CN107286067A - 一种马沙骨化醇的制备方法 - Google Patents
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- DTXXSJZBSTYZKE-ZDQKKZTESA-N Maxacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](OCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C DTXXSJZBSTYZKE-ZDQKKZTESA-N 0.000 title claims abstract description 27
- 229950006319 maxacalcitol Drugs 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 229940125898 compound 5 Drugs 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 9
- 229940125904 compound 1 Drugs 0.000 claims abstract description 6
- 229940126214 compound 3 Drugs 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- -1 p-methyl benzenesulfonic acid ester Chemical class 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 125000000746 allylic group Chemical group 0.000 claims abstract description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims abstract description 3
- 230000003647 oxidation Effects 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229940125782 compound 2 Drugs 0.000 claims description 7
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 6
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C401/00—Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/05—Preparation of ethers by addition of compounds to unsaturated compounds
- C07C41/06—Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
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Abstract
本发明属于药物化学领域，具体涉及一种马沙骨化醇的制备方法。该方法以化合物1为起始原料，经过对甲苯磺酸酯选择性保护二级羟基，在碱的作用下，在甲醇中发生分子内环化反应生成化合物3,3经过烯丙位氧化，选择性保护二级羟基得到化合物5，化合物5在酸作用下打开三元环得到化合物6，化合物6脱保护基得到目标化合物。本发明原料易得，操作简单，步骤短，只有6步反应。
Description
技术领域
本发明属于药物化学领域，特别涉及一种马沙骨化醇的制备方法。
背景技术
马沙骨化醇(Maxacalcitol)，化学名(1R,3S,Z)-5-((E)-2-((1S,7aS)-1-((S)-1-(3-hydroxy-3-methylbutoxy)ethyl)-7a-methylhexahydro-1H-inden-4(2H)-ylidene)ethylidene)-4-methylenecyclohexane-1,3-diol，美国化学文摘登记号CAS：103909-75-7，结构如I所示。
马沙骨化醇是一种新型的维生素D激动剂，用于治疗继发性甲状旁腺功能亢进引起的维生素D代谢异常症状，本品为日本中外制药公司开发的新型第三代活性维生素D类药物。其注射液于2000年上市，商品名为Oxarol，用于治疗肾透析(肾衰)患者的继发性甲状旁腺功能亢进症(SHPT)，日本上市以后，在临床应用过程中，显示了良好的治疗效果，并且不良反应如高血钙等反应不明显，患者耐受性高，适合临床推广。此外本品作用于成骨细胞样细胞，可促进骨钙素基因的表达。
现有技术中合成马沙骨化醇的合成路线是日本中外制药公司(Org.Pro.Res.Devel.,2005,9,278-287)报道的，有以下两种方法：
方法一：
该技术路线存在三个困难之处：(1)共轭二烯的不稳定性；(2)Williamson反应得到的目标产物6和7为1:1的比例，降低了反应产率；(3)化合物8易烯醇化，影响格氏试剂的加成反应。
方法二：
该技术路线要使用化学当量的CeCl3来避免烯醇化，而无水CeCl3价格昂贵，成本高。
发明内容
本发明的目的在于，克服现有的马沙骨化醇的合成存在的缺陷，提供一种新的马沙骨化醇的制备方法，本发明的方法原料易得，操作简单，步骤短，仅6步反应。
本发明的目的及解决其技术问题是采用以下技术方案来实现的。依据本发明提出的一种马沙骨化醇的制备方法，所述方法包括以下步骤：1)将化合物1的二级羟基用磺酸酯进行保护得到化合物2，然后在碱的作用下，在甲醇中，化合物2分子内环化得到化合物3，再对3进行烯丙位氧化，得到化合物4；2)将化合物4的二级羟基进行保护，得到化合物5，化合物在酸性条件下打开5中的三元环得到化合物6；3)将化合物6中的羟基保护基脱去，得到目标化合物马沙骨化醇。合成路线如下：
本发明的目的及解决其技术问题还可采用以下技术措施进一步实现。
前述的马沙骨化醇的制备方法，其中，步骤2)中，所述的化合物4的羟基可以用R1保护，得到化合物5，
R1可以是三甲基硅基，三乙基硅基，叔丁基二甲基硅基，三异丙基硅基，叔丁基二苯基硅基或苯甲酰基。
前述的马沙骨化醇的制备方法，其中，步骤2)中，所述的脱去化合物6中的保护基所用的试剂为质子酸或Lewis酸。
前述的马沙骨化醇的制备方法，其中，步骤2)中，所述的质子酸选自盐酸、硫酸、对甲基苯磺酸、樟脑磺酸中的一种或几种的混合物；所述的Lewis酸可以是三氟化硼、氯化锌、溴化镁、四丁基氟化铵中的一种或几种的混合物。
前述的马沙骨化醇的制备方法，其中，步骤2)中，制备化合物5所用的酸选自盐酸、醋酸、硫酸、草酸、柠檬酸、苹果酸、马来酸中的一种或几种的混合物。
借由上述技术方案，本发明马沙骨化醇的制备方法具有的显著效果是：本发明的方法所用的原料易得，操作简单，步骤短，仅6步反应即可得到没有副产物污染的目标产物。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，而可依照说明书的内容予以实施，并且为了让本发明的上述和其他目的、特征和优点能够更明显易懂，以下特举较佳实施例，详细说明说下。
具体实施方式
实施例1
1)化合物2的制备
取化合物1(20g,0.048mol)溶于吡啶(100ml)，搅拌下分批向其中加入对甲苯磺酰氯(21g,0.051mol)4-二甲氨基吡啶(1.1g)，搅拌过夜，待原料消失后，搅拌下将反应液缓慢倒入到饱和碳酸氢钠水溶液(250ml)中，搅拌30分钟，乙醚萃取，无水硫酸钠干燥。过滤浓缩，剩余物过硅胶柱层析纯化得到化合物2。
2)化合物3的制备
取化合物2(18g,0.023mol)加入到甲醇(220ml)中溶解，搅拌下向其中加入碳酸氢钠(53g,0.61mol)，加热回流6小时，减压蒸去甲醇，剩余物冷却至室温，加入乙酸乙酯搅拌30分钟过滤，滤饼用乙酸乙酯洗涤，滤液合并后浓缩的粗产物过硅胶柱层析纯化得到化合物3。
3)化合物4的制备
取化合物5(16g,0.019mol)溶于二氯甲烷(0.5ml)和甲醇(300ml)的混合溶剂中，再加入到二氧化硒(30g)中，再向其中加入干燥的过氧叔丁醇(19g)的甲苯溶液(90ml)，室温搅拌2小时，将化合物3的甲醇溶液缓慢滴入其中，滴完后，继续搅拌反应30分钟，向其中缓慢加入亚硫酸钠的水溶液，加完后搅拌反应1小时，二氯甲烷萃取，无水硫酸钠干燥，过滤，浓缩，剩余物过硅胶柱层析纯化得到化合物4。从化合物1开始到化合物4的总收率为55％。
4)化合物5的制备
取化合物5(18g,0.017mol)溶于三乙胺(250ml)中，加入叔丁基二甲基氯硅烷(11g,0.017mol)，室温搅拌过夜，原料反应完全，减压浓缩除去三乙胺，向剩余物中加入水和乙酸乙酯，萃取，分液，收集有机相，加入无水硫酸钠干燥，过滤，浓缩，剩余物过硅胶柱层析纯化得到化合物5。收率95％。
5)化合物6的制备
取化合物5(13g,0.014mol)溶于二甲基亚砜(120ml)中，加入醋酸(40ml)，搅拌，加热至75℃,待原料消失后，将反应液倒入冰水中，乙醚萃取，有机相用饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥。过滤，浓缩后剩余物过硅胶层析柱纯化得到化合物6。收率72％。
6)马沙骨化醇的制备
取化合物6加入到四氢呋喃中，加入四丁基氟化铵，室温搅拌24小时，原料反应完全，加入碳酸氢钠水溶液和乙酸乙酯萃取，分液，收集有机相，加入无水硫酸钠干燥，过滤，减压浓缩，剩余物过硅胶层析柱纯化得到化合物7，即马沙骨化醇。收率90％。
从化合物1到马沙骨化醇的总收率为33.8％。
1H NMR(400MHz,d6-DMSO)δ:0.48(s,3H,CH3),1.07(s,6H,2CH3),1.08(d,J＝1.6Hz,3H,CH3),1.21-1.27(m,1H),1.37-1.64(m,10H,),1.77-1.83(m,3H),1.91-1.96(m,1H),2.14-2.19(m,1H),2.35-2.36(m,1H),2.77-2.80(m,1H),3.17-3.20(m,1H),3.24-3.30(m,1H),3.59(q,J＝7.6Hz1H),3.98-4.03(m,1H,CHOH),4.11(s,1H,OH),4.17-4.20(m,1H,CHOH),4.53(d,J＝4Hz,1H,OH),4.75(s,1H,＝CH2),4.85(d,J＝4.4Hz,1H,OH),5.22(s,1H,＝CH2),5.98(d,J＝11.2Hz,1H,＝CH),6.17(d,J＝11.2Hz,1H＝CH)；13C NMR(75MHz,d-DMSO)δ:12.3,19.1,21.8,22.9,24.7,28.3,29.6,29.7,38.9,43.1,43.2,44.1,44.9,55.5,56.8,64.3,65.1,68.2,68.4,76.7,109.8,117.8,122.4,135.9,139.6,149.5；MS:m/z＝418,found 436(M+H2O)。
Claims (5)
1.一种马沙骨化醇的制备方法，其特征在于，所述的方法包括以下步骤：
1)首先将化合物1的二级羟基用磺酸酯进行保护得到化合物2，然后在碱的作用下，在甲醇中，化合物2分子内环化得到化合物3，再对3进行烯丙位氧化，得到化合物4；
2)将化合物4的二级羟基进行保护，得到化合物5，化合物在酸性条件下打开5中的三元环得到化合物6；
3)将化合物6中的羟基保护基脱去，得到目标化合物马沙骨化醇。
2.根据权利要求1所述的马沙骨化醇的制备方法，其特征在于：步骤2)中，所述化合物4的二级羟基可以用R1保护，得到化合物5，
R1可以是三甲基硅基，三乙基硅基，叔丁基二甲基硅基，三异丙基硅基，叔丁基二苯基硅基或苯甲酰基。
3.根据权利要求1所述的马沙骨化醇的制备方法，其特征在于：脱去化合物6中的保护基所用的试剂为质子酸或Lewis酸。
4.根据权利要求3所述的马沙骨化醇的制备方法，其特征在于，所述的质子酸选自盐酸、硫酸、对甲基苯磺酸、樟脑磺酸中的一种或几种的混合物；所述的Lewis酸可以是三氟化硼、氯化锌、溴化镁、四丁基氟化铵中的一种或几种的混合物。
5.根据权利要求1所述的马沙骨化醇的制备方法，制备化合物5所用的酸选自盐酸、醋酸、硫酸、草酸、柠檬酸、苹果酸、马来酸中的一种或几种的混合物。
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