JPH047755B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Technical Field> The present invention relates to a novel steroid derivative and a method for producing the same.

More specifically, a novel α-methylene-γ-hydroxy compound having a skeletal carbon number of 27 is synthesized by adding 2-halomethylpropenoic acid ester to a norkolene aldehyde having a skeletal carbon number of 23 in the presence of a low-valent metal. This article relates to esters and new manufacturing technology.

<Prior art> The importance of vitamin D metabolites as regulators of calcium and phosphate metabolism in the human body is
It has been well recognized through many disclosures in patents and general literature, and it has been clinically used as a therapeutic agent for various diseases, including some that have the ability to induce differentiation of tumorous bone marrow cells. We are seeing an increase in the number of applications.

Furthermore, a new vitamin _D3 metabolite with a lactone unit in the steroid side chain was discovered [Biochemstry 18 , 4775]
−4780, (1979), Hebrew Letters (FEBS
LETTERS) 134 , 207-211, (1981)]. These compounds are 25-hydroxyvitamin _D3-26 ,
23-lactone and 1α,25-dihydroxy-vitamin D ₃ -26,23-lactone, which has the structure shown below.

These compounds exhibit vitamin D3 _- like activity,
It is known to play an important role in controlling calcium and phosphate levels in the body (Japanese Patent Publication No.
-118516).

<Object of the invention> The present inventors have discovered that 25-hydroxyvitamin D ₃ −
26,23-lactone, 1α,25-dihydroxyvitamin D ₃ -As a result of intensive research to synthesize steroids useful as intermediates for the synthesis of vitamin D ₃ related compounds such as 26,23-lactone, we found that steroids with a skeleton number of 23 carbon atoms The present invention was achieved by discovering a new synthetic route for synthesizing a useful new steroid compound having 27 carbon atoms by adding 2-halomethylpropenoic acid esters to norcollenaldehydes.

<Structure and effects of the invention> In the present invention, the following formula [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to C ₁₀ alkyl group, R ² and R ³ are the same or different,
Represents a hydrogen atom or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom or OR ⁵ , where R ⁵ represents R ² and R ³
Represents a group that is the same or different from and forms an acetal bond with a hydrogen atom or an oxygen atom of a hydroxyl group. ] A steroid compound having 27 carbon atoms in the skeleton is provided.

The novel steroid derivative represented by the general formula [ ] of the present invention has a basic skeleton of a steroid having 27 carbon atoms, and has a hydroxyl group, an unsaturated bond, and an ester group on the side chain. It is useful as an intermediate in the synthesis of various vitamin _D3 analogs whose chains are modified with various functional groups. For example, it is an intermediate for the synthesis of vitamin _D3 metabolites having an α-hydroxylactone ring on the side chain as we separately propose.

Furthermore, since the novel steroid compound of the present invention has an α,β-unsaturated ester group in its molecule, it is itself a useful compound that can be expected to have pharmacological effects such as antitumor activity and antiviral activity.

In the above formula [], R ¹ represents a hydrogen atom or a C ₁ to C ₁₀ alkyl group. Examples of the alkyl group of the C ₁ to _{C 10} alkyl group include a methyl group,
Examples include linear or branched alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, bentyl group, and hexyl group.

In the above formula [], R ² and R ³ are the same or different and represent a hydrogen atom or a group that forms an acetal bond with the oxygen atom of a hydroxyl group.
Examples of groups that form an acetal bond with the oxygen atom of a hydroxyl group include methoxymethyl group, 1
Examples include -ethoxyethyl group, 2-methoxy-2-propyl group, (2-methoxyethoxy)methyl group, benzyloxymethyl group, 2-tetrahydropyranyl group, and 2-tetrahydrofuranyl group. Among these, methoxymethyl group and 2-tetrahydropyranyl group are particularly preferred.

In the above formula [], R ⁴ is a hydrogen atom or
represents OR ⁵ , where R ⁵ is the same as or different from R ² and R ³ and represents a hydrogen atom or a group that forms an acetal bond with the oxygen atom of a hydroxyl group.

Preferred examples of the group forming an acetal bond with the oxygen atom of the hydroxyl group include the same groups as exemplified above for R ² and R ³ .

Preferred specific examples of the steroid compound represented by the above formula [] and having 27 carbon atoms in the skeleton provided by the present invention include the compounds shown below.

(101) 23-Hydroxy-3β-methoxymethoxy-cholester-5,25-diene-26-ethyl uccinate (102) 23-hydroxy-1α,3β-di(methoxymethoxy)-cholesta-5,25-diene- 26−
Examples include, but are not limited to, ethyl otsucate.

Skeletal carbon number of the present invention represented by the above formula []
The 27 steroid compounds have the following formula [] [In the formula, R ³¹ represents a group that forms an acetal bond together with the oxygen atom of a hydroxyl group, R ⁴¹ represents a hydrogen atom or OR ⁵¹ , and R ⁵¹ represents R ³¹
It is the same as or different from , and represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] Norkolenaldehydes with a skeleton carbon number of 23 represented by the following formula [ ] [Wherein, X represents Cl, Br, or I,
R″ represents a C ₁ to C ₁₀ alkyl group.] 2-halomethylpropenoic acid ester represented by the following is subjected to a nucleophilic addition type reaction to an aldehyde in the presence of a low-valent metal having reducing power,
It is produced by carrying out protection and/or deprotection reactions as necessary. Norcholenaldehydes having 23 skeletal carbon atoms and represented by the above formula [], which are used as raw materials in the present invention, can be obtained from cholenic acids, which are concentrated known compounds, by the method shown in Process Scheme 1.

[In the formula, R ³¹ R ⁴¹ is the same as defined in the above formula []. ] That is, the methyl cholenate derivative [ ] can be prepared by known means (for example, lithium silipropylamide,
After reacting with a base such as lithium hexamethylsilazane, oxygen gas or molybdenum oxide
The C-23 position can be hydroxylated by a method of reacting with an oxidizing agent such as pyrisine-hexamethylphosphoramide complex to lead to [ ]. Furthermore, the hydroxy ester [ ] can be led to the diol [ ] by reducing the ester group to an alcohol group by a hydrogenation test such as lithium aluminum hydride.

Diol[] can be converted to aldehyde[] by well-known means (e.g., oxidative cleavage reaction using oxidizing agents such as sodium periodate or lead tetraacetate).
can lead to. Step 1 like this,
Reactions 2 and 3 are well known in this technical field, and some of the synthetic agents are listed as reference examples.

The following formula [] is applied to the thus obtained norkolene aldehyde [] [In the formula, X represents Cl, Br, or I, and R″ is
Represents a _C1 - _C10 alkyl group. ] When 2-halomethylpropenoic acid esters represented by the following are reacted in the presence of a low-valent metal having reducing power, a steroid compound represented by the formula [] is obtained.

In the above formula [], X represents chlorine, bromine or iodine, with bromine being particularly preferred. R″ is C ₁ ~
Represents a C ₁₀ alkyl group. Examples of _C1 to _C10 alkyl groups include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group,
sec-butyl group, tert-butyl group, pentyl group,
Examples include linear or branched ones such as hexyl groups.

Particularly preferred is ethyl group, but it is not limited thereto.

The low valence metals with reducing power used in the reaction between norkolene aldehydes [] and 2-halomethylpropenoic acid esters [] include:
For example, zinc, tin, magnesium, manganese,
Examples include bismuth, cerium, and chromium chloride. These metals can be used as powders, prepared in-system by reducing their chlorides with lithium aluminum hydride, potassium metal, or the like, or used as metal amalcum. Particularly preferred are metallic tin powder, metallic zinc powder and chromium chloride (2) prepared from chromium chloride (2) and lithium aluminum hydride.

Usually, the 2-halomethylpropenoic acid ester [] and the low valence metal are used in an amount of 0.8 to 10 equivalents, particularly preferably 1 to 2 equivalents, relative to the norkolenaldehyde []. Although the reaction temperature varies depending on the metal used, a temperature range of -78°C to 80°C, preferably -20°C to 30°C, particularly preferably 15 to 25°C is employed. The reaction time is usually about 30 minutes to 3 days, but with thin layer chromatography etc.
It is preferable to observe the progress of the reaction.

The reaction is carried out in an organic solvent or in water and a mixed solvent thereof. The solvent used varies depending on the metal used, but any solvent may be used as long as it does not react with the reaction reagent.

Preferably N,N-dimethylformamide,
Examples include N,N-dimethylacetamide, hexamethylene phosphoramide, tetraledrofuran, diethyl ether, and the like.

The reaction solution thus obtained can be post-treated, extracted, washed, dried, concentrated, and purified by chromatographic separation, recrystallization, etc. using conventional methods. At this time, the two C-23 stereoisomers of the product are in a so-called diastereomer relationship and can be separated by column chromatography, liquid chromatography, etc. The product thus obtained is subjected to a protection and/or deprotection reaction of the substituent at the 1-position, 3-position, or 23-position, which is known per se, in the steroid compound represented by the above formula [], as necessary. The ester group at the 26th position is subjected to a hydrolysis reaction and/or the ester group at the 26th position is subjected to a transesterification reaction to yield a steroid compound having 27 carbon atoms in the skeleton represented by the formula [ ].

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Reference Example 1 Synthesis of 23-hydroxy-1α,3β-(methoxymethoxy)-methyl cholate [] Diisopropylamine (0.81
g, 8.0 mmol) in tetrahydrofuran (30 ml) was added a 1.6 M hexane solution of n-butyllithium (5.0 ml, 8.0 mmol) at -78°C, and the mixture was stirred for 30 minutes. Add 1α,3β-di(methoxymethoxy) to this solution.
- A solution of methyl cholenate (2.04 g, 4.1 mmol) in tetrahydrofuran (30 ml) was added, and the mixture was stirred at -78°C for 30 minutes. Next, this reaction solution was stirred at -78°C for 1 hour while blowing dry oxygen gas. After stopping the oxygen gas blowing, triethyl phosphite (1.6 ml, 10 mmol) was added, and the mixture was stirred at -78°C for 1 hour and then at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer obtained was washed with brine, dried over anhydrous magnesium sulfate, and concentrated after washing to obtain a crude product. This product was separated by silica gel column chromatography (hexane:ethyl acetate 3:1), and methyl 23-hydroxy-1α,3β-di(methoxymethoxy)cholate (1.16 g,
2.28 mmol, 55%) was obtained. ^1H -NMR ( _CDCl3 , δ (ppm)); 0.6-2.4
(m.24H), 0.71 (s.3H), 0.99 (s.3H) 3.26
(s.3H), 3.32 (s.3H), 3.65 (s.3H), 3.4−
4.1 (m.4H), 4.58 (s.2H), 4.59 (q.2H.J=6
Hz), 5.3-5.5 (m.1H) Reference example 2 Synthesis of 1α,3β-di(methoxymethoxy)-5-cholene-23,24 diol [] Lithium aluminum hydride (1.16 g, 2.28 mmol) under nitrogen stream ) of tetrahydrofuran (20
ml) To the suspension, a solution of methyl 23-hydroxy-1α,3β-di(methoxymethoxy)-cholenate (212 mg, 5.5 5 mmol) synthesized in Reference Example 1 in tetrahydrofuran (30 ml) was slowly added dropwise at 0°C. did.
After stirring this at room temperature for 2 hours, diethyl ether (50 ml) was added, and then a saturated aqueous solution of sodium sulfate was added to decompose the excess reagent. The organic layer was collected, dried over anhydrous magnesium sulfate, and concentrated after heating to obtain a crude product. The product was obtained. This product was subjected to silica gel column chromatography (hexane: ethyl acetate).
1α,3β-di(methoxymethoxy)-5-cholene-23,24 diol (0.76 g,
1.59 mmol, 69%) was obtained. ^1H -NMR ( _CDCl3 , δ (ppm)); 0.6-2.4
(m.24H), 0.71 (s.3H), 0.97 (s.3H), 3.25
(s.3H), 3.29 (s.3H), 3.2−4.1 (m.5H),
4.55 (s.2H), 4.55 (q.2H.J=6Hz), 5.3−
5.5 (m.1H) IR (neat, cm ^-1 ): 3400, 2950, 1460, 1370,
1150, 1100, 1040, 910. Reference Example 3 Synthesis of 1α,3β-di(methoxymethoxy)-24-norchola-5-en-23-al[] 1α,3β-di(methoxymethoxy) synthesized in Example 2 )-5-cholene-23,24-diol (0.76
30 ml of methanol and 10 ml of water were added to a solution of tetrahydrofuran (30 ml), and then a solution of sodium periodate (0.50 g, 2.3 mmol) in water (20 ml) was added at room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to about 20 ml, 50 ml of water was added, and then extracted with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a crude product. This product was separated by silica gel column chromatography (hexane: ethyl acetate 6:1), 1α,
3β-di(methoxymethoxy)-24-norcola-5
-en-23-ar (0.49g, 1.09mmol, 68%)
I got it. ^1H -NMR ( _CDCl3 , δ (ppm)); 0.6-2.5
(m.24H), 0.72 (s.3H), 0.99 (s.3H), 3.27
(s.3H), 3.31 (s.3H), 3.3−4.0 (m.2H),
4.56 (s.2H), 4.57 (q.2H.J=6Hz), 5.3−
5.5 (m.1H), 9.59 (m.1H). IR (neat, cm ^-1 ): 2950, 1715, 1460, 1380,
1150, 1100, 1040, 910. Example 1 Synthesis of ethyl 23-hydroxy-3β-methoxymethoxy-cholesta-5.25-diene-26-otsuccinate Lithium aluminum hydride (158 mg, 4.1 mmol) was added little by little to a suspension of chromium chloride (1269 mg, 8.0 mmol) in tetrahydrofuran (10 ml) at 0°C, the temperature was raised to room temperature, and the mixture was stirred for 20 minutes. 3β-methoxymethyl-24-norcola-5-23
A solution of -R (779 mg, 2.0 mmol) in tetrahydrofuran (10 ml) was added, followed by slowly adding ethyl 2-bromomethylpropenoate (772 mg, 4.0 mmol), and the mixture was stirred at 25°C for 12 hours. The reaction mixture was poured into ice water, 1N hydrochloric acid was added, and the organic matter was extracted with ethyl acetate. The obtained organic layer was washed successively with 1N hydrochloric acid and brine, dried over anhydrous magnesium sulfate, concentrated after washing to obtain a crude product, and subjected to silica gel column chromatography (hexane: ethyl acetate = 6: 1) to separate the desired 23-hydroxy-3β-methoxymethoxy-
C-23-stereoisomer of cholesta-5.25-diene-26-ethyl ectucate, IA (258 mg,
0.5mmol, 25%) and IB (182mg, 0.36mmol,
18%).

(Spectral data of isomer IA) NMR (CDCl ₃ , δ (ppm)); 0.68 (s.3H), 0.95
(s.3H), 0.6-2.2 (m.28H), 1.24 (t.3H.J=
7Hz), 3.25 (s.3H), 3.1-4.0 (m.2H),
4.08 (q.2H.J=7Hz), 4.52 (s.2H), 5.2
(m.1H), 5.47 (m.1H), 6.06 (d.1H.J=2
Hz). IR (KBr.cm ^-1 ): 3500, 2970, 1715, 1630, 1370,
1340, 1220, 1150, 1110, 1050, 1040,
950, 910. MS (EI, m/e): 440 (M ⁺ -CH ₃ OCH ₂ OH),
394, 273, 255, (FD, m/e): 503 (M ⁺
+1) (Spectrum data of isomer B) NMR (CDCl ₃ , δ (ppm)); 0.67 (s.3H), 0.95
(s.3H), 0.6-2.2 (m.29H), 1.24 (t.3H.J=
7Hz), 3.24 (s.3H), 3.1-4.0 (m.2H),
4.09 (q.2H.J=7Hz), 4.53 (s.2H), 5.2
(m.1H), 5.50 (m.1H), 6.08 (d.1H.J=2
Hz). IR (KBr.cm ^-1 ): 3500, 2970, 1715, 1630, 1370,
1340, 1226, 1150, 1110, 1050, 1040,
950, 910. Example 2 Synthesis of ethyl 23-hydroxy-1α,3β-di(methoxymethoxy)-cholesta-5.25-diene-26-oitucate Using 1α,3β-di(methoxymethoxy)-24-nor-5-cholene-23-al as the starting material, the same reaction as in Example 1 was carried out to give 23-hydroxy-1α,3β-di(methoxymethoxy). The stereoisomers of ethyl -cholesta-5,25-diene-26-otschate were obtained: IC (33%) and ID (24%).

(Spectral data of isomer IC) NMR (CDCl ₃ , δ (ppm)); 0.71 (s.3H), 1.00
(s.3H), 1.27 (t.3H.J=7Hz), 0.6−2.5
(m.26H), 3.34 (s.3H), 3.5−4.1 (m.4H),
4.19 (q.2H.J=7Hz), 4.64 (s.2H), 4.64
(q.2H.J=6Hz), 5.4-5.7 (m.2H), 6.23
(d.1H.J=2Hz). IR (neat.cm ^-1 ): 3500, 2950, 1710, 1630,
1460, 1370, 1145, 1100, 1030, (ID spectrum data) NMR (CDCl ₃ , δ (ppm)); 0.71 (s.3H), 0.99
(s.3H), 1.27 (t.3H.J=7Hz), 0.6−2.6
(m.26H), 3.33 (s.3H), 3.36 (s.3H), 3.6−
4.1 (m.3H), 4.20 (q.2H.J=7Hz), 4.63
(s.2H), 4.63 (q.2H.J=6Hz), 5.4−5.6
(m.2H), 6.25 (d, 1H, J=2Hz). IR (neat.cm ^-1 ): 3500, 2950, 1710, 1625,
1460, 1370, 1145, 1100, 1035. Example 3 Under a nitrogen stream, ethyl 2-lomomethyl-propenoate (80 mg, 0.4 mmol), then aluminum powder (8 mg, 0.3 mmol) and tin powder (36 mg,
0.3mM) and stir at room temperature for 24 hours. 2 ml of 1N hydrochloric acid was added to the reaction mixture, stirred for 5 minutes, extracted with methylene chloride, and the organic layer was washed with an aqueous sodium bicarbonate solution and brine in sequence, dried over anhydrous magnesium sulfate, and concentrated after washing. A crude product was obtained. This product was separated by silica gel column chromatography (hexane: ethyl acetate 6:1), and the C-23 Stereoisomer IA (14 mg, 9%)
and IB (18 mg, 12%). These spectra matched those of IA and IB synthesized in Example 1.

Example 4 Synthesis was carried out in the same manner as in Example 3 using tin powder (2 equivalents) instead of aluminum powder-tin powder, resulting in the same products IA (15%),
IB (12%) was obtained.

Example 5 In the same manner as in Example 3, bismuth powder (1.5 equivalents) was used instead of aluminum powder-tin powder, and N, N was used instead of tetrahydrofuran as a solvent.
- Identical products IA (10%) and IB (9%) were obtained when the synthesis was carried out using dimethylformamide.

Claims (1)

[Claims] 1. The following formula [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to C ₁₀ alkyl group, R ² and R ³ are the same or different,
Represents a hydrogen atom or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom or OR ⁵ , where R ⁵ represents R ² and R ³
is the same as or different from , and represents a group that forms an acetal bond with a hydrogen atom or an oxygen atom of a hydroxyl group. ] A steroid compound represented by 2. The steroid compound according to claim 1, wherein R ² is a hydrogen atom, a methoxymethyl group, or a tetrahydropyranyl group. 3. The steroid compound according to claim 1 or 2, wherein R ³ is a methoxymethyl group or a tetrahydropyranyl group. 4. The steroid compound according to claim 1, wherein R ² and R ³ are hydrogen atoms. 5. The steroid compound according to any one of claims 1 to 4, wherein R ⁴ is a hydrogen atom. 6. The steroid compound according to any one of claims 1 to 4, wherein R ⁴ is OR ⁵ and R ⁵ is a hydrogen atom, a methoxymethyl group, or a tetrahydropyranyl group. 7. The steroid compound according to claim 6, wherein R ⁴ is OH, and R ² and R ³ are hydrogen atoms. 8. The steroid compound according to any one of claims 1 to 7, wherein the asymmetric center of C-23 has an (R)-sequence. 9. The steroid compound according to any one of claims 1 to 7, wherein the asymmetric center of C-23 has an (S)-sequence. 10 The following formula [] [In the formula, R ³¹ represents a group that forms an acetal bond with the oxygen atom of the hydroxyl group, R ⁴¹ represents a hydrogen atom,
or OR ⁵¹ , where R ⁵¹ is the same as or different from R ³¹ and represents a group that forms an acetal bond with the oxygen atom of a hydroxyl group. ] Steroid-23-aldehydes represented by
The following formula [] [In the formula, X represents Cl, Br, I, and R″ is C ₁
~ Represents a _{C 10} alkyl group. ] The 2-halomethylpropenoic acid esters represented by the formula [] are subjected to an addition reaction in the presence of a low-valent metal having reducing power, and the 1st and 3rd positions of the steroid compound represented by the following formula [] are reacted as necessary.
or 23-position substituents and/or
or protection, and/or the ester group at the 26th position is subjected to a hydrolysis reaction, and/or the ester group at the 26th position is subjected to a transesterification reaction [] [In the formula, R ¹ represents a hydrogen atom or a C ₁ to C ₁₀ alkyl group, R ² and R ³ are the same or different,
Represents a hydrogen atom or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R ⁴ represents a hydrogen atom or OR ⁵ , where R ⁵ represents R ² and R ³
is the same as or different from , and represents a group that forms an acetal bond with a hydrogen atom or an oxygen atom of a hydroxyl group. ] A method for producing a steroid compound represented by 11 2-halomethylpropenoic acid esters are 2
- ethyl bromomethylpropenoate. 12. The production method according to claim 10 or 11, wherein the low valence metal having reducing power is zinc. 13. The manufacturing method according to claim 10 or 11, wherein the low valence metal having reducing power is tin. 14 Claim 10 or 1, wherein the low-valent metal having reducing power is chromium chloride ()
The manufacturing method described in item 1. 15. The production method according to claim 10 or 11, wherein the low valence metal having reducing power is magnesium, manganese, cerium, a mixture of tin and aluminum, or bismuth.