CN101955498B - Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof - Google Patents

Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof Download PDF

Info

Publication number
CN101955498B
CN101955498B CN 201010220849 CN201010220849A CN101955498B CN 101955498 B CN101955498 B CN 101955498B CN 201010220849 CN201010220849 CN 201010220849 CN 201010220849 A CN201010220849 A CN 201010220849A CN 101955498 B CN101955498 B CN 101955498B
Authority
CN
Grant status
Grant
Patent type
Prior art keywords
compound
group
r3
hydrocarbon group
compounds
Prior art date
Application number
CN 201010220849
Other languages
Chinese (zh)
Other versions
CN101955498A (en )
Inventor
刘荣
薛吉军
郑保富
高强
Original Assignee
上海皓元化学科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Grant date

Links

Abstract

The invention relates to a preparation of organic compounds, in particular to a preparation method of a common side chain of a series of 25-hydroxyitamin D2 medicines. The structure of the compounds is represented in the formula 1. The compounds have wide application and are more stable than the traditional compounds with the same application, so that the compounds are convenient to storage and use. The method for synthesizing the target compounds (1) has high yield, short synthesis route and easily purified products.

Description

25-羟基维生素D2系列药物新型侧链及其制备方法 25-hydroxy vitamin D2 series of novel side chain and pharmaceutical preparation

-系列25-羟基维生素D2 - Series of 25-hydroxyvitamin D2

技术领域 FIELD

[0001] 本发明涉及一种有机化合物的制备方法,确切讲是关于-类药物的共同侧链的制备方法,其结构如下式1所示。 [0001] relates to a method for preparing an organic compound, it is exactly the present invention relates to - a common method for preparation of the side chain of drugs, having the structure shown in Formula 1.

[0002] [0002]

Figure CN101955498BD00031

[0003]式 1 [0003] Formula 1

[0004] 其中,R为氢原子或者-SiR3R4R5或者-R3或者-R6OR4或者_C( = 0)R3,这里R1、!?2 R3、R4、R5、R6为烃基或者烃氧基或者氨基或者烃基取代的氨基,它们可以相同,也可以不同。 [0004] wherein, R is a hydrogen atom or a -SiR3R4R5 or -R3 or -R6OR4, or _C (= 0) R3, where R1,!? 2 R3, R4, R5, R6 is a hydrocarbon group or a hydrocarbon group or a hydrocarbon group, or an amino a substituted amino group, they may be the same or different.

[0005] 背景技术 [0005] BACKGROUND OF THE INVENTION

[0006] [0006]

Figure CN101955498BD00032

[0007]式 2 [0007] Formula 2

[0008] [0008]

Figure CN101955498BD00033

[0009]式 3 [0009] Formula 3

[0010] 如式2所示的一系列25-羟基维生素D2类药物都有一个共同的侧链,这些药物可以由化合物1经过式3所示的过程来合成。 [0010] a series of 25-hydroxy vitamin D2 drugs such as shown in Formula 2 has a common side-chain, these drugs may be through a process shown by a formula 3 compound was synthesized. 这些药物包括25-羟基维生素D2,la,25-二羟基维生素D2,帕立骨化醇,等等。 These include 25-hydroxy vitamin D2, La, 25-dihydroxy vitamin D2, paricalcitol, and the like. 这些药物都是动物和人体内钙磷动态平衡的调节剂ι 2。 These drugs are calcium and phosphorus homeostasis in animals and humans modulator ι 2. 最近的研究还发现了它们在细胞识别中的活性3'4'5。 Recent studies have also found that their activity 3'4'5 in cell recognition. 因此,各种类型的维生素D类似物引起了研究者的广泛兴趣,例如维生素D侧链的衍生物、不同羟基模型的类似物、不同立体构型的类似物,等,都广泛的应用于多种类型的活性测试中,多个已知的该类化合物在体外体内都展示了很好的活性,显示了在多种疾病治疗中良好的应用效果和潜在的应用价值,如治疗骨质发育不良、耐维生素D的佝偻病6、骨质疏松症7、牛皮癣等维生素D缺乏症8。 Thus, various types of vitamin D analogues attracted much attention of researchers, for example, derivatives of vitamin D side chains, analogs hydroxy different models, different steric configuration analogs, etc., are widely used in multi- types of activity tests, a plurality of such compounds known in vitro and in vivo have demonstrated good activity, show bad good effect and potential applications, such as the treatment of bone development in the treatment of various diseases , vitamin D-resistant rickets 6, 7 osteoporosis, psoriasis and other vitamin D deficiency 8. 例如,帕立骨化醇是预防和治疗继发性甲状旁腺功能亢进症(SHPT)的药物,它对接受透析和移植手术前的III及IV期慢性肾脏疾病(CKD)患者的SHPT显示出预防及治疗疗效,已成为透析患者最广泛使用的SHPT预防及治疗药物。 E.g., paricalcitol drug prevention and treatment of secondary hyperparathyroidism (of SHPT), its pre-dialysis patients receiving transplants III and IV and of chronic kidney disease (CKD) SHPT exhibit prevention and treatment efficacy, has become SHPT prevention and treatment of drug most widely used in dialysis patients.

[0011] 现有的用于构筑上述25-羟基维生素D2系列药物侧链的化合物主要有如式4所示的两种,即专利(US4847012、US5^0290等)报道的砜4和其他文献报道的hlide盐5。 [0011] Existing for constructing the above-described two kinds of 25-hydroxyvitamin D2 side chain of a compound of the main series of drugs like the formula 4, i.e. patents (US4847012, US5 ^ 0290, etc.) and other reported sulfone reported in literature 4 5 hlide salts. 其中,化合物4在用于化合物2的一系列类似药物的合成时,收率很低。 Wherein the compound used for the synthesis of compound 4 when a series of drug-like 2, the yield is very low. 化合物5不仅在用于药物合成时收率低,而且化合物5本身的合成和纯化很难,它的合成过程对于保护基R官能团还造成一些局限。 Compound 5 not only at a low yield for the synthesis of pharmaceuticals, the compound 5 itself and the synthesis and purification difficult, the process for its synthesis protecting group R functional group and also cause some limitations.

[0013]式 4 发明内容 [0013] Summary of the invention of formula 4

[0014] 本发明提供一种新的可以克服上述不足的化合物,其结构如式1所示化合物1,本发明还提供该化合物的合成方法。 [0014] The present invention provides a new compound may be insufficient to overcome the above, the structure as shown in Formula 1 compound, the present invention also provides methods for synthesizing such compounds. 本发明所提供的如式1所示的化合物 As shown in Formula 1, compounds of the present invention is provided

[0015] 1Hafner, V. ;Rutsch, C. ;Ding, R. ;Heinrich, T. ;Diedrichs, L. ;Schmidt-Gayk, H. ;Walter-Sack, I. ;Bommer, J. ;Mikus, G. Int. J. Clin. Pharm. Therap. 2008,46(3), 131-135. [0015] 1Hafner, V.; Rutsch, C.; Ding, R.; Heinrich, T.; Diedrichs, L.; Schmidt-Gayk, H.; Walter-Sack, I.; Bommer, J.; Mikus, G . Int. J. Clin. Pharm. Therap. 2008,46 (3), 131-135.

[0016] 2Nakane, Masaki ;Ma, Junli ;Rose, Andrew Ε. ;Osinski, Mark Α. ;ffu-ffong, J. Ruth. J. Steroid Biochem. Mol. Biology 2007,103 (1),84—89 [0016] 2Nakane, Masaki; Ma, Junli; Rose, Andrew Ε;. Osinski, Mark Α;.... Ffu-ffong, J. Ruth J. Steroid Biochem Mol Biology 2007,103 (1), 84-89

[0017] 3Coyne, DW ;Grieff, Μ. ;Ahya, SN ;Giles, K. ;Norwood, K. ;Slatopolsky, E.Am. J. Kidney Diseases 2002,40 (6),1283-1288 [0017] 3Coyne, DW; Grieff, Μ;. Ahya, SN; Giles, K.; Norwood, K.; Slatopolsky, E.Am. J. Kidney Diseases 2002,40 (6), 1283-1288

[0018] 4Slatopolsky, E. ;Cozzolino, M. ;Finch, JL Kidney International 2002, 62(4),1277-1284. [0018] 4Slatopolsky, E.; Cozzolino, M.; Finch, JL Kidney International 2002, 62 (4), 1277-1284.

[0019] 5Rown, AJ ;Finch, J. ;Slatopolsky, Ε. J. Lab. Clin. Med. 2002,139 (5), 279-284. [0019] 5Rown, AJ; Finch, J.; Slatopolsky, Ε J. Lab Clin Med 2002,139 (5), 279-284.....

[0020] 6Puschett JB ;Genel Μ. ;Rastegar Α. ;Anast C. ;DeLuca HF ;Friedman A. Clin, pharm. Thera. 1975,17 (2), 202-11. [0020] 6Puschett JB; Genel Μ;. Rastegar Α;. Anast C.; DeLuca HF;. Friedman A. Clin, pharm Thera 1975,17 (2), 202-11..

[0021] 7Balint, Ε. ;Marshall, CF ;Sprague, S. Μ. Am. J. Kidney Diseases 2000,36(4), 789-796. [0021] 7Balint, Ε;. Marshall, CF;.. Sprague, S. Μ Am J. Kidney Diseases 2000,36 (4), 789-796.

[0022] 8Petkovich, P. Μ. ;Helvig, CF ;Melnick, J. Ζ. PCT Int. Appl. 2009,61pp. W02009124210. 1的合成尚未见文献报道。 [0022] 8Petkovich, P. Μ;. Helvig, CF;..... Melnick, J. Ζ PCT Int Appl Synthesis 2009,61pp W02009124210 1 has not been reported in the literature.

[0023] 本发明以(R)-2_甲基-3-羟基丙酸甲酯(即化合物6)为起始原料,通过如式5 所示的方法,制备化合物1 :首先,将化合物6与甲基金属试剂反应得到化合物7。 [0023] In the present invention, (R) -2_-methyl-3-hydroxy-propionic acid methyl ester (i.e., compound 6) as a starting material, by a method as shown in Formula 5, Preparation of Compound 1: First, Compound 6 with methyl metal reagent to give compound 7. 选择性地将化合物7中的伯醇进行卤代或者磺酰酯化即可得到化合物8,然后保护8中的三级醇得到化合物9,再将化合物9与二芳基膦的金属化合物反应得到目标化合物。 Selectively in 7 primary alcohol compound or a halogenated sulfonyl compound can be obtained by esterification of 8, 8 and the three protected alcohol to give compound 9, and then compound 9 to give a compound of a metal diaryl phosphines and the target compound. 这里与化合物6 反应的甲基金属试剂可以是甲基锂、甲基卤化镁、甲基锌。 Compound with methyl 6 metal reagent where the reaction may be methyl lithium, methyl magnesium halide, dimethyl zinc. 化合物7转化为化合物8可以通 Compound 8 may be converted to compound 7 pass

[0012] [0012]

Figure CN101955498BD00041

过醇与卤素的直接交换得到卤化物8,也可以将醇与磺酰化试剂反应得到磺酸酯8,还可以将化合物7中的伯醇酰用磺酰基保护起来再与金属卤化物进行卤代得到卤化物8。 Directly exchanged halides alcohols with 8 to give a halogen, an alcohol may be reacted with a sulfonylating agent 8 sulfonates, acyl may also be the primary alcohol of compound 7 with protected sulfonyl halide with a metal halide then Generation halide to give 8. 保护化合物8的三级羟基可以用硅醚、酰基、烷基、烷氧烷基、四氢吡喃、四氢呋喃。 Compound 8 is protected hydroxy may be three silicon ether, acyl, alkyl, alkoxyalkyl, tetrahydropyranyl, tetrahydrofuranyl. [0024] [0024]

Figure CN101955498BD00051

[0025]式5 [0025] Formula 5

[0026] 其中,R'为烃基,X为卤素或者磺酰氧基R” SO2O-,这里R”为烃基。 [0026] wherein, R 'is a hydrocarbon group, X is halogen or sulfonyloxy group R "SO2O-, where R" is a hydrocarbyl group. R为氢原子或者-SiR3R4R5或者-R3或者-R6OR4或者-C ( = 0) R3,这里R1jR2, R3,R4,R5,R6为烃基或者烃氧基或者氨基或者烃基取代的氨基,它们可以相同,也可以不同。 R is a hydrogen atom or a -SiR3R4R5 or -R6OR4 or -R3 or -C (= 0) R3, where R1jR2, R3, R4, R5, R6 is a hydrocarbon group or a hydrocarbon group, or an amino or hydrocarbon substituted amino group and they may be the same, It may be different.

[0027] 本发明具有以下优点:1。 [0027] The present invention has the following advantages: 1. 本发明提供一类新的合成25-羟基维生素D2系列药物侧链的化合物,该化合物用途广泛,而且比现有的同样用途的化合物稳定,便于保存和使用; 2。 The present invention provides a novel series of synthetic 25-hydroxyvitamin D2 side chain of the drug class of compounds, the extensive use of the compounds and more stable than the conventional compounds to the same use, convenient to store and use; 2. 本发明提供的合成目标化合物1的方法收率高,路线简短,产品易于纯化。 Target compound of the present invention provides a method for high yield, short route, easily purified product.

具体实施方式 detailed description

[0028] [0028]

Figure CN101955498BD00052

以下提供本发明的具体实施例,以展示可能的实施过程。 The following provides specific embodiments of the present invention, to show a possible implementation.

[0029] 实施例一:化合物la,其分子结构如下,其中Rl = R2 = 0CH2CH3, R = CH20CH3。 [0029] Example a: La compound, the molecular structure below, wherein Rl = R2 = 0CH2CH3, R = CH20CH3.

[0030] [0030]

[0031] [0031]

[0032] [0032]

Figure CN101955498BD00053

[0033] 取(R)-3-羟基-2-甲基丙酸甲酯(11.8g,100mmOl)溶于乙醚中,零摄氏度下,氩气氛中向其中滴入MeMgBr (3M,IOOmL, 300mmol),滴完后,继续搅拌6小时,向其中缓慢滴入IM盐酸淬灭反应,乙酸乙酯萃取(300mL每次)三次,合并有机相,无水硫酸镁干燥,过滤浓缩得到无色油状物11(10. 7g),收率90%。 [0033] Take (R) -3- hydroxy-2-methyl-propionic acid methyl ester (11.8 g of, 100 mmol) was dissolved in diethyl ether, at zero degrees Celsius, was added dropwise thereto under argon atmosphere MeMgBr (3M, IOOmL, 300mmol) after finishing the dropping, stirring was continued for 6 hours, and thereto was slowly added dropwise the reaction was quenched with IM hydrochloric acid, extracted with ethyl acetate (300 mL each) three times, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to give a colorless oil 11 (10. 7g), in 90% yield. 1H NMR(300MHz, δ , ppm)0. 81 (3H, d, J = 6. 9Hz),1. 14 (3H, s),1. 22 (3H, s),1. 77 (1H, m),3. 58 (1H, b),3. 66 (2H, m),3. 84 (1H, b) · 13C NMR(75MHz, δ,ppm) 12. 9,23. 9,29. 6,43. 9,66. 1,74. 5. ESI-HRMS (m/z) [M+] 118. 0,100. 0, 85. 0,59. 0. 1H NMR (300MHz, δ, ppm) 0. 81 (3H, d, J = 6. 9Hz), 1. 14 (3H, s), 1. 22 (3H, s), 1. 77 (1H, m) , 3. 58 (1H, b), 3. 66 (2H, m), 3. 84 (1H, b) · 13C NMR (75MHz, δ, ppm) 12. 9,23. 9,29. 6,43 . 9,66. 1,74. 5. ESI-HRMS (m / z) [m +] 118. 0,100. 0, 85. 0,59. 0.

[0034] 将上述所得无色油状物溶于二氯甲烷(IOOmL)和吡啶(IOmL)中,向其中加入4-(N, N-二甲基胺基)吡啶(Ig)和对甲苯磺酰氯O0g,105mmol),室温搅拌过夜,待原料消失后,将反应液缓慢倒入NaHC03(15g)的冰水溶液QOOmL)中,室温搅拌30分钟,分液, 水相用二氯甲烷萃取OOOmL)三次,合并有机相用IM盐酸(20mL)洗,无水硫酸钠干燥,过 [0034] The above-obtained colorless oil was dissolved in dichloromethane (IOOmL) and pyridine (IOmL), to which was added 4- (N, N- dimethylamino) pyridine (Ig) and p-toluenesulfonyl chloride O0g, 105mmol), stirred overnight at room temperature, until starting material disappeared, the reaction solution was slowly poured into NaHC03 (15g) in ice-water solution QOOmL) and stirred at room temperature for 30 minutes, the liquid, aqueous phase was extracted with dichloromethane OOOmL) three times, The combined organic phases with IM HCl (20mL), dried over anhydrous sodium sulfate, through

5滤浓缩后,硅胶柱层析纯化得到无色油状化合物12 QOg),收率82%。 After 5 filtered and concentrated, purified by silica gel column chromatography to give a colorless oily compound 12 QOg), yield 82%. ΐ NMR (300ΜΗζ, δ , ppm) 0. 93 (3Η, d, J = 6. 9Ηζ),1. 09 (3Η, s),1. 16 (3Η, s),1. 83 (1H, m),2. 42 (3H, s),3. 89 (1H, dd, J = 7. 5,9. 6Hz),4. 22 (1H, dd, J = 4. 5,9. 6Hz),7. 32 (2H, d, J = 7. 5Hz),7. 76 (2H, d, J =7. 5Hz). 13C NMR(75MHz, δ,ppm) 12. 6,21. 6,26. 0,28. 5,43. 4,71. 9,72. 6,127. 8,129. 8, 132. 9,144. 7. ΐ NMR (300ΜΗζ, δ, ppm) 0. 93 (3Η, d, J = 6. 9Ηζ), 1. 09 (3Η, s), 1. 16 (3Η, s), 1. 83 (1H, m) , 2. 42 (3H, s), 3. 89 (1H, dd, J = 7. 5,9. 6Hz), 4. 22 (1H, dd, J = 4. 5,9. 6Hz), 7. 32 (2H, d, J = 7. 5Hz), 7. 76 (2H, d, J = 7. 5Hz). 13C NMR (75MHz, δ, ppm) 12. 6,21. 6,26. 0,28 . 5,43. 4,71. 9.72. 6,127. 8,129. 8, 132. 9,144. 7.

[0035] 将上述对甲苯磺酸酯(19. 0g,70mmol)溶于干燥的CH3CN(50mL)中,向其中加入无水妝1(118,7311111101),加热回流5小时后,浓缩去除013^加入乙醚(IOOmL)过滤,用乙醚(200mL)洗涤滤饼,合并滤液用硫代硫酸钠水溶液洗涤(50mL),有机相经无水硫酸镁干燥, 过滤去干燥剂,浓缩后直接用于下一步。 [0035] The above-toluenesulfonate (19. 0g, 70mmol) was dissolved in dry CH3CN (50 mL), and thereto was added anhydrous makeup 1 (118,7311111101), was heated at reflux for 5 hours, concentrated to remove 013 ^ was added diethyl ether (IOOmL) filtered, washed with diethyl ether (200mL) filter cake was washed and the combined filtrate was washed with aqueous sodium thiosulfate solution (50mL) and the organic phase was dried over anhydrous magnesium sulfate, the drying agent filtered off, concentrated and used directly in the next step .

[0036] 取上述碘化物13(16g,70mmol)溶于干燥CH2C12 (300mL)中,冰水浴冷却下,向其中加入二异丙基乙基胺(10g,100mmOl)和甲氧甲基氯(7g,85mmol)。 [0036] Take the above iodide 13 (16g, 70mmol) was dissolved in dry CH2C12 (300mL) in an ice water bath, thereto was added diisopropyl ethyl amine (10g, 100 mmol) and methoxymethyl chloride (7g , 85mmol). 室温反应12小时后,加水洗,水相用CH2C12萃取。 After reacting 12 hours at room temperature, add water, the aqueous phase was extracted with CH2C12. 合并有机相,用无水硫酸钠干燥,过滤浓缩后,残余物用硅胶柱层析纯化得到无色油状物14(13. 6g),两步总收率71%。 The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil residue was purified by silica gel column chromatography using 14 (13. 6g), 71% yield over two steps. 1H NMR(300MHz, δ ,ppm) 1. 08 (3H, d, J = 5. 7Hz),1. 12 (3H, s),1. 23 (3H, s),1. 97 (1H, m),2. 85 (1H, dd, J = 9. 3,11. IHz), 3. 35 (3H, s),3· 68 (1H, dd, J=L 8,9. 3Hz) ,4. 67 (2H, m). 13C NMR(75MHz, δ,ppm)。 1H NMR (300MHz, δ, ppm) 1. 08 (3H, d, J = 5. 7Hz), 1. 12 (3H, s), 1. 23 (3H, s), 1. 97 (1H, m) , 2. 85 (1H, dd, J = 9. 3,11. IHz), 3. 35 (3H, s), 3 · 68 (1H, dd, J = L 8,9. 3Hz), 4. 67 (2H, m). 13C NMR (75MHz, δ, ppm).

[0037] 取上述所得物色油状物14(Ilg)与亚磷酸三乙酯(20g)混合,加热回流5小时后, 减压蒸去过量的亚磷酸三乙酯,残余物用硅胶柱层析快速纯化得到无色油状物la(9g),收率79%。 After the [0037] obtained as described above to identify oil was taken 14 (Ilg) with triethylphosphite (20g) were mixed and heated to reflux for 5 hours and evaporated under reduced pressure and the excess of triethyl phosphite, and the residue was purified by silica gel flash column chromatography to give a colorless oil la (9g), 79% yield.

[0038] 实施例二:1b的合成。 Synthesis of 1b: Example Two [0038] FIG. 其中Rl = R2 = OMe, R = THP,分子结构如下所示: Wherein Rl = R2 = OMe, R = THP, the molecular structure as follows:

[0039] [0039]

Figure CN101955498BD00061

[0040] 其合成路线如下: [0040] The synthesis route is as follows:

[0041] [0041]

Figure CN101955498BD00062

[0042] 取(R)-3-羟基-2-甲基丙酸乙酯(11.8g,100mmOl)溶于乙醚中,零摄氏度下,氩气氛中向其中滴入MeLi (1M,300mL, 300mmol),滴完后,继续搅拌6小时,向其中缓慢滴入IM 盐酸淬灭反应,乙酸乙酯萃取(300mL每次)三次,合并有机相,无水硫酸镁干燥,过滤浓缩得到无色油状物11(10. Ig),收率85%。 [0042] Take (R) -3- hydroxy-2-methyl-propionic acid ethyl ester (11.8 g of, 100 mmol) was dissolved in diethyl ether, at zero degrees Celsius, was added dropwise thereto under argon atmosphere MeLi (1M, 300mL, 300mmol) after finishing the dropping, stirring was continued for 6 hours, and thereto was slowly added dropwise the reaction was quenched with IM hydrochloric acid, extracted with ethyl acetate (300 mL each) three times, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to give a colorless oil 11 (10. Ig), in 85% yield.

[0043] 将上述所得无色油状物溶于二氯甲烷(IOOmL)和三乙胺(IOmL)中,冰盐浴冷却下向其中加入甲磺酰氯(11.4g,100mmOl),继续搅拌2小时待原料消失后,加水淬灭反应,分液,水相用二氯甲烷萃取OOOmL)三次,无水硫酸钠干燥,过滤浓缩后直接用于下一步。 [0043] The above-obtained colorless oil was dissolved in dichloromethane (IOOmL) and triethylamine (IOmL) in an ice salt bath to which was added methanesulfonyl chloride (11.4 g of, 100 mmol), stirring was continued for 2 hours until after the raw material disappeared, water was added to quench the reaction, liquid separation, the aqueous phase was extracted with dichloromethane OOOmL) three times, dried over anhydrous sodium sulfate, filtered and concentrated directly in the next step.

[0044] 将上述甲磺酸酯16溶于干燥的CH3CN(100mL)中,向其中加入无水NaI (15g, lOOmmol),加热回流5小时后,浓缩去除CH3CN,加入乙醚(IOOmL)过滤,用乙醚QOOmL)洗涤滤饼,合并滤液用硫代硫酸钠水溶液洗涤(50mL),有机相经无水硫酸镁干燥,过滤去干燥剂,浓缩后经硅胶层析纯化得到碘化物13(13. 7g),两步收率60%。 After [0044] 16 The above mesylate was dissolved in dry CH3CN (100mL), to which was added anhydrous NaI (15g, lOOmmol), heated at reflux for 5 hours, concentrated to remove CH3CN, was added diethyl ether (IOOmL) was filtered, dried ether QOOmL) filter cake was washed and the combined filtrate was washed with aqueous sodium thiosulfate solution (50mL) and the organic phase was dried over anhydrous magnesium sulfate, the drying agent filtered off, and concentrated to give the iodide 13 (13. 7g chromatographed on silica gel) , 60% yield for two steps. 屯NMR(300MHz, δ ,ppm) 1. 08 (3H, d, J = 6. 3Hz),1. 14 (3H, s),1. 23 (3H, s),1. 85 (1H, m),2. 89 (1H, dd,J = 9. 3, 11. 1Hz) ,3. 65 (1H, dd, J = 1. 5,9. 3Hz). 13C NMR(75MHz, δ,ppm) 11. 1,16. 0,25. 1,28. 5, 47. 6,73. 1. Tun NMR (300MHz, δ, ppm) 1. 08 (3H, d, J = 6. 3Hz), 1. 14 (3H, s), 1. 23 (3H, s), 1. 85 (1H, m) , 2. 89 (1H, dd, J = 9. 3, 11. 1Hz), 3. 65 (1H, dd, J = 1. 5,9. 3Hz). 13C NMR (75MHz, δ, ppm) 11. 1,16. 0,25. 1,28. 5, 47. 6,73. 1.

[0045] 取上述碘化物13 (11. 4g,50mmol)溶于干燥CH2C12 (IOOmL)中,冰水浴冷却下,向其中加入对甲苯磺酸(0.5g),然后缓慢向其中滴入二氢吡喃(5g,60mmol)。 [0045] Take the above iodide 13 (11. 4g, 50mmol) was dissolved in dry CH2C12 (IOOmL) in an ice water bath, thereto was added p-toluenesulfonic acid (0.5g), and then was slowly added dropwise thereto dihydro-pyrazol furans (5g, 60mmol). 室温反应12小时后,加水洗,水相用CH2C12萃取。 After reacting 12 hours at room temperature, add water, the aqueous phase was extracted with CH2C12. 合并有机相,用无水硫酸钠干燥,过滤浓缩后,残余物用硅胶柱层析纯化得到无色油状物17 (13g),收率82 %。 The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue as a colorless oil 17 (13g) was purified by silica gel column chromatography to yield 82%.

[0046] 取上述所得物色油状物17(9. 4g)与亚磷酸三甲酯(20g)混合,加热回流5小时后,减压蒸去过量的亚磷酸三甲酯,残余物用硅胶柱层析快速纯化得到无色油状物Ia (7. 9g),收率81%。 [0046] taken to identify the above-obtained oil was 17 (9. 4g) and trimethyl phosphite (20g) mixed and refluxed for 5 hours, evaporated under reduced pressure and excess trimethyl phosphite, and the residue was purified by silica gel column chromatography rapid analysis of a colorless oil was purified Ia (7. 9g), yield 81%.

[0047] 实施例三:1c的合成。 1c is synthesized: Example Three [0047] FIG. 其中Rl = R2 = Ph, R = Bz,其分子结构如下图所示: Wherein Rl = R2 = Ph, R = Bz, its molecular structure as shown below:

[0048] [0048]

Figure CN101955498BD00071

[0051] 取上述对甲苯磺酸酯12(13. 6g,50mmol)溶于干燥CH2C12 (IOOmL)中,冰水浴冷却下,向其中加入吡啶(IOg)和4-(N,N-二甲基胺基)吡啶,然后缓慢向其中滴入苯甲酰氯(IOg)。 [0051] take the above tosylate 12 (13. 6g, 50mmol) was dissolved in dried CH2C12 (IOOmL), cooled in an ice-water bath, thereto was added pyridine (IoG) and 4- (N, N- dimethyl amino) pyridine, and benzoyl chloride was slowly added dropwise thereto (IOg). 室温反应12小时后,加水洗,水相用CH2C12萃取。 After reacting 12 hours at room temperature, add water, the aqueous phase was extracted with CH2C12. 合并有机相,用无水硫酸钠干燥, 过滤浓缩后,残余物用硅胶柱层析纯化得到产物18 (13g),收率78%。 The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, the residue to give product 18 (13g) was purified by silica gel column chromatography, in 78% yield.

[0052] 将上述甲磺酸酯18 (11. 3g)溶于干燥的CH3CN (IOOmL)中,向其中加入无水Nal(5g),加热回流5小时后,浓缩去除CH3CN,加入乙醚(IOOmL)过滤,用乙醚QOOmL)洗涤滤饼,合并滤液用硫代硫酸钠水溶液洗涤(50mL),有机相经无水硫酸镁干燥,过滤去干燥剂,浓缩后经硅胶层析纯化得到碘化物19 (7g),收率70%。 After [0052] The above mesylate 18 (11. 3g) was dissolved in dry CH3CN (IOOmL), to which was added anhydrous Nal (5g), refluxed for 5 hours, concentrated to remove CH3CN, was added diethyl ether (IOOmL) filtered, washed with diethyl ether QOOmL) filter cake was washed and the combined filtrate was washed with aqueous sodium thiosulfate solution (50mL) and the organic phase was dried over anhydrous magnesium sulfate, the drying agent filtered off, and concentrated to give the iodide 19 (7g chromatographed on silica gel ), in 70% yield.

[0053] 将二苯基磷化氢(3.72g)溶于无水THF中,氩气氛下冷却至零下78摄氏度后, 向其中缓慢滴入丁基锂的正己烷溶液(2. 8M,7ml),搅拌反应30分钟后,向其中加入碘化物19(4. 5g)的THF溶液,继续搅拌2小时,向其中加水淬灭反应,然后向其中加入双氧水(30%,3ml),继续搅拌并自然升温,5分钟后,分液,水相用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤蒸干后残余物用硅胶柱层析纯化得到目标化合物lc,收率75%。 [0053] The diphenyl phosphine (3.72 g of) was dissolved in anhydrous THF, under an argon atmosphere was cooled to minus 78 degrees Celsius, and thereto was slowly added dropwise n-hexane solution of butyl lithium (2. 8M, 7ml) after the reaction was stirred for 30 minutes, wherein the iodide 19 (4. 5g) in THF was added, stirring continued for 2 hours, water was added thereto to quench the reaction, and then thereto was added hydrogen peroxide (30%, 3ml), and stirring was continued and naturally heating, after 5 minutes, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the title compound lc residue was purified by silica gel column chromatography to yield 75%.

[0054] 实施例四:ld的合成。 ld Synthesis: four cases of [0054] FIG. 其中Rl = R3 = Ph, R = S让t3,其分子结构如下图所示: Wherein Rl = R3 = Ph, R = S so t3, the molecular structure shown below:

[0055] [0055]

Figure CN101955498BD00072

[0049] 其合成路线如下 [0049] The synthetic procedure is as follows

[0050] [0050]

Figure CN101955498BD00081

[0056] 其合成路线如下 [0056] The synthetic procedure is as follows

[0057] [0057]

Figure CN101955498BD00082

[0058] 将碘代醇13(2. 72g)溶于二氯甲烷QOml)中,室温下向其中加入三乙胺CBml)和三乙基氯硅烷(5g),室温搅拌过夜,向反应液中加水淬灭反应,分液,水相用二氯甲烷萃取, 合并有机相,用无水硫酸钠干燥,过滤蒸干后残余物用硅胶柱层析纯化得到硅醚20 (3g),收率80%。 [0058] The iodo alcohol 13 (2. 72g) was dissolved in dichloromethane QOml), a solution of triethylamine CBml) and triethylsilyl chloride (5g), stirred at room temperature overnight, the reaction mixture the reaction was quenched with water, partitioned, the aqueous phase was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, evaporated to dryness and the residue was filtered to give silyl ether 20 (3g) was purified by silica gel column chromatography to yield 80 %.

[0059] 将二苯基磷化氢(3.72g)溶于无水THF中,氩气氛下冷却至零下78摄氏度后, 向其中缓慢滴入丁基锂的正己烷溶液(2. 8M,7ml),搅拌反应30分钟后,向其中加入碘化物2(K4.5g)的THF溶液,继续搅拌2小时,加水淬灭反应,然后向其中加入双氧水(30%, 3ml),继续搅拌并自然升温,5分钟后,分液,水相用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤蒸干后残余物用硅胶柱层析纯化得到目标化合物ld,收率85%。 [0059] The diphenyl phosphine (3.72 g of) was dissolved in anhydrous THF, under an argon atmosphere was cooled to minus 78 degrees Celsius, and thereto was slowly added dropwise n-hexane solution of butyl lithium (2. 8M, 7ml) after the reaction stirred for 30 minutes, a THF solution of iodide 2 (K4.5g) was added thereto, stirred for 2 hours, the reaction was quenched with water, and then hydrogen peroxide was added thereto (30%, 3ml), and stirring was continued warm naturally, after 5 minutes, separated, the aqueous phase was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered and evaporated to dryness to give the title compound ld residue was purified by silica gel column chromatography to yield 85%.

Claims (3)

  1. 1.如式1所示化合物1 : 1. As shown in Formula 1 Compound 1:
    Figure CN101955498BC00021
    式1其中,R为氢原子或者-SiR3R4R5或者-R3或者-R6OR4或者_C( = 0)R3,这里R1、R2、R3、 R4、R5、R6为烃基或者烃氧基或者氨基或者烃基取代的氨基,它们可以相同,也可以不同。 Formula 1 wherein, R is a hydrogen atom or a -SiR3R4R5 or -R3 or -R6OR4, or _C (= 0) R3, where R1, R2, R3, R4, R5, R6 is a hydrocarbon group or a hydrocarbon group or a substituted hydrocarbon group or an amino group group, which may be the same or different.
  2. 2.根据权利要求1所述的化合物1中,R1和R2分别为芳基或者烷氧基或者烷基。 2. The compound of claim 1 according to claim 1, R1 and R2 are each an aryl group or an alkyl group or an alkoxy group.
  3. 3.根据权利要求1所述的化合物1的制备方法,该制备方法经过如式2所示的过程: 3. A method of preparing a compound according to claim 11, over the course of the preparation process as shown in Equation 2:
    Figure CN101955498BC00022
    其中,R'为烃基,X为卤素或者磺酰氧基R”SO2O-,这里R”为烃基,R为氢原子或者-SiR3R4R5或者-R3或者-R6OR4或者_C( = 0)R3,这里R1UHj6为烃基或者烃氧基或者氨基或者烃基取代的氨基,它们可以相同,也可以不同;化合物2经过步骤a,即与甲基金属试剂反应得到化合物3 ;化合物3经过步骤b得到化合物4,步骤b可以是通过通过磺酸酯化后然后再与金属卤化物盐反应得到化合物4,也可以直接与卤素反应得到化合物4,或者通过磺酸酯化得到化合物4 ;化合物4经过步骤c,即保护化合物4中的三级醇得到化合物5 ;化合物5经过步骤d,即通过与二芳基膦的金属化合物反应得到目标化合物1。 Wherein, R 'is a hydrocarbon group, X is halogen or sulfonyloxy group R "SO2O-, where R" is a hydrocarbon group, R is a hydrogen atom or a -SiR3R4R5 or -R3 or -R6OR4, or _C (= 0) R3, where R1UHj6 It is a hydrocarbon group or a hydrocarbon group, or an amino or hydrocarbon substituted amino group and they may be the same or different; compound 2 after steps a, i.e. metal reagent to give compound 3 is reacted with methyl; compound 3 compound 4 obtained after step b, step b can be then obtained by esterification of acid by the reaction of a metal halide salt with the compound 4 may be reacted with a halogen compound 4 directly, or obtained by the sulfonated compound 4; 4 compound after step C, i.e. protect the compound 4 three alcohol to give compound 5; compound 5 through step d, i.e. the title compound obtained by reacting a metal compound with a diaryl phosphines.
CN 201010220849 2010-07-06 2010-07-06 Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof CN101955498B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN 201010220849 CN101955498B (en) 2010-07-06 2010-07-06 Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN 201010220849 CN101955498B (en) 2010-07-06 2010-07-06 Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof

Publications (2)

Publication Number Publication Date
CN101955498A true CN101955498A (en) 2011-01-26
CN101955498B true CN101955498B (en) 2012-06-27

Family

ID=43483114

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 201010220849 CN101955498B (en) 2010-07-06 2010-07-06 Novel side chain of 25-hydroxyitamin D2 series medicines and preparation method thereof

Country Status (1)

Country Link
CN (1) CN101955498B (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102351901A (en) * 2011-08-15 2012-02-15 上海皓元化学科技有限公司 25-hydroxy vitamin D2 series medicament side chain and its preparation method
CN102643302A (en) * 2012-04-06 2012-08-22 上海皓元化学科技有限公司 Method for preparing intermediates for synthesizing 25-hydroxyvitamin D2 and 1 alpha, 25-dihydroxyvitamin D2

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4847012A (en) * 1988-04-29 1989-07-11 Wisconsin Alumni Research Foundation Vitamin D related compounds and processes for their preparation
US5260290A (en) * 1990-02-14 1993-11-09 Wisconsin Alumni Research Foundation Homologated vitamin D2 compounds and the corresponding 1α-hydroxylated derivatives

Also Published As

Publication number Publication date Type
CN101955498A (en) 2011-01-26 application

Similar Documents

Publication Publication Date Title
CN103121999A (en) Method for synthesizing tyrosine kinase inhibitor PCI-32765
WO2005044780A1 (en) Aminocarboxylic acid derivative, addition salt thereof, and s1p receptor control agent
CN101531681A (en) High-purity minodronic acid and preparation method thereof
JP2006510706A (en) 18f- solid-phase production of labeled amino acids
CN102127092A (en) Preparation of Everolimus
CN1528738A (en) Method for preparing 2-para octylphenyl ehtyl-2-amino propanediol
US6359012B1 (en) Method for making 24(S)-hydroxyvitamin D2
Morell et al. Stereospecific synthesis of (2S, 3R)-2-amino-3-mercaptobutyric acid-an intermediate for incorporation into. beta.-methyllanthionine-containing peptides
JP2004175703A (en) METHOD FOR PRODUCING N-ALKOXYCARBONYL-tert-LEUCINE
Manzotti et al. Improved synthesis of prostanoids on a non-cross-linked polystyrene soluble support
JP2011157326A (en) Maxacalcitol intermediate and process for producing the same
DeVries et al. Potential antiatherosclerotic agents. 4.[(Functionalized-alkyl) amino] benzoic acid analogs of cetaben
CN102264751A (en) The method of synthesis of vitamin d analogues
US20100099875A1 (en) New ortho-functionalized p-chiral arylphosphines and derivatives: their preparation and use in asymmetric catalysis
Sanchez-Dominguez et al. Synthesis of triphilic, Y-shaped molecular surfactants
JP2006035125A (en) Asymmetric catalyst, production method for optically active alcohol, and binaphthol derivative
US2945038A (en) 5-fluorocytosine and preparation thereof
US20120108554A1 (en) PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2
JP2002069086A (en) Optically active phosphorus compound
US8173623B2 (en) Process for preparation of HIV protease inhibitors
CN1145065A (en) Process for producing bis(4-alkylthiophenyl) disulfide
Pallikonda et al. BuLi-triggered phospha-Brook rearrangement: efficient synthesis of organophosphates from ketones and aldehydes
JP2002371033A (en) ω-ARYL-α-SUBSTITUTED FATTY ACID DERIVATIVE
Al-Momani et al. Radiosynthesis of [18F] FEt-Tyr-urea-Glu ([18F] FEtTUG) as a new PSMA ligand
JP2007291010A (en) Method for producing optically active 2-methylepihalohydrin or the like

Legal Events

Date Code Title Description
C06 Publication
C10 Entry into substantive examination
C14 Grant of patent or utility model
C56 Change in the name or address of the patentee