JPH02215766A - 22,23-seco-vitamin d and active-type 22,23-seco-vitamin d or derivative thereof and production thereof - Google Patents

Abstract

NEW MATERIAL:Compounds represented by formula I [X is H, OH or derivatives thereof; as R1 and R2, R1 is benzoyl(PhCO2) and R2 is tetrahydropyranyl(THP), H or p-toluenesulfonyl(TS): R1 is H and R2 is THP, TB or CH3: R1 is triethylsilyl and R2 is THP: R1 is H or OH protective group and R2 is OH protective group]. EXAMPLE:1alpha, 3beta-Di-benzoyloxy-20(S)-tetrahydropyranyloxymehtyl-9,10-seco- pregna-5(Z),7(E),10(19)-triene. USE:An intermediate for synthesis of vitamin D compound adaptable for aryloxylation at C(1) position. PREPARATION:A compound of formula II (R1 to R4 are H or OH protective group) is subjected to a reductive elimination through a 7,8-dihydroxy-cyclic orthoester or a homologue thereof or to an elimination of the 7,8-dihydroxy form by a metal such as a reduced-type titanium to obtain the objective compound of formula I (R1 and R2 are H or OH protective group).

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention provides 22.23-secovitamin D and active 22-secovitamin D.
．． The present invention relates to 23-secovitamin D or derivatives thereof and a method for producing the same from 22.23-seco-7,8-dihydroxyvitamin D or derivatives thereof.

(Traditional branch technique) Research on vitamin D has focused on lα, which has the strongest activity among the currently known vitamin D3 metabolites.
Since the discovery of 25-dihydroxyvitamin D3 in 1971 (Il, F., De Luca et al., Ann, R.
ev, Biochem J Vol. 45, P, 631.1
97111; H,F, De Luca, rNu
tr, ReyJ Vol. 37, P, 1131. The active form of vitamin D3, lα, has undergone rapid development and has been the result of collaborative research in many fields.

25-dihydroxyvitamin D3 and its homologue lα-hydroxyvitamin D3 have been developed as therapeutic agents for renal diseases, bone diseases, and parathyroid gland disorders.

(D, E, Mawson, rVitamin D
″', Academic Press, Inc., N
ew York, 1978; A. W. Norsan
.

Vitamin D”, The Calcius
Ho*eostatic 5teroidHorIlo
n, Acade+sic Press, Inc.
New York, 1878).

Recently, the target organs on which lα,25-dihydroxyvitamin D3 acts are the kidney, pancreas+i, pituitary gland, thymus, parathyroid gland, skin, and breast. Many tissues and organs such as lymphocytes were found ()1. F. De Luca et al. rPro
c, Natl, Acad, Sci, USA, J+
77, P. 1149, 1980), and the presence of receptors has also been confirmed in various tumor cells.

(K, Co15tan et al. Endocrinolog
y, J Vol. 108, P, 1083, 1981;
H.F., Freake et al.

rBiochem,Bio Ph7g,Res,Com
mun,, J Volume 101.

P, l+31, 1981; S, C, Manola
gag et al.

rJ, Biol, chem, J Vol. 255, P.
4414, 11380; T, 5uda et al., r
Biochem, J, J Vol. 204, P, 713.

P.? +3, 1982).

In particular, 1α,25-dihydroxyvitamin D suppresses the proliferation and promotes differentiation of myeloid leukemia cells (T
, 5uda et al., rProc, Natl, Acad, S
ci.

USA, J Vol. 78, P, 4990, 1981)
A relationship with the immunological effects of Ab and E is also found (E, Ab
e, r vitamins” Volume 59, P, 418, 19
(1985), new developments in vitamin D are expected.

Various vitamin n7J conductors have been synthesized and their physiological effects have been investigated from the viewpoint of L,
ekawa, r Biochemistry J Vol. 55, P, +297
, II383; T, 5uda et al., rBone
& Mineral Res, J Volume 4, ed, W
, A., Peck, Pl., Elsevier, Am5t.
erda+s, 1986; E, Mura2ama et al. rChem, Pharm, Bull, J No. 34
Volume, P, 4410, 198E1; N, Ike
Kawa et al., rchem.

Phars, Bull, J +533 volumes, P.
878.4815.1985) Since the lα-hydroxy form is considered to be an essential condition for becoming a physiologically active species, research institutes around the world have been seriously working on its synthesis.

However, most of the syntheses to date have been based on each vitamin DJ.
For each conductor, starting with the synthesis of the 1α-hydroxylated steroid, the corresponding lα-hydroxy-5,
After converting into a 7-dininosterol derivative, the desired vitamin D? is obtained by a well-known photochemical method. This is an extremely inefficient method that requires multiple steps to obtain the A conductor.

(N. Ikekawa, et al., “Organic Synthetic Chemistry” No. 3
Volume 7, P, 755.1979; C, Kaneko,
rOrganic Synthetic Chemistry J Volume 33, P, 75, 1975
Year; B, Lythgae, rchevx, sac.

Rev, J Vol. 9, P, 449. 1980; R,
Pardo, et al., rBull, De La
5ocI: him, Ds Fr, JP, 98
．． (1985).

Therefore, in order to improve these problems, 22.23-seco-1α-hydroxyvitamin D was used as a common synthetic intermediate for the synthesis of various lα-hydroxyvitamin DFJ conductors.
Synthesis of this compound by setting derivatives, and various lα-hydroxyvitamin D from this compound. Attempts have been made to synthesize a J4 conductor.

(R, H, Hesge et al., rJ, Org, chem
, J Vol. 51.

P, 4819, 19811i; H, F, De L
uca et al.

r Tetrahedron Lett, J No. 28
Vol., P, 8129, 1987; H, F, De
Luca et al., r J, Org, Che*, J No. 5
Volume 3.

P, 345Q, 1988.

However, in these reports, in the former case, the vitamin D form is changed to -H transvitamin D form, and then c (
i), and this is exchanged again to vitamin D form by photoreaction etc. In the latter report, after the vitamin D form is once converted to 3.5-cyclovitamin D form, Aryl oxidation is carried out at the C(1) position, and this is converted back into vitamin D form. In both of these cases, the yield of aryl oxidation is not very good, and the conversion to vitamin D form is also satisfactory. It's not something you should do.

(Problem to be solved by the invention) Even with the currently representative synthesis methods as described above,
All of these are unsatisfactory from a practical standpoint, and there is a desire to develop a more efficient synthesis method. However, claim (1) is a novel 22.23-secovitamin in view of conventional compounds. D and active q22.23-secovitamin D
Alternatively, the object is to obtain very useful compounds related to derivatives thereof, and in claim (2), vitamins applicable to various chemical reactions, particularly 7-aryl oxidation at position c (i). As a result of intensive research to develop an efficient method for synthesizing an important synthetic intermediate of D-form, 22.23
-Seco-7,8-dihydroxyvitamin D or its derivatives are converted into the desired product 22. by a reductive reaction via a cyclic orthoester of 7,8-dihydroxy or an elimination reaction with a metal such as reduced titanium. This method is fundamentally different from conventional methods for producing 23-secovitamin D or active 22.23-secovitamin D or derivatives thereof, both conceptually and in practice. The aim is to find effective and efficient methods for industrial engineering.

(Means for resolving the issue) The present invention solves the above objects.

In claim (1).

A compound having the following formula (wherein, Tetratobiropyranyl, p-toluenesulfonyl, methyl, R 凰 is triethylsilyl, R2 is tetratobilopyranyl, R1 is a hydrogen atom or a hydroxy protecting group, and R2 is the same or different hydroxy protecting group excluding hydrogen. ).

In claim (2), the elimination reaction of the following formula (II) (wherein R+, R2, R3 and R4 are the same or different hydrogen atoms or hydroxy protecting groups) is carried out by the elimination reaction of the following formula (I).

Reduction of 22.23-seco-7,8-dihydroxyvitamin D represented by (X represents hydrogen, hydroxy or a derivative thereof) or a derivative thereof via a cyclic orthoester of 7.8-dihydroxy or a homologue thereof elimination reaction or by a metal such as reduced titanium of the 7.8-dihydroxy form (where R1 and R2 are the same or different hydrogen atoms or hydroxy protecting groups, and X represents hydrogen, a hydroxy group, or a derivative thereof) 22.23-secovitamin D or active form 22 expressed as
．． The present invention provides a method for producing 23-secovitamin D or derivatives thereof.

(Example) Isolation of the target product from the reaction mixture is extremely simple.
2. 23-Seco-7,8-dihydroxyvitamin D or its active homolog was heated to reflux in a Dean-9tark apparatus in a toluene solvent in the presence of an excess of orthoethyl formate and a catalytic amount of pyridinium paratoluenesulfonate. The purpose is to distill off the solvent from the reaction mixture and purify the resulting residue by means such as column chromatography. 22.23-Secovitamin D or their active analogues are obtained in high yields.

The 20-formyl compound (R+ = 1-butyldimethylsilyl;
24R) -1α,25-dihydroxyvitami 7D2(
7) (cited above) 1. F, De Luca et al.), and in formula (II) (R1=)ethylsilyl;
The derivative of Rz = paratoluenesulfonyl;
The compound of formula (II), which is a synthetic intermediate and is synthesized by the present invention, can be said to be a very useful compound.

Specific examples will be described below, and the number of each example process is shown in parentheses in the diagram for explaining all the steps.

Implementation step example (1) 3β,7.8-)di(t-butyldimethylsilyloxy)-tα-hydroxy-20(S)-tetrahydropyranyloxymethyl-3,10-secopregna-5(
A suspension of 300 mg of 10(19)-diene, 2 g of tetra-n-butylammonium fluoride trihydrate and 4 AI of activated molecular sieves in 30 IlfL of acetonitrile is heated under reflux for 20 hours with stirring.

The reaction solution is Serai) i! ! After that, the solvent is distilled off.

The obtained residue is dissolved in ethyl acetate, washed with water, and then dried over sodium sulfate.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography [silica gel Ig, solvent: ethyl acetate] to obtain lα, 3β, 7.8-tetrahydroxy-20(S)-tetrahydropyranyloxymethyl. −
9,10-Secopregna-5 (Z).

120 mg of 10(19)-diene are obtained.

1R spectrum pmax (GHGI:+)cm-
1:340ONMR spectrum (CDCJI 3) δ:
4.50 (IH, brs).

4.90 (IH, brs), 5.30 (+8.brs
), 5.70 (IH, d, J=10Hz) Mass spectrum (FD) m/e; 447 (Mr-17)
, 44G (M"-18).

410.409,296,295,283 Pregna-5
(Z), 150 tags of benzoyl chloride are added dropwise under stirring to a 20-ml methylene chloride solution containing 200 kg of 10(19)-diene, 1 portion of pyridine, and a catalytic amount of dimethylaminopyridine under water cooling.

The reaction solution was stirred at room temperature for 1 hour, then diluted with methylene chloride, washed successively with water, 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water, and then dried over sodium sulfate.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (1 g of silica gel, solvent: n-hexane-ethyl acetate (10:5 m/m)).
α,3β-di-benzoyloxy-7,8-dihydroxy-20(S)-tetrahydropyranyloxymethyl-
9,1O-Secopregna-5 (Z).

222 mg of 10(19)-diene are obtained.

Implementation step example (2) lα, 3β, 7.8-tetrahydroxy-20(S)
-tetrahydropyranyloxymethyl-9,10-seco IR spectrum Jl/ymax (GHGI3) cm
-”: 3500, 170ONMR spectrum (CC14
) δ: 0. BO(3H,S), 4.48(28
, brs), 4.53 (IH, d, J-101(z)
.

5.00-13.10 (5H, s), 7.10-7.6
0 (6H9 Otori), 7.80-8. Et5(4H,m) mass spectrum/lz(FD)m/eH655(M-17
), 837,550°515.377.295 Dimethyl-3,1O-secopregna-5(Z), 10
De
Heat to reflux for 20 minutes under an -5tprk apparatus.

After the reaction, the solvent was distilled off and the resulting residue was subjected to silica gel column chromatography [1 g of silica gel, solvent: n-hexane-ethyl acetate (100: 2 m/m)]
and lα,3β-di-benzoyloxy-20(S
)-tetrahydropyranyloxymethyl-9,IQ-secopregna-5 (Z), 7. (E), IQ (19
) -) 150 mg of diene are obtained.

Implementation process example (3) Engineering α,3β-dibenzoyloxy-7,8-dihydroxy-20(S)-tetrahydrobyranyloxy IR spectrum v ffiaw (CHCI 1) cm-”
:171ONMR spectrum (CC statement 4) δ: 0.3
0(38,S), 4.47(IH,brs),
5.10 (i) I, brs), 5.47 (IH, br
s), 5.20-8.20 (3) 1. m).

8.43 (IH, d, J=l'QHz), 7.2Q
~7.60 (8H,s), 7.80~8.20 (4
H, m) Mass spectrum (FD) m/e; 638 (M”
), 554,518; n-hexane-acetic acid ethyl ester (100:20 m/m)] and lα,3β-di-benzoyloxy-20(S)-hydroxymethyl-
9,10-Secopregna-5(Z), 7(E), 10(
19)-) Obtain Lien IloIIIg.

Implementation step example (4) lα,3β-di-benzoyloxy-20(S)-tetrahydropyranyloxymethyl-9,10-secopreg+-5(Z),? (E), 10(19) - IJ
A mixture of 5 methanol and methylene chloride containing 120 + sg o and a catalytic amount of para-toluene sulfonic acid is stirred at room temperature for 30 minutes.

After the reaction, the mixture was diluted with methylene, washed with saturated sodium TX acid, and dried over sodium sulfate.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography [silica gel 500eg, solvent IR spectrum ymax (CHCA, *)c+s: 3
E100,172ONMR spectrum (CG view 4) δ:
0.30 (3H, S), 5.11 (IH, brs
), 5.48 (IH, brg), 5. IO~Ei.

10 (2H, layer), 5.93 (18, d, J=lOHz
).

6.43 (IH, d, JlllQHz), 7.20
~7.70 (138,m), 7.80~8.30 (4+
1. m) Mass spectrum (FD) m/e; 554 (
M)), 49[1, 484, 432 Example of implementation process (5
) lα,3β-di-benzoyloxy-20(S)-tetrahydropyranyloxymethyl-9,lO-secopregna-5(Z), ? (E), 10(19)-) Lien 4
To 5,011 g of methylene chloride (5 m + 100 g) was added 10 layers of lθ% methanolic caustic soda solution, and the mixture was heated to reflux with stirring for 30 minutes.

After the reaction, the reaction solution is washed with water and dried over sodium sulfate.

The residual liquid obtained by distilling off the solvent was subjected to silica gel column chromatography [5 g of silica gel, solvent: n-hexane-acetic acid ethyl ester (3:2 manoma)], and lα
, 3β-dihydroxy-20(S)-tetrahydropyranyloxymethyl-9,10-secopregna-5(Z)
, 7(E), 10(19)-triene 30 hg are obtained.

IR spectrum pmax (in HG 3) CI-”
:3θ0ONMR spectrum (CC44) δ: 0
．． 5B(3H,S), 0.97(3H,d,JI-
8Hz), 3.20-3.83 (4H, m), 3.
94-4.45 (2H, m), 4.50 (1) 1. br
s), 4.93 (IH, brs), 5.30 (
IH, brs), 8.00 (IH, d, J proverb 10H
z).

8.33 (IH, d, J-IIOHz) mass spectrum (F[1) s/e; 430 (M'), 412,394,
328'.

310.295 Implementation step example (8) lα,3β-dihydroxy-20(S)-tetrahydropyranyloxymethyl-9,10-secopregna-5(
Z), 7(E), 10(19)-triene 200mg
and 30 g of triethylsilyl chloride in a solution of 200 g of imidasol and 5 tQ of dry dimethylformamide.
Add 0 g and stir at room temperature for 3 hours.

After the reaction, the reaction mixture was diluted with ether, washed successively with 10% JL acid, water, saturated sodium bicarbonate and water, and dried over sodium sulfate.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography [4 g of silica gel, solvent: n-hexane-ethyl acetate (100: I/m)] to give 1α,3β-di-triethylsilyloxy- 20(S
200 mg of )-tetrahydropyranyloxymethyl-8,10-secopregna-5(Z),7(E),10(19)-)riene are obtained.

NMR spectrum/l/CCC1a) δ: 0.53
(3H,S), 3.20-3.90(4)1. m)
, 4.00-4.43 (2H.

m), 4.50 (IH, brs), 4.87 (IH, b
rs).

5.20 (lH, brs), 8.00 (l) I, d,
J-10Hz), 8.27(lH,d, J-101(z
) Mass spectrum (FD) m/e; 859 (M)-1)
, 658(M”), 394.

393.392,344 Implementation process example (7) lα,3β-di-benzoyloxy-20(S)-hydroxymethyl-9,10-secopregner 5(Z)
.

7(E), 10(19)-triene 110+*g,
To a 10-layer solution of pyridine and a catalytic amount of dimethylaminopyridine in methylene chloride, add 9180 g of a layer of rose-toluenesulfonylchloride and stir at room temperature for 1 hour.

Anti-J5? & is 10% Hanawa brewed after diluting with methylene chloride,
Wash sequentially with saturated sodium bicarbonate and water, then dry over sodium sulfate.

The residue obtained by distilling off the solvent was subjected to silica gel column chromatography [2 g of silica gel, solution 61; n-hexane-ethyl acetate (1,0: iv/ma)]
and lα,3β-di-benzoyloxy-20(S
)-para-toluenesulfonyloxymethyl-9,1
0-Secopregna-5(Z), 7(E), 10(1
9) Obtain 100+eg of -triene.

! R spectrum ν1TomiCCHC1x) C layer: 17
1ONMR spectrum (C:C14) δ: 0.33(
3H,S), 2.50(3)1. S), 3. E
i8~4.03 (2H, +a), 5.14 (IH,
brs), 5.50 (IH, brs), 5.9
0 (IH, d, J = 10Hz), 5.30-6.00 (
2) 1゜a+), 8.43(IH, d, J-10H
z), 7.20-8.30 (14H, intestine) Mass spectrum (FD) m/e; 708 (M”), 5
88.484,364 Implementation step example (8) lα13β-di-benzoyloxy-20(S)-para-toluenesulfonyloxymethyl-9,10-secopregna-5(Z), 7(E), 10(19) - Triene 10% in 60 mg methylene chloride 20i+ 1 solution
Add 1 liter of methanolic caustic soda solution and stir at room temperature.
Stir for 3 hours.

After the reaction, the solvent is distilled off, and the residue is dissolved in methylene chloride, washed with water, and dried over sodium sulfate.

The residue obtained by distilling off the solvent e) was subjected to silica gel column chromatography [1 g of silica gel, solvent: n-hexane-acetic acid ethyl ester (3:2 m/m)], and 1α, 3β-dihydroxy was extracted from the first fraction. -20(
S)-methoxymethyl-9,10-secopregna-5 (
21 mg of Z), 7(E), 10(19)-triene are obtained.

IR spectrum ymax (CHCrfLz)c+
g:360ONMR spectrum (00 sentence 4) δ:
0.43 (3H, S), 0.90 (3H, d, J-
GHz), 3.13 (3H,S), 3.70~
4.40 (2B, m), 4.80 (IH, brs)
.

5.17(I)I,brg), 5.83(IH,d
, JIlloHz), 6. +5 (1) 1. d, J-10
) 1z) Mass Spect J FD) m/e; 360.3
58,342,324,281゜287.250,22
4 lα,3β-dihydroxy-20 from the second fraction
(S)-para-toluenesulfonyloxymethyl-9
,10-Secoplegna-5(Z),? (E), 10(1
9) - Obtain 15 mg of triene.

IR spectrum p mat (CHCI y ) am
-' :3Ef0ONMR spectrum (000 sentence 3) δ
: 0.47(3)1. S), 0.94(38,d
, J=6)1z), 2.44(38,S), 3
．． 70-4.10 (2H, m), 4.90 (l)!
,brs).

5.25 (IH, brg), 5.93 (l) l, d, J
-10Hz), 8.30(+1(,d,J=10)1z
), 7.30 (2H.

d, J-18Hz), 7.78 (2H, d, J-8
Hz) Mass spectrum (FD) @/e; 500 (Mr)
, 482 (M'-18).

4138.482 The reaction solution was diluted with methylene chloride and 10% hydrochloric acid.

After sequentially washing with water, saturated sodium bicarbonate solution, and water, drying with sodium sulfate.

The residual liquid obtained by distilling off the solvent was subjected to silica gel column chromatography (500 mg of silica gel, solvent; n-
Hexane-acetic acid ethyl ester (loo:tmar)]
and lα,3β-di-t-butyldimethylsilyloxy-20(S)-para-toluenesulfonyloxymethyl-9,10-secopregna-5(Z),? (E
), 10(19)-) 13 mg of liene is obtained.

Implementation step example (9) lα,3β-dihydroxy-20(S)-p-toluenesulfonyloxymethyl-9,lO-secopregna-5(Z),? (E), 10(19)-triene 1
To a solution of 2 mg of imidazole, 20 mg of imidazole, and a catalytic amount of dimethylaminopyridine in dry dimethylformamide, 20 g of 1-butyldimethylsilyl chloride was added and stirred at room temperature for 1 hour.

The various equipment data in this section are from De Luca et al. (rJ
, org, chem, J 53, 3450 (1988
) The structure was confirmed by a complete match with ).

(Effect of the invention) The present invention provides an unprecedented and useful 22.23-seco-7,8
- Dihydroxyvitamin D or derivatives thereof, which can be produced by a reductive elimination reaction via a cyclic orthoester of 7,8-dihydroxy or an elimination reaction with a metal such as reduced titanium. This has made it possible to provide a method that is revolutionary and more efficient than conventional methods.

[Brief explanation of the drawing]

The figure is an explanatory view of the entire process of the method according to claim (2) of the present application. Agent Patent attorney Yoshi Saifuji Otetomi: ? 'in Official document (method) Indication of case Patent application Hei 1-35783 Title of invention 22, 23-Secovitamin D and active form 22.23
- Relationship between secovitamin D or its derivatives and the case of a person amending its manufacturing method Patent applicant Hakusan University Co., Ltd. Date of amendment order to Kotari Building, 1-6-6 Yurakucho, Chiyoda-ku, Tokyo 100 Japan (1999) (May 30, 2016) "Brief explanation of one drawing of the specification subject to amendment" column and drawings. 7 Contents of the amendment 1) Amended “Figure 1 is” on page 31, line 14 of the specification to “Figure 1 is,”

Claims (2)

[Claims] (1) Compounds with the following formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (Here, X is hydrogen, hydroxy or a derivative thereof, R_1 is benzoyl, R_2 is tetratoviropyranyl, hydrogen, p-toluene sulfonyl, R_1 is hydrogen, R_2 is tetratoviropyranyl, p-toluenesulfonyl, methyl, R_1 is triethylsilyl, R_2 is tetratoviropyranyl, R_1 is a hydrogen atom or a hydroxy protecting group, and R_2 is (Indicates the same or different hydroxy protecting groups excluding hydrogen, respectively.) (2) Below [I] Formula▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・〔I
] (Here, R_1, R_2, R_3 and R_4 are the same or different, and represent a hydrogen atom or a hydroxy protecting group
represents hydrogen, hydroxy or a derivative thereof. ) Reductive elimination reaction of 22,23-seco-7,8-dihydroxyvitamin D or its derivatives with a 7,8-dihydroxy cyclic orthoester or its homolog or reduction of the 7,8-dihydroxy form The following [II] formula is characterized by an elimination reaction with metals such as titanium ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ... [II] (Here, R_1 and R_2 are the same or different, and hydrogen atoms or a hydroxy protecting group, X represents hydrogen, hydroxy or a derivative thereof) 22,2
A method for producing 3-secovitamin D and active 22,23-secovitamin D or derivatives thereof.