Precursors of the A-ring of vitamin D and method and...

Details Precursors of the A-ring of vitamin D and method and... Precursors of the A-ring of vitamin D and method and...

1999-12-08

2001-02-20

Qazi, Sabiha N. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

9,10-seco-cyclopentanohydrophenanthrene ring system or...

C552S653000, C549S214000, C549S426000, C549S427000, C549S493000, C549S497000, C549S498000, C549S502000, C556S413000, C556S465000, C560S001000, C560S125000, C562S507000, C562S508000

Reexamination Certificate

active

06191292

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention discloses precursors that can be used effectively for the synthesis of 19-nor-vitamin D analogues, as well as a method and intermediates for the preparation thereof. More specifically, the invention relates to precursors of the A-ring of said vitamin D analogues, which A-ring is represented by the structure below
(see for instance Mazur et al.,
Tetrahedron Letters
1995, 2987).
The synthesis of bicyclo[3.1.0]hexane derivatives, as 19-nor- A-ring precursors has been developed from (−)-quinic acid or cyclohexane-triol by M. Vandewalle et al. (
Tetrahedron Letters
, 1995, 36 (45), 8299-8302) and is based on the well-known sigmatropic rearrangement of cyclopropylic alcohol into homoallylic alcohol. The potential of this rearrangement in natural vitamin D has been first demonstrated by Mazur et al. (op. cit.). An alternative synthesis from 2,4-pentane-dione was also reported (S. Z. Zhou, S. Anne, M. Vandewalle,
Tetrahedron Letters
, 1996, 37 (42), 7637-7640). 3-Cyclopentenol was also used as a precursor for this preparation (W. Yong, M. Vandewalle;
Synlett
, 1996, 9, 911-912).
These methods however present the following disadvantages:
The preparation from (−)-quinic acid involves a radicalar desoxygenation which is difficult to control on large quantity, and the use of toxic tributltinhydride;
The process from cyclohexane triol is conducted via a large number of steps (12) and needs two enzymatic reactions;
The starting material, 3-cyclopentenol is not commercially available. It must be prepared from cyclopentadiene via a low yielding (30%) hydroboration step. Furthermore the cyclopropanation and the introduction of the formyl group are cumbersome;
The synthesis starting from 2,4-pentane dione (10 steps) suffers from low yields in the first step for preparing the intermediate bis epoxide. Furthermore, due to their low molecular weight some intermediates are rather volatile and difficult to purify in a large scale process.
SUMMARY OF THE INVENTION
It has now been found that a broad range of 19-nor-A-ring precursors can be prepared starting from 3,5-dihydroxybenzoic acid derivatives or their 4-alkyl substituted homologues. These precursors can be obtained on a large scale by a method which is more efficient than previously disclosed methods.
Thus, according to a first feature, the invention relates to a method of preparing a compound of formula (I):
in which:
A is a group —CH
2
OH, —CH
2
—OCOR′, —COR″, —CSR″ or an ethynyl;
R is hydrogen or a (C
1
-C
6
)alkyl;
R
1
is hydrogen, a (C
1
-C
6
)alkyl or a group —(CH
2
)
n
—OP;
R
2
is hydrogen or a group —OP;
R′ is a (C
1
-C
6
)alkyl or a phenyl;
R″ is hydrogen, a hydroxyl, a (C
1
-C
6
)alkyl, a (C
1
-C
6
)alkoxy, a (C
1
—C
6
)alkylthio, or a di(C
1
-C
3
)alkylamino;
P is hydrogen; a (C
1
-C
6
)alkanoyl; a benzoyl in which the phenyl is optionally substituted by a (C
1
-C
4
)alkyl, a halogen or a nitro; a (C
1
-C
6
)alkoxycarbonyl; a group —Si(R
3
)
3
in which each R
3
independently represents a (C
1
-C
6
)alkyl or a phenyl; a mono- or di-(C
1
-C
6
)alkoxy(C
1
-C
6
)alkyl; a tetrahydrofuranyl; or a tetrahydropyranyl;
n is 0, 1, 2, 3 or 4, preferably 0 or 1,
which method comprises the steps of
(i) reacting a compound of formula 1
 in which A is a (C
1
-C
6
)alkoxycarbonyl, preferably a methoxycarbonyl, or a di(C
1
-C
3
)alkylaminocarbonyl and R is as defined above, with a lipase in a vinylalkanoate or an acid anhydride, and
(ii) converting the resulting compound of formula 2 or 2′
 in which Z is an alkyl such as a (C
1
-C
6
)alkyl, preferably a (C
1
-C
3
)alkyl to the corresponding compound of formula (I).
DETAILED DESCRIPTION OF THE INVENTION
As shown in general scheme 1, the starting material for the preparation of the A-ring precursors is obtained by hydrogenation of a methyl 3,5-dihydroxybenzoic acid or an ester thereof or of their 4-alkyl substituted homologues following a modified procedure from that described by P. Wang and J. Adams in
J. Am Chem Soc
1994, 116, 3296-3305.
The first step comprises the enzyme catalyzed asymmetrisation of 1-alkoxy (or dialkylamino)carbonyl-3,5-dihydroxy-cyclohexane or its 4-alkyl-substituted homologues in a solvent such as a vinylalkanoate, for example vinylacetate, vinylpropionate or vinylbutyrate or an acid anhydride, for example acetic anhydride, propionic anhydride or butyric anhydride and using a lipase such as SAM II (lipase from
Pseudomonas fluorescens
), CCL (lipase from
Candida cylindracea
), PPL (lipase from porcine pancreas), PSL (lipase from
Pseudomonas cepacia
), GCL (lipase from
Gotrichum candidum
), at a temperature between 10 and 40° C., preferably 20° C., during 6 to 72 hours, which affords the corresponding alkyl (or dialkyl) (1S,3S,5R)-3-alkylcarbonyloxy-5-hydroxy or (1S,3S,4R,5R)-4-alkyl-3-alkylcarbonyloxy-5-hydroxy-cyclohexanecarboxylate (or carboxamide) 2 or the corresponding alkyl (or dialkyl) (1S,3S,5R)-5-alkylcarbonyloxy-3-hydroxy or (1S,3S,4R,5R)-4-alkyl-5-alkylcarbonyloxy-3-hydroxy-cyclohexanecarboxylate (or carboxamide) 2′.
Also, asymetrisation via an enantiotoposelective enzyme-catalysed hydrolysis of diesters 3 with an appropriate enzyme can take place to conduct to the same family of compounds.
Schemes 2 and 3 describe the synthesis of all diastereoisomers of general formula (I) with R
1
=H and R
2
=OP, from compounds 2 and 2′ described in scheme 1.
As shown in these schemes, the conversion of compounds 2 or 2′ to compounds (I) is carried out via one or several of each of the following steps which can be performed partially or totally in a varying order depending on the eventual diastereoisomer: (1) protection of hydroxy groups (P=TBDMS, TBDPS for example), (2) ester saponification, (3) inversion of a 3 or 5-hydroxy group, (4) formation of a leaving group (L=OTos, OBros, OMs for example), (5) base included ring closure to the desired bicyclo[3.1.0]hexane, (6) transformation of the carboalkoxy or carbamoyl function (A) to the desired substituent A.
Steps (2) and (4) are conventional reactions well known to those skilled in the art. Step (1) can be carried out according to
J. Am. Chem. Soc
. 1972, 94, 6190 or
Protective groups in Organic Synthesis
, T. W. Greene, John Wiley Sons, New York. Step (3) can be carried out according to
Synthesis
1981, 1, or by a two-step process (elimination, hydroboration). Step (5) can be carried out according to
Tetrahedron Letters
, 1995, 36 (45), 8299-8302. Step (6) can be carried out according to
J. Gen. Chem. USSR
1964, 34, 1021.
Scheme 2 specifically describes the synthesis of all diastereoisomers with a 3aS configuration (&agr; oriented cyclopropyl ring).
Scheme 3 specifically describes the synthesis of all diastereoisomers with a 3aR configuration (&bgr; oriented cyclopropyl ring).
As shown in general Scheme 4, the 3a hydroxymethyl substituted bicyclo[3.1.0]hexane compounds (I) with R=H and A=CH
2
OH can also be useful for the synthesis of A-ring precursors for vitamin D analogues modified at C-1. This possibility is examplified from I.a (R=H, P=TBDPS, A=CH
2
OH) via ketone 4.2 as a key intermediate. Grignard reaction (for example R
1
=Me or Et) leads diastereoselectively to the tertiary alcohols I.i, with concomitant removal of the protecting ester function. On the other hand methylenation of 4.2 gives 4.3. The best result (68% yield) was obtained with the Lombardo procedure (
Tetrahedron Lett
., 1982, 23, 4293). Alternatively Wittig or Tebbe reaction (
J. Org. Chem
.,1985, 50, 1212) gave respective yields of 39% and 54%.
Dihydroxylation of 4.3 affords the expected diol I.m. as the major product next to the epimer 4.4 (ratio 85:15, not shown). On the other hand, the hydroboration of 4.3 gives 2R and 2S hydroxymethyl compounds in a 75:25 ratio (73%). These epimeric alcohols were separated to give I.j and I.k after TBDPS ether formation (81%) and subsequent ester hydrolysis (81%). Mercury acetate medi

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