CN104693087A - 24, 28-ene-1alpah-hydroxyl vitamin D derivatives and preparation method thereof - Google Patents

Abstract

The invention discloses 24, 28-ene-1alpah-hydroxyl vitamin D derivatives and a preparation method thereof, and particularly relate to two synthesized novel vitamin D derivatives 24, 28-ene-1alpha-hydroxyl vitamin D2 and 24, 28-ene-1alpha-hydroxyl vitamin D3. By taking aldehyde of vitamin D2 as a raw material, the 24, 28-ene-1alpha-hydroxyl vitamin D2 is synthesized by four-step reaction and the 24, 28-ene-1alpha-hydroxyl vitamin D3 is synthesized by five-step reaction. The invention discloses a synthetic method of two vitamin D derivatives, and the synthetic raw materials are easily available, the reaction condition is mild and the yield is relatively high.

Description

24,28-ene-1α-hydroxyvitamin D derivatives and preparation method thereof

technical field

The invention belongs to the field of synthesis of vitamin _D3 derivatives, in particular to the synthesis of two new vitamin D derivatives 24,28-ene-1α-hydroxyvitamin _D2 and 24,28-ene-1α-hydroxyvitamin _D3 method.

Background technique

Vitamin D compounds in the human body are mainly transformed by cholesterol compounds (such as: 7-dehydrocholesterol, ergosterol) on the surface of the skin through ultraviolet radiation. The produced vitamin D is then transported to the liver through the blood, and is first metabolized into 25-hydroxyvitamin D ₃ by the 25-hydroxylase in the liver, and then 1α, 25-dihydroxyvitamin D is obtained by hydroxylation at the 1α-position in the kidney ₃ . In addition to the well-known function of regulating calcium balance in the body, 1α, 25-dihydroxyvitamin D ₃ has also been found in recent years to have the function of inhibiting the excessive proliferation of keratinocytes and inducing the differentiation of keratinocytes, which can be used to regulate epidermal growth, keratin and inflammation, inhibit psoriasis, treat malignant tumors and leukemia, etc., but in therapeutic doses, long-term use can cause side effects such as hypercalciuria, hypercalcemia, nephrocalcinosis, nephrolithiasis and soft tissue calcification. restricted. Therefore, developing a vitamin D analog that can reduce calcium activity and increase cell differentiation activity to inhibit psoriasis has become the main development direction of vitamin D analog research today.

In order to overcome the side effects of vitamin metabolites, people try to synthesize various vitamin D derivatives. Most of the analogs synthesized to date have focused on side chain modifications. Many side chain modified vitamin D derivatives have become specific drugs or have entered the stage of clinical testing. 1α, 24R-dihydroxyvitamin D analogs calcipotriol (MC903) and tacalcitol (TV-02) were marketed as anti-psoriasis drugs in 1991 and 1993 respectively; Cancer drugs have entered clinical phase III testing.

In 2007, Kimberly S et al. reported that in the absence of the 25-hydroxyl group, a series of vitamin D ₃ derivatives exhibited high anti-proliferative activity and low calcium activity. Among them, compound I and compound II exhibit higher antiproliferative activity and lower side effects of hypercalcemia than 1α, 25-dihydroxyvitamin _D3 .

In recent years, some natural products of vitamin D precursor cholesterol have been extracted from marine organisms. The common feature is that the branched chain is 2-isopropyl-1-butene, and the isolated compounds show good biological activity. For example: compound III has good anti-inflammatory activity, and compound IV has certain anti-cancer activity in addition to good anti-inflammatory activity. Compound V has significant neuroprotective activity. These compounds may form derivatives of vitamin _D3 as shown in formula I after ultraviolet irradiation on the skin surface of animals and humans.

 

Contents of the invention

The object of the present invention is to provide two kinds of synthetic new vitamin D compounds 24,28-ene-1α-hydroxyvitamin _D2 and 24,28-ene-1α-hydroxyvitamin _D3 with naturally occurring vitamin D2 as raw _material method.

Realize the technical scheme of the present invention as:

24,28-ene-1α-hydroxyvitamin D derivatives, the structure has the following general formula:

  Specifically, it is a synthesis method of 24,28-ene-1α-hydroxyvitamin D ₂ shown in formula 6 and 24,28-ene-1α-hydroxyvitamin D ₃ shown in formula 9.

24,28-ene-1α-hydroxyvitamin D derivatives, the preparation method is as follows:

(1) Synthesis of compound 2: under nitrogen protection, add (3-methyl-2-oxobutyl) diethyl phosphate to the solution of sodium hydrogen in anhydrous tetrahydrofuran, stir at room temperature for a period of time and then add compound 1 in anhydrous THF, reflux reaction. After the reaction was completed, it was slowly poured into water, extracted, washed, dried, concentrated and subjected to column chromatography to obtain compound 2;

(2) Synthesis of Compound 3: Compound 2, sodium dithionite, sodium bicarbonate and tri-decylmethylammonium chloride were dissolved in a mixed solvent of toluene and water, reflux reaction under nitrogen protection, and extracted after the reaction , washed, dried, concentrated and then separated by column chromatography to obtain compound 3;

(3) Synthesis of compound 4 or 7: under nitrogen protection, add sodium hydrogen and methyltriphenylphosphine bromide into anhydrous THF, stir at a certain temperature for a period of time, then add compound 3 or compound 2 in THF, Reflux reaction, after the reaction is completed, slowly pour into water for extraction, wash, dry, filter, concentrate and then separate by column chromatography to obtain compound 4 or compound 7;

(4) Synthesis of Compound 5 or 8: Dissolving Compound 4 or Compound 7 and 9-acetylanthracene in toluene, irradiating with a high-pressure mercury lamp at room temperature, and distilling off the solvent after the reaction to obtain Compound 5 or Compound 8;

(5) Synthesis of compound 6 or 9: Dissolve compound 5 or compound 8 in THF, add TBAF THF solution, reflux reaction, slowly pour the reaction system into water, extract, wash, dry, concentrate and separate by column chromatography Compound 6 or Compound 9 was obtained.

Wherein, the dosage ratio of sodium hydrogen, (3-methyl-2-oxobutyl) diethyl phosphate and compound 1 in step (1) is 1.1:1.2:1.0-2.5:3.0:1.0. (3-Methyl-2-oxobutyl) diethyl phosphate is added to the tetrahydrofuran solvent of sodium hydrogen and needs to be stirred at room temperature for 0.5h-1h before adding the tetrahydrofuran solution of compound 1.

The reaction water in step (2) should use freshly treated deionized water or distilled water.

In step (3), the amount ratio of sodium hydrogen, methyltriphenylphosphorus bromide and compound 3 or compound 2 is 1.1:1.1:1.0-2.5:2.5:1.0, and the ratio of methyltriphenylphosphorus bromide and sodium hydrogen The tetrahydrofuran solution needs to be stirred at 40°C under reflux for 0.5h-1h before adding the tetrahydrofuran solution of compound 3 or compound 2.

The light in step (4) needs to use 9-acetyl anthracene (9-AA) as a catalyst, and 300-400nm ultraviolet light irradiates the reaction.

In step (5), the usage ratio of tetrabutylammonium fluoride and compound 5 or compound 8 is 1.2: 1.0- 5.0: 1.0.

Compared with the prior art, the present invention has the following significant advantages: (1) The branched chain of vitamin D ₂ is modified, and the target compounds 24,28-ene-1α-hydroxyvitamin D ₂ and 24,28-ene- 1α-Hydroxyvitamin D ₃ . Use it to obtain drugs with excellent biological activity and low side effects of hypercalcemia, especially as drugs for treating skin diseases such as psoriasis; (2) The synthesis method of two vitamin D derivatives is disclosed for the first time ; (3) Synthetic raw materials are readily available, the reaction conditions are mild, and the yield is high.

Description of drawings

Fig. 1 is a flowchart of the synthesis method of 24,28-ene-1α-hydroxyvitamin D ₃ of the present invention.

Fig. 2 is a flowchart of the synthesis method of 24,28-ene-1α-hydroxyvitamin D ₂ of the present invention.

Fig. 3 is a ( ¹ H NMR, 500 MHz, solvent: CDCl ₃ ) nuclear magnetic resonance spectrum of 24,28-ene-1α-hydroxyvitamin D ₃ .

Fig. 4 is a ( ¹³ C NMR, 125 MHz, solvent: CDCl ₃ ) nuclear magnetic resonance spectrum of 24,28-ene-1α-hydroxyvitamin D ₃ .

Fig. 5 is a ( ¹ H NMR, 500 MHz, solvent: CDCl ₃ ) nuclear magnetic resonance spectrum of 24,28-ene-1α-hydroxyvitamin D ₂ .

Fig. 6 is a ( ¹³ C NMR, 125 MHz, solvent: CDCl ₃ ) nuclear magnetic resonance spectrum of 24,28-ene-1α-hydroxyvitamin D ₂ .

the

Specific implementation method

In conjunction with Fig. 1, the synthetic method of 24,28-ene-1α-hydroxyvitamin D ₃ , the steps are as follows:

Step 1 Synthesis of compound 2: under nitrogen protection, (3-methyl-2-oxobutyl) diethyl phosphate was added to NaH in anhydrous tetrahydrofuran solution, stirred at room temperature for 30 min, and then the compound 1 without Aqueous THF solution was added to the reaction system, and the reaction was refluxed. After the reaction was completed, the reaction system was slowly poured into water, extracted, washed, dried, concentrated and subjected to column chromatography to obtain compound 2.

Step 2 Synthesis of compound 3: compound 2, Na ₂ S ₂ O ₄ , NaHCO ₃ and tri-decylmethylammonium chloride were dissolved in a mixed solvent of toluene and water, and reflux reaction was carried out under the protection of nitrogen. After extraction, washing, drying, and concentration, compound 3 was obtained by column chromatography.

Step 3 Synthesis of compound 4: Add NaH and methyltriphenylphosphine bromide to tetrahydrofuran under nitrogen protection, stir at 45°C for 60 min, then add the anhydrous tetrahydrofuran solution of compound 3 into the reaction system, and reflux for reaction. After the reaction, the reaction system was slowly poured into water for extraction, washed, dried, filtered, concentrated and then separated by column chromatography to obtain compound 4. the

Step 4 Synthesis of Compound 5: Compound 4 and 9-acetylanthracene were dissolved in toluene and irradiated by a high-pressure mercury lamp at room temperature for 90 minutes. After the reaction, the solvent was evaporated to obtain Compound 5.

Step 5 Synthesis of Compound 6: Dissolve Compound 5 in THF, add THF solution of TBAF, reflux reaction, slowly pour the reaction system into water, extract, wash, dry, concentrate and then separate by column chromatography to obtain Compound 6. the

In conjunction with Fig. 2, the synthetic method of 24,28-ene-1α-hydroxyvitamin D ₂ , the steps are as follows:

Step 1 Synthesis of Compound 7: NaH and methyltriphenylphosphine bromide were added to anhydrous THF, stirred at 45°C for 60 min, then the anhydrous THF solution of Compound 2 was added to the reaction system, and refluxed. After the reaction, it was slowly poured into water for extraction, washed, dried, filtered, concentrated and then separated by column chromatography to obtain compound 7. the

Step 2 Synthesis of Compound 8: Compound 7 and 9-acetylanthracene were dissolved in toluene, and irradiated by a high-pressure mercury lamp at room temperature for 90 minutes. After the reaction, the solvent was evaporated to obtain Compound 8.

Step 3 Synthesis of Compound 9: Dissolve Compound 8 in THF, add THF solution of TBAF, reflux reaction, slowly pour the reaction system into water, extract, wash, dry, concentrate and then separate by column chromatography to obtain Compound 9.

In the above synthesis steps, TLC was used to track the reaction process and judge the reaction end point.

the

The present invention will be further described below through specific examples, but the present invention is not limited to the following examples, and within the scope not departing from the purpose described before and after, all changes and implementations are included in the technical scope of the present invention.

the

Embodiment 1: the synthesis of compound 2

Under nitrogen protection, a solution of (3-methyl-2-oxobutyl) diethyl phosphate (1.49g, 6.72mmol) in anhydrous THF was added dropwise to NaH (60%, 269mg, 6.72mmol) in anhydrous THF The solution was stirred at room temperature for 30 min, then a solution of compound 1 (3.5 g, 6.11 mmol) in anhydrous THF was added dropwise, and the reaction mixture was heated to reflux for 2 hours. After TLC showed that the reaction was complete, the reaction system was slowly poured into water, extracted with EA, the organic layer was washed with water, washed with saturated brine, dried, filtered, and the solvent was evaporated, and the residue was subjected to column chromatography (SiO ₂ , PE: Et ₂ O =100:3) to obtain 3.53g of compound 2 as a white solid. ¹ H NMR(500MHz, CDCl ₃ ): δ: 6.73(1H,m), 6.46(1H, d, J=11.4Hz), 6.09(1H, d, J=15.7Hz), 5.83(1H, d, J =11.4Hz), 4.98(2H, d, J=20.3Hz), 4.54(1H, m),4.23(1H, m), 1.11(9H, m), 0.91(9H, s), 0.87(9H, s ), 0.59(3H, s), 0.07(12H, s).

Example 2: Synthesis of Compound 3

Compound 2 (2.7g, 4.21mmol), Na ₂ S ₂ O ₄ (7.33g, 42.1mmol), NaHCO ₃ (3.54g, 42.1mmol) and tri-decylmethylammonium chloride dissolved in toluene and water In a mixed solvent, the reaction mixture was refluxed for 3 h at 80° C. under nitrogen protection, and TLC showed that the reaction was complete. The reaction mixture was cooled to room temperature, then ethyl acetate and water were added to the reaction system, the organic layer was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to obtain a yellow oil. After column separation, 2.12 g of compound 3 was obtained as a white solid. ¹ H NMR (500MHz, CDCl ₃ ): δ: 6.46 (1H, d, J=11.5Hz), 5.82 (1H, d, J=11.5Hz), 4.96 (2H, d, J=21.6Hz), 4.54 ( 1H, m), 4.22 (1H, m), 1.09 (6H, d, J=6.9Hz), 0.92 (3H, d, J=6.9Hz), 0.90 (9H, s), 0.86 (9H, s), 0.54 (3H, s), 0.06 (12H, s).

Example 3: Synthesis of Compound 4

Under the protection of nitrogen, 60% NaH (144mg, 3.6mmol) and methyltriphenylphosphine bromide (1.39g, 3.9mmol) were added into anhydrous THF, stirred at 45°C for 60min, and then compound 3 (1.92g , 3mmol) anhydrous tetrahydrofuran solution was added to the reaction system, and refluxed for 2 hours. TLC showed that the reaction was complete, and the reaction mixture was slowly poured into water, extracted with EA, the organic layer was washed with water, washed with saturated brine, dried, filtered, and the solvent was evaporated, and the residue was subjected to column chromatography (SiO ₂ , PE: Et ₂ O= 100:1) to obtain 1.85 g of compound 4 as a white solid. ¹ H NMR(500MHz, CDCl ₃ ): δ: 6.47(1H, d, J=11.5Hz), 5.84(1H, d, J=11.5Hz), 4.98(2H, d, J=24.2Hz), 4.71( 2H, d, J=27.8Hz), 4.55(1H, m), 4.24(1H, m), 1.05(3H, d, J=6.85Hz), 1.04(3H, d, J=6.85Hz), 0.97( 3H, d, J=6.5Hz), 0.91(9H, s), 0.89(9H, s), 0.56(3H, s), 0.08(12H, s).

Embodiment 4: the synthesis of compound 5

Compound 4 (1.28g, 2.0mmol) was dissolved in toluene, 9-acetylanthracene (200mg) was added, irradiated with 365nm ultraviolet light generated by a 500W high-pressure mercury lamp for 90 minutes, TLC showed that the reaction was complete. The solvent was evaporated to obtain compound 5 as a yellow solid. The residue was directly carried on to the next reaction without purification.

Embodiment 5: the synthesis of compound 6

Dissolve the compound 5 mixture obtained in the previous step in THF, add a THF solution of TBAF (10mL, 1M), and reflux for 3 hours. TLC shows that the reaction is complete. Slowly pour the reaction system into water, extract with EA, and wash the organic layer with water. , washed with saturated brine, dried, filtered, and evaporated to remove the solvent, the residue was subjected to column chromatography (SiO2, PE:EA=4:1), and recrystallized to obtain 683 mg of compound 6 as colorless crystals. ¹ H NMR(500MHz, CDCl ₃ ): δ:6.36(1H, d, J=11.0Hz),6.02(1H, d, J=11.3Hz), 5.32(1H, s), 4.99(1H, s), 4.71(1H, s), 4.66(1H, s), 4.41(1H, m), 4.20(1H, m), 1.03(3H, d, J=6.85Hz), 1.02(3H, d, J=6.85Hz ), 0.95(3H, d, J=6.45Hz), 0.55(3H,s); ¹³ C NMR(500MHz, CDCl ₃ ): δ: 155.57, 146.45, 141.88, 131.91, 123.67, 115.92, 110.61, 104.81, 69.5 , 65.58, 55.28, 55.18, 44.76, 43.98, 41.64, 40.76, 39.33, 27.91, 26.44, 22.43, 21.12, 20.83, 20.69, 17.66, 10.84.

Embodiment 6: the synthesis of compound 7:

Under the protection of nitrogen, 60% NaH (418mg, 1.17mmol) and methyltriphenylphosphine bromide (386mg, 1.08mmol) were added into anhydrous THF, stirred at 45°C for 1 hour, and then compound 2 was added dropwise ( 580 mg, 0.9 mmol) in anhydrous THF, and the reaction mixture was heated to reflux for 2 hours. TLC showed that the reaction was complete, the reaction system was slowly poured into water, extracted with EA, the organic layer was washed with water, washed with saturated brine, dried, filtered, and the solvent was evaporated, and the residue was subjected to column chromatography (SiO ₂ , PE: Et ₂ O= 100:1) to obtain 546 mg of compound 18 as a white solid. ¹ H NMR(500MHz, CDCl ₃ ): δ: 6.48(1H, d, J=11.3Hz), 5.97(1H, d, J=15.8Hz), 5.84(1H, d, J=11.2Hz), 5.61( 1H, q), 4.98(2H, d, J=22.4Hz), 4.86(2H, d, J=16.2Hz), 4.56(1H, m), 4.24(1H, m), 1.10(9H, m), 0.92(9H,s), 0.89(9H,s), 0.56(3H,s), 0.08(12H,s).

Embodiment 7: the synthesis of compound 8:

Compound 7 (400mg, 0.63mmol) was dissolved in toluene, 9-acetylanthracene (70mg) was added, and 365nm ultraviolet light generated by a 500W high-pressure mercury lamp was irradiated for 90 minutes. TLC showed that after the reaction was complete, the solvent was evaporated to obtain compound 8. The yellow solid was directly carried on to the next reaction without purification.

Embodiment 8: the synthesis of compound 9:

The compound 8 obtained in the previous step was dissolved in THF, and a THF solution of TBAF (3.2mg, 1M) was added, and the reaction was refluxed for 3 hours. TLC showed that the reaction was complete. The reaction system was slowly poured into water, extracted with EA, and the organic layer was washed with water and saturated. Wash with brine, dry, filter, and evaporate the solvent. The residue is subjected to column chromatography (SiO2, PE:EA=4:1) and recrystallized to obtain 193 mg of compound 9 as colorless crystals. ¹ H NMR(500MHz, CDCl ₃ ): δ: 6.37(1H, d, J=11.0Hz),6.01(1H, d, J=11.0Hz), 5.94(1H, d, J=15.5Hz), 5.59( 1H, q), 5.32(1H, s), 4.99(1H, s), 4.82(2H, d, J=16Hz), 4.43(1H, m), 4.22(1H, m), 1.07(9H, m) , 0.57(3H,s).

Claims (7)

1.24,28-ene-1α-hydroxyvitamin D derivatives, characterized in that the structure has the following general formula: where R is or . 2. 24,28-ene-1α-hydroxyvitamin D derivatives according to claim 1, characterized in that the preparation method is as follows: (1) Synthesis of compound 2: under nitrogen protection, add (3-methyl-2-oxobutyl) diethyl phosphate to the solution of sodium hydrogen in anhydrous tetrahydrofuran, stir at room temperature for a period of time and then add compound 1 in anhydrous THF, reflux reaction, slowly poured into water after the reaction, extraction, washing, drying, concentration and column chromatography to obtain compound 2; (2) Synthesis of Compound 3: Compound 2, sodium dithionite, sodium bicarbonate and tri-decylmethylammonium chloride were dissolved in a mixed solvent of toluene and water, reflux reaction under nitrogen protection, and extracted after the reaction , washed, dried, concentrated and then separated by column chromatography to obtain compound 3; (3) Synthesis of compound 4 or 7: under nitrogen protection, add sodium hydrogen and methyltriphenylphosphine bromide into anhydrous THF, stir at a certain temperature for a period of time, then add compound 3 or compound 2 in THF, Reflux reaction, after the reaction is completed, slowly pour into water for extraction, wash, dry, filter, concentrate and then separate by column chromatography to obtain compound 4 or compound 7; (4) Synthesis of Compound 5 or 8: Dissolving Compound 4 or Compound 7 and 9-acetylanthracene in toluene, irradiating with a high-pressure mercury lamp at room temperature, and distilling off the solvent after the reaction to obtain Compound 5 or Compound 8; (5) Synthesis of compound 6 or 9: Dissolve compound 5 or compound 8 in THF, add TBAF THF solution, reflux reaction, slowly pour the reaction system into water, extract, wash, dry, concentrate and separate by column chromatography Compound 6 or Compound 9 was obtained. 3. The 24,28-ene-1α-hydroxyvitamin D derivative according to claim 2, characterized in that: in step (1), sodium hydrogen, (3-methyl-2-oxobutyl) phosphate di The dosage ratio of ethyl ester and compound 1 is 1.1:1.2:1.0-2.5:3.0:1.0; (3-methyl-2-oxobutyl) diethyl phosphate needs to be cooled at room temperature after being added to the tetrahydrofuran solvent of sodium hydrogen After stirring for 0.5h-1h, the solution of compound 1 in tetrahydrofuran was added. 4. The 24,28-ene-1α-hydroxyvitamin D derivative according to claim 2, characterized in that: freshly treated deionized water or distilled water is used for the reaction water in step (2). 5. The 24,28-ene-1α-hydroxyvitamin D derivative according to claim 2, characterized in that: sodium hydrogen, methyl triphenylphosphine bromide and compound 3 or compound 2 in step (3) The dosage ratio is 1.1:1.1:1.0-2.5:2.5:1.0; the tetrahydrofuran solution of methyl triphenylphosphine bromide and sodium hydrogen needs to be stirred at 40°C under reflux for 0.5h-1h before adding compound 3 or compound 2 THF solution. 6. The 24,28-ene-1α-hydroxyvitamin D derivative according to claim 2, characterized in that 9-acetylanthracene (9-AA) should be used as a catalyst for the light in step (4), and 300- The reaction was irradiated with 400nm ultraviolet light. 7. The 24,28-ene-1α-hydroxyvitamin D derivative according to claim 2, characterized in that: in step (5), the dosage ratio of tetrabutylammonium fluoride and compound 5 or compound 8 is 1.2: 1.0-5.0: 1.0.