesen der entsprechenden homologen nickelorganischen Butyroverbindungen sind in DE 41 05 503 A1 und Tetrahedron letters 31, 1257 (1990), publiziert.The reactions of quasi aliphatic iodine compounds with nickel alactones are known from steroid chemistry. Within J. Organo Met. Chem. 427 (1992), 395, the side chain extension of an iodine compound with a described nickel-organic propionic acid derivative. The syntheses of the corresponding homologous nickel organic butyro compounds are in DE 41 05 503 A1 and Tetrahedron letters 31, 1257 (1990).

Es wurde nun gefunden, daß diese nickelorganischen Verbindungen oder Nickelalactone der allgemeinen Formel III sich als Synthesebausteine innerhalb der Herstellung von Vitamin-D-Derivaten sehr gut einsetzen lassen.It has now been found that these organo-nickel compounds or Nickel alactones of the general formula III as synthesis building blocks within the Have the production of vitamin D derivatives used very well.

Bei der Reaktion der jodhaltigen Verbindungen gemäß der allgemeinen Formel II, enthaltend ein trans-Triensystem, mit den Nickelalactonen der allgemeinen Formel III lassen sich die Verbindungen der allgemeinen Formel I sehr gut darstellen. Überraschenderweise bleibt das Triensystem in seiner Konfiguration während der Reaktion fast vollständig erhalten, als Nebenprodukt dieser Reaktion wird nur wenig cis-Trienverbindung gefunden.In the reaction of the iodine-containing compounds according to the general formula II, containing a trans-triene system with the nickel alactones of the general formula III the compounds of general formula I can be prepared very well. Surprisingly, the trien system remains in its configuration during the Almost completely preserved reaction, as a by-product of this reaction is little cis-triene compound found.

Bei der Umsetzung ist es jedoch erforderlich, die Hydroxylgruppen in den Positionen 1 und 3 mit Schutzgruppen zu versehen. Als geeignete Schutzgruppen haben sich beispielsweise der tert.-Butyldimethylsilyl- und/oder tert.-Butyldiphenylsilyläther erwiesen. Als direktes Reaktionsprodukt werden Verbindungen der allgemeinen Formel I, wobei R₅ Wasserstoff bedeutet, erhalten. Durch Veresterung mit niedrigen Carbonsäuren oder Diazomethan lassen sich die entsprechenden Ester erhalten. Diese Ester lassen sich weiter mit Grignard-Reagenzien unter Standardbedingungen in die entsprechenden tertiären Alkohole umsetzen. However, the reaction requires the hydroxyl groups in the positions 1 and 3 with protective groups. Have proven themselves as suitable protecting groups for example the tert-butyldimethylsilyl and / or tert-butyldiphenylsilyl ether proven. As a direct reaction product, compounds of the general Formula I, wherein R₅ is hydrogen, obtained. By esterification with low The corresponding esters can be obtained with carboxylic acids or diazomethane. This Esters can be further incorporated into the Grignard reagents under standard conditions implement corresponding tertiary alcohols.  

Die folgenden Beispiele sollen die Erfindung näher erläutern:The following examples are intended to illustrate the invention:

AusgangsmaterialienRaw materials 1. (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1-dimethylethyl(diphenyl)silyloxy]-20-[[[(4- methylphenyl)sulfonyl]oxy]methyl]-9,10-secopregna-5,7,10(19)-trien 2 1. (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyloxy] -20 - [[[(4-methylphenyl) sulfonyl] oxy] methyl] -9.10-secopregna-5,7,10 (19) -triene 2

Man löst 2,3 g (2,8 mmol) (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1-dimethylethyl­ (diphenyl)silyl]oxy]-20-hydroxymethyl-9,10-secopregna-5,7,10(19)-tri-en 1 (DE 41 01 953) in 50 ml Pyridin und gibt bei 0°C 2,3 g (9 mmol) p-Toluolsulfonsäurechlorid zu. Es wird über Nacht bei Raumtemperatur gerührt und anschließend auf Eiswasser gegossen. Nach Extraktion mit Essigester, Waschen der organischen Phase mit verd. Salzsäure und Natriumhydrogencarbonat-Lösung und Trocknen über Natriumsulfat entfernt man das Lösungsmittel im Vakuum und reinigt den Rückstand durch Chromatographie an Kieselgel mit Hexan/Essigester als Laufmittel, wobei 2,3 g (85,2%) der Titelverbindung 2 als farbloser Schaum anfallen.2.3 g (2.8 mmol) of (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-hydroxymethyl- 9,10-secopregna-5,7,10 (19) -tri-en 1 (DE 41 01 953) in 50 ml pyridine and adds 2.3 g (9 mmol) p-toluenesulfonic acid chloride at 0 ° C. It is stirred overnight at room temperature and then poured onto ice water. After extraction with ethyl acetate, washing the organic phase with dilute hydrochloric acid and sodium hydrogen carbonate solution and drying over sodium sulfate, the solvent is removed in vacuo and the residue is purified by chromatography on silica gel with hexane / ethyl acetate as the eluent, 2.3 g (85 2%) of the title compound 2 are obtained as a colorless foam.

¹H-NMR(CDCI₃): δ=0,40 ppm (s, 3H, H-18); 0,89 und 0,91 (2×s, je 9H, Si-t- butyl); 0,93 (d, J=7 Hz, 3H, H-21); 2,39 (s, 3H, Tos); 3,78 (dd, J=11,7 Hz, 1H, H-22); 3,93 (dd, J=11,4 Hz, H-22′); 4,20 (m, 1H, H-3); 4,57 (m, 1H, H-1); 4,66 und 4,70 (2×s, je 1H, H-19); 5,53 und 6,29 (2×d, J=11 Hz, je 1H, H-6 und H-7); 7,15- 7,75 (m, 24H, Si-Phenyl und Tos).1 H-NMR (CDCI₃): δ = 0.40 ppm (s, 3H, H-18); 0.89 and 0.91 (2 × s, 9H each, Si-t- butyl); 0.93 (d, J = 7 Hz, 3H, H-21); 2.39 (s, 3H, Tos); 3.78 (dd, J = 11.7 Hz, 1H, H-22); 3.93 (dd, J = 11.4 Hz, H-22 ′); 4.20 (m, 1H, H-3); 4.57 (m, 1H, H-1); 4.66 and 4.70 (2 x s, 1H each, H-19); 5.53 and 6.29 (2 x d, J = 11 Hz, 1H, H-6 and H-7 respectively); 7.15- 7.75 (m, 24H, Si-phenyl and Tos).

2. (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1-dimethylethyl(diphenyl)silyl]oxy]-20-jodmethyl- 9,10-secopregna-5,7,10(19)trien 3 2. (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-iodomethyl-9,10-secopregna-5,7, 10 (19) trien 3 Methode AMethod A

Man löst 4 g (4,1 mmol) 1 in 200 ml Aceton, gibt 10,3 g (61,5 mmol) Kaliumiodid zu und erhitzt 6 Std. zum Sieden. Nach dem Abkühlen gießt man in Wasser, extrahiert mit Methylenchlorid und wäscht die organische Phase mit Natriumthiosulfat-Lösung sowie Natriumchlorid-Lösung, trocknet über Natriumsulfat, entfernt das Lösungsmittel und reinigt den Rückstand durch Chromatographie an Kieselgel mit Hexan/Essigester als Laufmittel, wobei man 2,77 g (72%) der Titelverbindung 3 als farblosen Schaum erhält.4 g (4.1 mmol) of 1 are dissolved in 200 ml of acetone, 10.3 g (61.5 mmol) of potassium iodide are added and the mixture is heated to boiling for 6 hours. After cooling, the mixture is poured into water, extracted with methylene chloride and the organic phase is washed with sodium thiosulfate solution and sodium chloride solution, dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel with hexane / ethyl acetate as the eluent, 2 , 77 g (72%) of the title compound 3 as a colorless foam.

¹H-NMR(CDCI₃): δ=0,49 ppm (s, 3H, H-18); 0,89 und 0,92 (2×s, je 9H, Si-t-butyl); 0,99 (d, J=7 Hz, 3H, H-21); 3,16 (dd, J=10,5, 5 Hz, 1H, H-22); 3,30 (dd, J=10,3 Hz, H-22′); 4,20 (m, 1H, H-3); 4,58 (m, 1H, H-1); 4,69 und 4,83 (2×s, je 1H, H-19); 5,57 und 6,32 (2×d, J=11 Hz, je 1H, H-6 und H-7); 7,18-7,60 (m, 20H, Si- phenyl.1 H-NMR (CDCI₃): δ = 0.49 ppm (s, 3H, H-18); 0.89 and 0.92 (2 x s, 9H each, Si-t-butyl); 0.99 (d, J = 7 Hz, 3H, H-21); 3.16 (dd, J = 10.5, 5 Hz, 1H, H-22); 3.30 (dd, J = 10.3 Hz, H-22 ′); 4.20 (m, 1H, H-3); 4.58 (m, 1H, H-1); 4.69 and 4.83 (2 x s, 1H each, H-19); 5.57 and 6.32 (2 x d, J = 11 Hz, 1H, H-6 and H-7 respectively); 7.18-7.60 (m, 20H, Si  phenyl.

3. (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1-dimethylethyl(diphenyl)silyl]oxy]-20-jodmethyl- 9,10-secopregna-5,7,10(19)-trien 3 3. (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-iodomethyl-9,10-secopregna-5,7, 10 (19) -triene 3 Methode BMethod B

Man legt 5,2 g (20 mmol) Triphenylphosphin und 1,36 g (20 mmol) Imidazol in 40 ml Methylenchlorid vor und tropft bei 0°C 3,8 g (4,6 mmol) 1 in 8 ml Methylenchlorid zu. Anschließend gibt man 2,79 g (11 mmol) Jod in kleinen Portionen zu, so daß die Lösung farblos bleibt. Man läßt innerhalb von 2,5 Std. auf Raumtemperatur kommen, gibt Natriumthiosulfat-Lösung zu und extrahiert mit Essigester. Die organische Phase wäscht man mit Natriumchlorid-Lösung, trocknet über Natriumsulfat, entfernt das Solvens und chromatographiert den Rückstand an Kieselgel mit Hexan/Essigester, wobei man 2,7 g (63%) der Titelverbindung 3 als farblosen Schaum neben 0,27 g (7%) des Ausgangsmaterials erhält.5.2 g (20 mmol) of triphenylphosphine and 1.36 g (20 mmol) of imidazole in 40 ml of methylene chloride are introduced and 3.8 g (4.6 mmol) of 1 in 8 ml of methylene chloride are added dropwise at 0.degree. Then 2.79 g (11 mmol) of iodine are added in small portions so that the solution remains colorless. The mixture is allowed to come to room temperature within 2.5 hours, sodium thiosulfate solution is added and the mixture is extracted with ethyl acetate. The organic phase is washed with sodium chloride solution, dried over sodium sulfate, the solvent is removed and the residue is chromatographed on silica gel with hexane / ethyl acetate, 2.7 g (63%) of the title compound 3 being a colorless foam in addition to 0.27 g ( 7%) of the starting material.

¹H-NMR-Spektrum s. o.1 H-NMR spectrum see. O.

Erfindungsgemäße UmsetzungenImplementations according to the invention 4. (5E, 7E)-(1S, 3R, 20S)-1,3-bis[[1,1- dimethylethyl(diphenyl)silyl]oxy]-20-[4-methoxycarbonylbutyl]- 9,10-secopregna-5,7,10(19)-trien 4a 4. (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20- [4-methoxycarbonylbutyl] - 9,10-secopregna- 5,7,10 (19) -triene 4a

Man legt die Lösung von 0,527 g (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1- dimethylethyl(diphenyl)silyl]oxy]-20-jodmethyl-9,10-secopregna-5,7,1-0(19)-trien 3 in DMF unter Argon bei Raumtemperatur vor und gibt 0,350 g Nickel, (2,2′-Dipyridin- N,N′)[butanoato(2-)-C4,01]-,(SP-4-2)-(9CI) {Nickelalacton der allgemeinen Formel III} ein und 0,360 g wasserfreies Mnl₂ fest zu. Das ganze wird auf einer Schüttelmaschine in einem Schlenk-Gefäß, das mit schwarzer Farbe vor Lichteinwirkung geschützt ist, 3-4 Tage geschüttelt. Der Reaktionsfortschritt wird im DC (Kieselgel 60 G/MERCK: Laufmittel: Cyclohexan/Toluen = 2 : 1) verfolgt.The solution of 0.527 g of (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20-iodomethyl-9,10-secopregna is placed -5,7,1-0 (19) -triene 3 in DMF under argon at room temperature and gives 0.350 g of nickel, (2,2'-dipyridine-N, N ') [butanoato (2 -) - C4.01 ] -, (SP-4-2) - (9CI) {nickel alactone of the general formula III} and 0.360 g of anhydrous Mnl₂ solid. The whole is shaken on a shaker in a Schlenk vessel, which is protected from light by black paint, for 3-4 days. The progress of the reaction is monitored in TLC (silica gel 60 G / MERCK: mobile phase: cyclohexane / toluene = 2: 1).

Nach dem Abziehen des Lösungsmittels im Vakuum wird mit verdünnter Salzsäure angesäuert und mit frisch destilliertem Methylenchlorid extrahiert. Die organische Phase wird mit Thiosulfatlösung zur Entfernung von Jodspuren ausgeschüttelt, das Extraktionsmittel abdestilliert, der Rückstand in Methanol/Wasser aufgenommen und mit einer etherischen Lösung von Diazomethan verestert. Nach Stehen über Nacht im offenen Gefäß wird alles Lösungsmittel abgezogen und auf Florisil (150-250 µm) von SERVA mit Cyclohexan gereinigt. After removing the solvent in vacuo with dilute hydrochloric acid acidified and extracted with freshly distilled methylene chloride. The organic Phase is shaken out with thiosulfate solution to remove traces of iodine Extractant distilled off, the residue taken up in methanol / water and esterified with an ethereal solution of diazomethane. After standing overnight in the open solvent, remove all solvent and place on Florisil (150-250 µm) cleaned by SERVA with cyclohexane.  

Man erhält 300 mg (58%) des Vitamin-D₃-Esters 4a.300 mg (58%) of the vitamin D₃ ester 4a are obtained .

Die ¹H-NMR-Spektren wurden mit einem AC-200 der Firma BRUKER erstellt: Als interner Standard diente HMDS.The 1 H-NMR spectra were created with an AC-200 from BRUKER: As HMDS served internal standard.

¹H-NMR (200 MHKz, CDCl₃, δ): 5a 0,50 (3H, s, 18-H); 0,95 (3H, d, J=7 Hz, 21-H); 0,97 bzw. 0,99 (je 9H, s, tH₉C₄-Si); 3,65 (3H, s, COOCHK₃); 4,25 (1H, m, 3-H); 4,63 (1H, m, 1-H); 4,73 bzw. 4,88 (je 1H, s, 19-H); 5,59 bzw. 5,65 und 6,34 bzw. 6,40 (2H, AB-System, 6-H und 7-H); 7,22- 7,67 (20H, m, H₅C₆-Si).1 H-NMR (200 MHz, CDCl₃, δ): 5a 0.50 (3H, s, 18-H); 0.95 (3H, d, J = 7 Hz, 21-H); 0.97 and 0.99 (each 9H, s, t H₉C₄-Si); 3.65 (3H, s, COOCHK₃); 4.25 (1H, m, 3H); 4.63 (1H, m, 1-H); 4.73 and 4.88 (1H, s, 19-H each); 5.59 and 5.65 and 6.34 and 6.40 (2H, AB system, 6-H and 7-H); 7.22 - 7.67 (20H, m, H₅C₆-Si).

5. (5E, 7ER)-(1S, 3R, 20S)-1,3-Bis[[1,1- dimethylethyl(diphenyl)silyl]oxy]-24,24-dimethyl-9,10-secochola- 5,7,10(19)-trien-24-essigsäure-methylester 4b 5. (5E, 7ER) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -24,24-dimethyl-9,10-secochola- 5, 7,10 (19) -triene-24-acetic acid methyl ester 4b

0,552 g (5E, 7E)-(1S, 3R, 20S)-1,3-Bis[[1,1-dimethylethyl(diphenyl)silyl]oxy]-20- jodmethyl-9,10-secopregna-5,7,10(19)-trien 3 und 0,4 g Nickel (2,2′-dipyridyl-N,N′)- [3,3-dimethylbutanoato(2-)-C4,01]-(9Cl) wurden unter analogen Bedingungen wie Beispiel 4 umgesetzt. Es wurden 0,25 g (45% d. Th.) der Titelverbindung 4b erhalten.0.552 g (5E, 7E) - (1S, 3R, 20S) -1,3-bis [[1,1-dimethylethyl (diphenyl) silyl] oxy] -20- iodomethyl-9,10-secopregna-5,7, 10 (19) -triene 3 and 0.4 g of nickel (2,2'-dipyridyl-N, N ') - [3,3-dimethylbutanoato (2 -) - C4.01] - (9Cl) were prepared under analogous conditions implemented as example 4. 0.25 g (45% of theory) of the title compound 4b were obtained.

¹H-NMR (200 MHz, CDCL₃, δ): 0,50 (3H, s, 18-H); 0,95 (3H, d, J=7 Hz, 21-H); 0,95 (6H, s, 23a-H); 0,97 bzw. 0,99 (je 9H, s, tH₉C₄-Si); 2,19 (s, 24a-H); 3,63 (3H, s, COOCH₃); 4,25 (1H, m, 3-H); 4,63 (1H, m, 1-H); 4,73 bzw. 4,88 (je 1H, s, 19-H); 5,59 bzw. 5,65 und 6,34 bzw. 6,40 (2H, AB-System, 6-H und 7-H); 7,22-7,67 (20H, m, H₅C₆-Si).1 H-NMR (200 MHz, CDCL₃, δ): 0.50 (3H, s, 18-H); 0.95 (3H, d, J = 7 Hz, 21-H); 0.95 (6H, s, 23a-H); 0.97 and 0.99 (each 9H, s, t H₉C₄-Si); 2.19 (s, 24a-H); 3.63 (3H, s, COOCH₃); 4.25 (1H, m, 3H); 4.63 (1H, m, 1-H); 4.73 and 4.88 (1H, s, 19-H each); 5.59 and 5.65 and 6.34 and 6.40 (2H, AB system, 6-H and 7-H); 7.22-7.67 (20H, m, H₅C₆-Si).

Claims (4)

1. Verfahren zur Herstellung von Zwischenprodukten der allgemeinen Formel I worin
R¹, R² Wasserstoff oder eine Schutzgruppe,
R³, R⁴ und R⁵ Wasserstoff oder eine niedrige Alkylgruppe und
n = 0 oder 1 bedeuten,
dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel II worin R¹ und R² die o. g. Bedeutung besitzen, mit einem Nickelalacton der allgemeinen Formel III worin n, R³ und R⁴ die o. g. Bedeutungen haben und (bipy) für 2 Pyridinringe steht, umsetzt, gegebenenfalls mit einer niederen Carbonsäure oder Diazomethan verestert und gegebenenfalls die Schutzgruppen abspaltet.1. Process for the preparation of intermediates of the general formula I wherein
R¹, R² are hydrogen or a protective group,
R³, R⁴ and R⁵ are hydrogen or a lower alkyl group and
n = 0 or 1,
characterized in that compounds of the general formula II wherein R¹ and R² have the meaning given above, with a nickel alactone of the general formula III in which n, R³ and R⁴ have the abovementioned meanings and (bipy) stands for 2 pyridine rings, is reacted, optionally esterified with a lower carboxylic acid or diazomethane and, if appropriate, the protective groups are split off. 2. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man als Schutzgruppen die tert.-Butyldimethylsilyl- und/oder die tert.-Butyldiphenylsilylgruppe einsetzt.2. The method according to claim 1, characterized in that as Protecting groups, the tert-butyldimethylsilyl and / or the tert-butyldiphenylsilyl group starts. 3. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man als niedrige Alkylgruppen eine Methyl, Ethyl, Propyl, Isopropyl, Butyl oder Isobutylgruppe einsetzt.3. The method according to claim 1, characterized in that one as a low Alkyl groups are methyl, ethyl, propyl, isopropyl, butyl or isobutyl group starts. 4. Verfahren gemäß Anspruch 1, dadurch gekennzeichnet, daß man als niedrige Carbonsäure die Ameisen-, Essig-, Propion- oder Buttersäure einsetzt.4. The method according to claim 1, characterized in that one as low Carboxylic acid that uses formic, acetic, propionic or butyric acid.
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Publication number Priority date Publication date Assignee Title
EP0927721A1 (en) * 1997-12-17 1999-07-07 Schering Aktiengesellschaft Novel vitamine D derivatives having phosphorus atoms in the side chains, intermediates for their preparation and their use for the preparation of drugs

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EP0078704B1 (en) * 1981-11-02 1987-04-29 Research Institute For Medicine And Chemistry Inc. Intermediates in the synthesis of vitamin d derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0078704B1 (en) * 1981-11-02 1987-04-29 Research Institute For Medicine And Chemistry Inc. Intermediates in the synthesis of vitamin d derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0927721A1 (en) * 1997-12-17 1999-07-07 Schering Aktiengesellschaft Novel vitamine D derivatives having phosphorus atoms in the side chains, intermediates for their preparation and their use for the preparation of drugs

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