WO2013023327A1 - Side chain of 25-hydroxyvitamin d2 series drug and preparation method thereof - Google Patents

Abstract

A new compound 1 which structure is as shown in formula 1 and its preparation method are provided. The synthesization of it is as follows: reacting (S)-2-methyl-3-hydroxy-methyl propionate as the original material with methyl metallic reagent; selectively halogenating or esterifying with sulfonic acid and then selectively halogenating; being protected by the third-class alcohol; and allowing to react with the metallic compound of diarylphosphine or trialkoxyphosphine to obtain the target compound 1. The compound is broadly used, easy to be saved and used, and it is more stable than those available compounds having the same use. The present method for preparing the target compound 1 has the advantages of high yield, easy route, and easy purification for the product.

Description

 25-hydroxy vitamin D2 series drug side chain and preparation method thereof

 The present invention relates to an organic compound and a process for the preparation thereof, and more particularly to a chain of a phosphorus-containing compound and a process for the preparation thereof. Background technique

 2a 25-OH Vitami n D2 2b 1alfa, 25-(OH)2 Vitamin D2 2c Paricalcitol

A series of 25-hydroxyvitamin D ₂ drugs as shown in Formula 1 have a common side chain. These drugs include 25-hydroxyvitamin D2, 1 alpha, 25-dihydroxyvitamin D ₂ , paricalcitol, and the like. These drugs are regulators of calcium and phosphorus homeostasis in animals and humans ¹ ' ² . Recent studies have also found their activity in cell recognition ³ ' ⁴ ' ⁵ . Therefore, various types of vitamin D analogs have attracted wide interest of researchers, such as derivatives of vitamin D side chains, analogs of different hydroxyl models, analogs of different stereoconfigurations, etc., which are widely used in many applications. In various types of activity tests, a number of known such compounds exhibit excellent activity in vitro, showing good application effects and potential application values in the treatment of various diseases, such as treatment of bone dysplasia. , resistant to vitamin D

¹ Hafher, V.; Rutsch, C; Ding, R.; Heinrich, T.; Diedrichs, L.; Schmidt-Gayk, H.; Walter-Sack, I.; Bommer, Mikus, G. Int. J. Clin Pharm. Therap. 2008, 46 (3), 131-135.

² Nakane, Masaki; Ma, Junli; Rose, Andrew E.; Osinski, Mark A.; Wu-Wong, J. Ruth. J. Steroid Biochem. Mol. Biology 2007, 103 (1), 84-89

³ Coyne, DW; Grieff, M.; Ahya, SN; Giles, K.; Norwood, K.; Slatopolsky, E. Am. J. Kidney Diseases 2002, 40 (6), 1283-1288

⁴ Slatopolsky, E.; Cozzolino, M.; Finch, JL Kidney International 2002, 62 (4), 1277-1284.

⁵ Rown, AJ; Finch, J.; Slatopolsky, EJ Lab. Clin. Med. 2002, 139 (5), 279-284. Rickets ⁶ , osteoporosis ⁷ , psoriasis and other vitamin D deficiency ⁸ . For example, paricalcitol is a drug for the prevention and treatment of secondary hyperparathyroidism (SHPT), which shows SHPT in patients with stage III and IV chronic kidney disease (CKD) before dialysis and transplantation. Therapeutic and therapeutic effects have become the most widely used SHPT prevention and treatment drugs for dialysis patients.

 The existing side chain methods for constructing such compounds mainly construct the side chains by constructing double bonds on the side chains. The commonly used reactions are Wittig reaction, Julia coupling olefination reaction and Wiitig-Horner reaction. Among them, the Julia coupling olefination reaction mainly uses Compound 4 as shown in Formula 2 as a side chain fragment, and the Wittig reaction uses Compound 5 as shown in Formula 2 as a side chain fragment (Patent Document US4847012, US5260290, etc.). Among them, the compound 4 has a low yield in the synthesis of a series of similar drugs for the compound 2, and is constructed by a two-step reaction by coupling and desulfurization of Na-Hg, which is inconvenient to handle and highly polluting. The compound 5 is not only low in yield for drug synthesis, but also the synthesis and purification of the compound 5 itself is difficult, and its synthesis process also imposes some limitations on the protecting group R functional group.

 Formula 2 Summary

The present invention provides a novel compound which overcomes the above disadvantages and which has the structure of the compound 1 of the formula 3, and the present invention also provides a method for synthesizing the compound. The synthesis of Compound 1 as shown in Formula 3 provided by the present invention has not been reported in the literature.

 Equation 3

Puschett J. Β·; Genel M.; Rastegar A.; Anast C; DeLuca H. F.; Friedman A. Clin, pharm. Thera. 1975, 17 !), 202-11.

 Balint, E.; Marshall, C. F.; Sprague, S. M. Am. J. Kidney Diseases 2000, 36 (4), 789-796.

Petkovich, PM; Helvig, CF; Melnick, JZ PCT Int. Appl. 2009, 61 pp. WO2009124210. Wherein R is a hydrogen atom or a mercapto group or a trialkylsilyl group or a nonyloxy group-substituted alkyl group or an acyl group or a tetrahydropyranyl group or a tetrahydrofuranyl group; and R ¹ and R ² are each an aryl group or a decyloxy group; One.

The present invention uses (S)-2-methyl-3-hydroxypropanoic acid methyl ester (i.e., compound 6) as a starting material, and a compound 1 is prepared by the method shown in Formula 4: First, compound 6 and methyl group are prepared. The metal reagent reacts to give compound 7. Selectively reacting the primary hydroxyl group of the diol compound for 3⁄4 or the sulfonic acid ester compound obtained by esterifying the primary hydroxysulfonic acid of the diol compound with a halogen anion to carry out halogenation to obtain compound 8, and then protecting The tertiary hydroxy group of 8 gives the compound 9, and the compound 9 is reacted with a metal compound of a diarylphosphine or a trimethoxyphosphine to obtain the target compound 1. The methyl metal reagent reacted here with the compound 6 may be methyl lithium or methyl magnesium halide or methyl zinc. The conversion of compound 7 to compound 8 can be obtained by direct halogenation of a hydroxyl group, and the primary hydroxyl group in compound 7 can also be converted into a sulfonate ester and then halogenated with a halogen anion to give a halide 8. Direct halogenation of compound 7 The halogenating agent used in the preparation of compound 8 is a phosphorus trihalide or a phosphorus oxyhalide or a halogenated sulfoxide or a phosphorus pentoxide or a carbon tetrahalide or iodine such as thionyl chloride or phosphorus tribromide or phosphorus pentachloride. Or phosphorus trichloride or phosphorus oxychloride or carbon tetrabromide or carbon tetrachloride or iodine. The reagent used for the sulfonylation reaction of the compound 7 may be methanesulfonyl chloride or methanesulfonic anhydride or p-toluenesulfonyl chloride or benzenesulfonyl chloride or trifluoromethanesulfonic anhydride, and the halogen anion used for halogenation is derived from a lithium salt of chlorine or bromine or iodine or A sodium salt or a potassium salt or a magnesium salt such as lithium chloride or lithium bromide or sodium bromide or potassium bromide or magnesium bromide or magnesium chloride or sodium iodide or lithium iodide or potassium iodide or magnesium iodide. The protection of the tertiary hydroxyl group of the compound 8 may be carried out by using a mercaptosilyl group or a benzoyl group or a decyloxy group or a tetrahydropyranyl group or a tetrahydrofuranyl group. The reagent used is trimethylsilyl chloride or benzoyl chloride or anthraquinone. Chlorine or dihydropyran or dihydrofuran. The metal compound of the diarylphosphine herein may be lithium diphenylphosphinate or lithium di-p-tolylphosphonate or the corresponding sodium reagent or potassium reagent. The trialkoxy group used herein Phosphorus may be trimethoxyphosphorus or triethoxyphosphorus or tributoxide

HO

Equation 4

Wherein R is a hydrogen atom or an alkyl group or a trimethylsilyl group or an alkoxy-substituted alkyl group or an acyl group or a tetrahydropyranyl group or a tetrahydrofuranyl group; and R ¹ and R ² are each an aryl group or a decyloxy group; One.

 The Wittig-Homer reaction is used to construct a drug molecule such as Compound 2 with Compound 1. Compound 1 is treated with a strong base (e.g., butyllithium, potassium t-butoxide, etc.), and then reacted with compound 3 to give compound 2, and finally, the R protecting group is removed, and then drug molecule 2a-2c can be obtained.

式 5

Equation 5

The present invention has the following advantages: 1. The present invention provides a novel class of compounds for synthesizing a side chain of a 25-hydroxyvitamin D ₂ series drug which is versatile and stable over existing compounds of the same use, and is convenient for storage and use; 2. The method for synthesizing the target compound 1 provided by the present invention has a high yield, a short route, and the product is easy to purify. detailed description

 Specific embodiments of the invention are provided below to illustrate possible implementations. Preferably, the R protecting group in compound 1 may be tert-butyldimethylsilyl or trimethylsilyl or triethylsilyl or methoxymethyl or benzyloxymethyl or 2-tetrahydrofuranyl or 2- Tetrahydropyranyl or a hydrogen atom or a benzoyl group, and R1 and R2 may be a methyl group or an ethyl group or a butyl group.

Example 1: Compound la, the molecular structure of which is as follows, wherein R^R^-OEt, R=-CH ₂ OCH ₃ , the molecular structure of which is shown in the following formula 6: EtO-P.

EtO OCH ₂ OCH ₃

式 7 The synthetic route of Equation 6 is as follows _:

Equation 7

 Methyl (S)-2-methyl-3-hydroxypropionate (11.8 g, 100 mmol) was dissolved in diethyl ether, and MeMgBr (3 M, 100 mL, 300 mmol) was added dropwise thereto under an argon atmosphere at 0 ° C. After the completion of the dropwise addition, the mixture was stirred for 6 hours, and the reaction mixture was slowly added dropwise with 1 M hydrochloric acid, and then the mixture was evaporated to ethyl acetate. 10.7g), yield 90%.

Structural Analytical Data: NMR (300 MHz, δ, ppm) 0.81 (3H, d, J=6.9 Hz), 1.14 (3H, s), 1.22 (3H, s), 1.77 (1H, m), 3.58 (1H, b), 3.66 (2H, m), 3.84 (1H, b). ¹³ C NMR (75 MHz, δ, ppm) 12.9, 23.9, 29.6, 43.9, 66.1, 74.5. ESI-HRMS (m/z) [IVT 118.0, 100.0, 85.0, 59.0.

The obtained colorless oil 11 was dissolved in CH ₂ C1 ₂ (100 mL) and pyridine (10 mL), and 4-(N,N-dimethylamino)pyridine (1 g) and p-toluene were added thereto. Sulfonyl chloride (20 g, 105 mmol), stirred at room temperature overnight. After the material disappeared, the reaction mixture was slowly poured into NaHC0 ₃ (15 g) in ice water (200 mL), stirred at room temperature for 30 min, Extracted with dichloromethane (200 mL) The organic phase was combined with EtOAc (EtOAc)EtOAc.

Structural Analytical Data: NMR (300 MHz, δ, ppm) 0.93 (3H, d, J=6.9 Hz), 1.09 (3H, s), 1.16 (3H, s), 1.83 (1H, m), 2.42 (3H, s), 3.89 (1H, dd, J=7.5, 9.6 Hz), 4.22 (1H, dd, =4.5, 9.6 Hz), 7.32 (2H, d, J=7.5 Hz), 7.76 (2H, d, J= 7.5 Hz). ¹³ C NMR (75 MHz, δ, ppm) 12.6, 21.6, 26.0, 28.5, 43.4, 71.9, 72.6, 127.8, 129.8, 132.9, 144.7.

The above-described resultant tosylate 12 (19.0 g, 70 mmol) was dissolved in dry CH ₃ CN (50 mL), and thereto is added anhydrous Nal (11 g, 73 mmol) , heated under reflux for 5 hours and concentrated The CH ₃ CN was removed, and diethyl ether (100 mL) was added, and the mixture was filtered, and the filtrate was washed with diethyl ether (200 mL). Used directly in the next step.

The above-obtained iodide 13a (16 g, 70 mmol) was dissolved in dry CH ₂ C1 ₂ (300 mL), and iced water was cooled, and diisopropylethylamine (10 g, 100 mmol) and Oxymethyl chloride (7 g, 85 mmol). After reacting for 12 hours at room temperature, it was washed with water and the aqueous phase was extracted with CH ₂ C1 ₂ . The combined organic layers were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

Structural Analytical Data: NMR (300 MHz, δ, ppm) 1.08 (3H, d, J = 5.7 Hz), 1.12 (3H, s), 1.23 (3H, s), 1.97 (1H, m), 2.85 (1H, Dd, «7=9.3, 11.1 Hz), 3.35 (3H, s), 3.68 (1H, dd, «7=1.8, 9.3 Hz), 4.67 (2H, m). ¹³ C NMR (75 MHz, δ, ppm )o

The obtained color oil 14a (l lg) was mixed with triethoxyphosphoric acid (20 g), and the mixture was heated under reflux for 5 hr., then, the excess triethoxyphosphoric acid was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography. Colorless oil la (9g), yield 79%. Example 2: Synthesis of lb. Wherein R^R^OMe, R=THP, the molecular structure is as shown in the following formula 8:

 Equation 9

Compound 11 (40.0 mmol) was dissolved in CH ₂ C1 ₂ (100 mL) and pyridine (4.0 g), and then thionyl chloride (5.1 g, 50 mmol) was slowly added dropwise thereto under ice-cooling, and stirring was continued. After the disappearance of the raw materials in an hour, the reaction was quenched with water, and the mixture was separated, and the aqueous phase was extracted with methylene chloride (200 mL) three times, dried over anhydrous sodium sulfate, filtered and concentrated.

The above chloride 13b (11. 4 g, 50 mmol) was dissolved in dry CH ₂ C1 ₂ (100 mL), and ice-water bath was cooled, and p-toluenesulfonic acid (0.5 g) was added thereto, and then dihydrogen was slowly added thereto. Pyran (5 g, 60 mmol). After reacting for 12 hours at room temperature, it was washed with water and the aqueous phase was extracted with CH ₂ C1 ₂ . The combined organic layers were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

The obtained color oil 14b (9.4 g) was mixed with trimethoxyphosphoric acid (20 g), and the mixture was heated under reflux for 5 hours, and then excess trimethoxyphosphoric acid was evaporated under reduced pressure. Color oil lb (7.9 g), yield 81%. Example 3: Synthesis of lc. Wherein R^R^Ph, R=Bz, the molecular structure thereof is as shown in the following formula 10

 Equation 10

 The synthetic route is shown in the following formula:

 Equation 11

The diol 11 (11. 8g) was dissolved in dry diethyl ether (100 mL), and anhydrous PBr ₃ (30 g) was added thereto under ice-cooling. After the addition, the mixture was stirred for 1 hour, quenched with water, and extracted with diethyl ether. The phase was dried over anhydrous magnesium sulfate, filtered and evaporated, and then evaporated to silica.

13c (2g) was dissolved in CH ₂ C1 ₂ (20 mL), and pyridine ( lg) and DMAP (100 mg) were added thereto, and then benzoyl chloride (1.7 g) was added dropwise thereto, and stirring was continued for 2 hours after the addition. After quenching with water, the organic phase was dried, concentrated and purified by silica gel column chromatography to afford compound 14c (2.3 g).

Diphenylphosphine (3.72 g) was dissolved in anhydrous THF, and cooled to -78 ° C under an argon atmosphere. Then, a solution of butyllithium in n-hexane (2.8 M, 7 ml) was slowly added dropwise thereto, and the reaction was stirred. After a minute, a solution of iodide 14c (4.5 g) in THF was added thereto, stirring was continued for 2 hours, water was added thereto to quench the reaction, and then hydrogen peroxide (30%, 3 ml) was added thereto, stirring was continued and the temperature was naturally raised, after 5 minutes. , the liquid phase was extracted with ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography toiel

Example 4: Synthesis of Id. Wherein R^R^Ph, R=SiEt ₃ , the molecular structure of which is as follows:

 Combined

 Equation 13

 Compound 11 (1.18 g) was dissolved in diethyl ether (20 mL) and acetonitrile (12 mL), and triphenylphosphine (3.12 g) was added thereto, and then iodine (2.54 g) was added thereto in portions, stirred at room temperature for 3 hours, and then water was added. After quenching, extraction with ether, the organic phase was dried, filtered and concentrated to give compound 13d.

 Iodyl alcohol 13d (2.72g) was dissolved in dichloromethane (20ml), triethylamine (3ml) and triethyl chlorosilane (5g) were added thereto at room temperature, stirred at room temperature overnight, and water was added to the reaction solution. The reaction was quenched, and the mixture was evaporated. EtOAcjjjjjjjjjjjjjjj .

Diphenylphosphine (3.72 g) was dissolved in anhydrous THF, and cooled to minus 78 ° C under an argon atmosphere. Then, a solution of butyl lithium in n-hexane (2.8 M, 7 mL) was slowly added dropwise thereto, and the reaction was stirred. After 30 minutes, a solution of iodide 14d (4.5 g) in THF was added thereto, stirring was continued for 2 hours, and the reaction was quenched with water, then hydrogen peroxide (30%, 3 mL) was added thereto, stirring was continued and the temperature was naturally raised, after 5 minutes. The liquid phase was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate. Example 5: Synthesis of le. Wherein R^R^-C^-Me-p, R=H, the molecular structure thereof is as shown in the following formula 14:

 Equation 14

 The synthetic route is as follows:

^1e Formula 15 Compound 11 (1.18 g) was dissolved in diethyl ether (20 mL) and acetonitrile (12 mL), and triphenylphosphine (3.12 g) was added thereto, and then iodine (2.54 g) was added thereto in portions, and stirred at room temperature for 3 hours. After that, it was quenched with water, extracted with diethyl ether. The organic phase was dried, filtered and concentrated to give compound 13d.

Di-p-tolylphosphine (3.72 g) was dissolved in anhydrous THF, and after cooling to below 78 ° C in an argon atmosphere, a solution of butyl lithium in hexane (2.8 M, 7 mL) was slowly added dropwise thereto, and stirred. After reacting for 30 minutes, a 13 d (2.0 g) solution of iodide in THF was added thereto, stirring was continued for 2 hours, and the reaction was quenched with water, then hydrogen peroxide (30%, 3 mL) was added thereto, stirring was continued, and the temperature was naturally raised for 5 minutes. After the mixture was separated, the aqueous phase was extracted with ethyl acetate. Example 6: Synthesis of If. Wherein R^R^OBu, R=THF, the molecular structure is as follows:

 Equation 16

The synthetic route is as follows:

Compound 17 (40.0 mmol) was dissolved in CH ₂ C1 ₂ (100 mL) and CH ₃ CN (4.0 g), and PPh3 (12 g, 45 mmol) and CBr4 (1. mmol), stirring was continued for 1 hour after the raw material disappeared, water was added to quench the reaction, liquid separation, the aqueous phase was extracted with ₂ C1 ₂ CH (200mL) three times, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude compound 13f was used directly Next step. The above bromide 13f (11. 4 g, 50 mmol) was dissolved in dry CH ₂ C1 ₂ (100 mL), and ice-water bath was cooled, and p-toluenesulfonic acid (0.5 g) was added thereto, and then dihydrogen was slowly added thereto. Furan (4.7 g, 60 mmol). After reacting for 12 hours at room temperature, it was washed with water and the aqueous phase was extracted with CH ₂ C1 ₂ . The combined organic layers were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHH The obtained colorless oil 14f (9.4 g) was mixed with tributylphosphine (20 g), and the mixture was heated under reflux for 5 hours, and then excess tributoxyphosphine was evaporated under reduced pressure. Purification gave a colorless oil, If (7.9 g), yield 81%.

Example 7: Application of Compound 1 : Compound 2b was prepared using the compounds 3b and 1a under the action of a base.

式 18

Equation 18

The compound la (1.0 mmol) was dissolved in anhydrous tetrahydrofuran, and cooled to below 78 °C under nitrogen atmosphere. Then, a solution of butyllithium in tetrahydrofuran (1.6 M, 1.0 mmol) was slowly added dropwise thereto, and the reaction was continued after the dropwise addition. After a minute, a 3b solution of tetrahydrofuran was slowly added dropwise thereto, and the reaction was further stirred for 2 hours. It is naturally stirred to room temperature, quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate, and then dried over anhydrous sodium sulfate. After adding tetrabutylammonium fluoride, the mixture was stirred at room temperature for 1 hour, quenched with water, extracted with ethyl acetate, dried and concentrated to silica gel column chromatography to give the title compound 101,25-dihydroxyvitamin ( _{2 )} (21).

Claims

Rights request 1. Compound 1 as shown in Formula 1:

 Formula 1 Wherein R is a hydrogen atom or a fluorenyl group or a trialkylsilyl group or a decyloxy group-substituted fluorenyl group or an acyl group or a tetrahydropyranyl group or a tetrahydrofuranyl group; and R ¹ and R ² are each an aryl group and an alkoxy group; One.  The compound 1 according to claim 1, wherein R is a hydrogen atom or a methyl group or a methoxymethyl group or a methoxyethyl group or a trimethylsilyl group or a triethylsilyl group or a 2-tetrahydrofuranyl group. Or 2-tetrahydropyranyl or benzoyl. 3. The compound 1 according to claim 1, wherein R ¹ and R ² are each one of a phenyl group, a methoxy group and an ethoxy group. 4. A process for the preparation of a compound 1 according to claim 1, characterized by a process as shown in formula 2: starting material (S)-2-methyl-3-hydroxypropionate and excess A The base metal reagent is reacted to obtain a diol compound, and then the primary hydroxy group of the diol compound is selectively halogenated or the sulfonate compound obtained by esterifying the primary hydroxysulfonate of the diol compound is substituted with a halogen anion. Halogenating, protecting another hydroxyl group in the obtained molecule, and finally reacting the obtained compound with a metal reagent of diarylphosphine or a trimethoxyphosphorus compound to obtain a target compound.

 Equation 2 Wherein R is a hydrogen atom or an alkyl group or a trimethylsilyl group or a decyloxy group-substituted fluorenyl group or an acyl group or a tetrahydropyranyl group or a tetrahydrofuranyl group; and R ¹ and R ² are each an aryl group and a decyloxy group; One. The method for producing a compound 1 according to claim 4, wherein the methyl metal reagent used in the reaction of the (S)-2-methyl-3-hydroxypropionic acid methyl ester to obtain a diol compound is a methyl group. Magnesium halide Or methyl lithium or dimethyl zinc.  6. The method for preparing compound 1 according to claim 4, wherein the halogenating agent used for halogenation of the diol compound is phosphorus trihalide or phosphorus oxyhalide or halogenated sulfoxide or phosphorus pentoxide or carbon tetrahalide or iodine.  7. A process for the preparation of a compound 1 according to claim 4, wherein the halogenation of the diol compound is carried out by a process of first sulfonating the primary hydroxyl group of the diol compound to obtain a sulfonate compound. The halogenation reaction is carried out by a substitution reaction with a halogen anion. The reagent for sulfonation may be methanesulfonyl chloride or methanesulfonic anhydride or p-toluenesulfonyl chloride or benzenesulfonyl chloride or trifluoromethanesulfonic anhydride. The halogen anion used for halogenation is derived from chlorine. Or a lithium or sodium or potassium or magnesium salt of bromine or iodine. 8. The method of preparing compound 1 according to claim 7, wherein the halogenated anion is lithium chloride or lithium bromide or sodium bromide or potassium bromide or magnesium bromide or magnesium chloride or sodium iodide or lithium iodide. Or potassium iodide or magnesium iodide.  9. Process for the preparation of compound 1 according to claim 4, characterized in that the diarylphosphine metal reagent used is lithium diphenylphosphinate or lithium di-p-tolylphosphonate or the corresponding potassium reagent or sodium reagent.  The process for producing a compound 1 according to claim 4, wherein the phosphorus oxyphosphorate is trimethoxyphosphorus or triethoxyphosphorus or tributoxide.