CN102516259A - 制备hiv蛋白酶抑制剂的方法 - Google Patents
制备hiv蛋白酶抑制剂的方法 Download PDFInfo
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- CN102516259A CN102516259A CN2011103155782A CN201110315578A CN102516259A CN 102516259 A CN102516259 A CN 102516259A CN 2011103155782 A CN2011103155782 A CN 2011103155782A CN 201110315578 A CN201110315578 A CN 201110315578A CN 102516259 A CN102516259 A CN 102516259A
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- 238000000034 method Methods 0.000 title claims abstract description 101
- 238000002360 preparation method Methods 0.000 title claims description 44
- 230000008569 process Effects 0.000 title abstract description 3
- 239000004030 hiv protease inhibitor Substances 0.000 title abstract 3
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- 239000003795 chemical substances by application Substances 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 11
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- 230000002829 reductive effect Effects 0.000 claims description 9
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- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 229960000884 nelfinavir Drugs 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical group 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229960002814 rilpivirine Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- CFPVQGQJRGIWSP-UHFFFAOYSA-N scandium(3+) Chemical compound [Sc+3] CFPVQGQJRGIWSP-UHFFFAOYSA-N 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- PODWXQQNRWNDGD-UHFFFAOYSA-L sodium thiosulfate pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].[O-]S([S-])(=O)=O PODWXQQNRWNDGD-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960000658 sumatriptan succinate Drugs 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- 229910052713 technetium Inorganic materials 0.000 description 1
- 229960004556 tenofovir Drugs 0.000 description 1
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- VZZUPGZLDMTMFL-UHFFFAOYSA-N triazine;trithiole Chemical compound S1SC=CS1.C1=CN=NN=C1 VZZUPGZLDMTMFL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
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Abstract
本文公开了用于合成可用于制备抗病毒HIV蛋白酶抑制剂化合物的式(0)的二呋喃中间体的方法。还公开了式(IV)的HIV蛋白酶抑制剂以及其各种中间体。
Description
本申请是中国发明专利申请(申请日:2007年3月29日;申请号:200780017888.8(国际申请号:PCT/US2007/007564);发明名称:制备HIV蛋白酶抑制剂的方法)的分案申请。
相关申请的交叉参考
本申请要求2006年3月29日提交的美国临时专利申请60/787,126号的优先权。
发明领域
本发明总体上涉及用于制备具有抗-HIV蛋白酶性质的抗病毒化合物的方法。本发明涉及用于制备氨基甲酸酯磺酰胺氨基膦酸酯和其中间体的方法。本发明还涉及通过这些方法制备的新型中间体。通过本发明方法制备的氨基甲酸酯磺酰胺氨基膦酸酯是HIV蛋白酶抑制剂,可用于治疗人自身免疫缺陷综合征(AIDS)。
发明背景
AIDS是一种主要的全球性公共健康问题。尽管以HIV病毒为目标的药物被广泛使用并且显示了效力,但是毒性和耐药性病毒株的发展已经限制了它们的有效性。能够确定HIV病毒的存在、不存在或量的分析方法在探索抑制剂以及诊断HIV的存在中是有实际用途的。
制备式I的HIV蛋白酶抑制剂(PI)
的传统方法是太长的,给出大约1%的低收率,可重复性差,要求很多色谱纯化步骤,并且使用不希望的试剂如臭氧、氰基硼氢化钠和氢化三丁基锡。式I的化合物是一种HIV蛋白酶抑制剂,其已经被制备和公开在WO2003/090690中。
用于制备在式I化合物的合成中使用的二呋喃醇中间体的方法已经被Pezechk(Pezechk,M.等人,Tetrahedron Letters,1986,27,3715)和Ghosh(Ghosh,A.K.等人,J.Med.Chem.,1994,37,2506;Ghosh A.K.等人,J.Med.Chem.,1996,39,3278;Ghosh,A.K.等人,Tetrahedron Letters,1995,36,505)描述。
路线1显示了Ghosh,A.K.等人,Tetrahedron Letters,1995,36,505描述的二呋喃醇合成
路线1
常规的方法要求多个步骤并使用有毒的试剂。在一种方法(Ghosh,A.K.等人,Tetrahedron Letters,1995,36,505)中,外消旋混合物的拆分通过暴露于固定化的酶并然后进行色谱分离来实现。
已经从二呋喃醇(1)和碳酸二吡啶基酯(Ghosh A.K.等人,J.Med.Chem.,1996,39,3278)和对硝基苯酚氯代甲酸酯(X.Chen等人,Bioorganicand Medicinal Chemistry Letters,1996,6,2847)制备了活性的碳酸酯。这些试剂与亲核反应物偶联,但不总是显示合适的反应性和功效。
存在用于制备衍生自N-保护的氨基酸的手性卤代醇的方法(Albeck,A.等人,Tetrahedron,1994,50,6333)。用于将这样的氯代醇转化为氨基甲酸酯磺酰胺衍生物的方法是已知的(Malik,A.等人,WO 01/46120A1)。卤代醇也可以被转化为环氧化物,并以类似方式转化为氨基甲酸酯磺酰胺衍生物(WO 03/090690)。
氨基膦酸的氨基甲酸酯衍生物的制备和随后转化成膦酸单酯和二酯已经被描述在Yamauchi,K.等人,J.Org.Chem.,1984,49,1158;Yamauchi,K.等人,J.Chem.Soc.Perkin Trans.I,1986,765中。
氨基乙基膦酸二酯可以通过包括如下步骤的方法制备:用酰卤或氯代甲酸苄基酯(CBZCl)酰化氨基膦酸,以形成式VII的化合物
式VII的化合物可以被活化和与苯酚缩合,以形成式VIII的化合物
式VIII的化合物可以被活化和与第二种醇或酚缩合,以形成IX
式IX的化合物可以被脱酰基,以形成式X的氨基膦酸酯化合物
式X的化合物可以以有机或无机酸的盐的形式被分离。
用于二呋喃醇的Ghosh方法(Ghosh,A.K.等人,J.Org.Chem.,1995,36,505)要求使用三丁基锡氢化物和臭氧。
式I化合物的游离碱是非结晶性的和吸湿的,在极性溶剂中具有有限的稳定性。
因此,需要开发更稳定形式的式I的PI的合成方法。还需要开发合成式I的PI的更有效的方法。
发明概述
本发明提供了合成二呋喃醇衍生物、氨基膦酸酯衍生物的改进方法,并提供了制备可用于治疗人自身免疫缺陷综合征(AIDS)的氨基甲酸酯磺酰胺氨基乙基膦酸二酯的方法。
在一个实施方案中,本发明提供了制备式0的二呋喃醇的方法:
该方法包括
使2,3-二氢呋喃和乙醇醛或乙醇醛二聚体在镧系或过渡金属催化剂存在下反应,以形成式0的二呋喃醇。
具体而言,本发明涉及以下方面:
项1.一种制备式0的二呋喃醇的方法:
该方法包括:使2,3-二氢呋喃与乙醇醛或乙醇醛二聚体在镧系或过渡金属催化剂存在下反应,以形成式0的二呋喃醇。
项2.项1的方法,其中所述催化剂包含与选自下组中的配体络合的Yb,Pr,Cu,Eu或Sc:
项3.项2的方法,其中所述催化剂是Yb(hfc)3(+),Yb(hfc)3(-),Eu(hfc)3(+),Eu(hfc)3(-),Yb(fod)3(+)和S-联萘酚,Yb(tfc)3(+),Sc(OTf)3和(S)-pybox,和Pr(tfc)3(+)
其中
其中,M表示Yb,Pr,Cu,Eu或Sc。
项4.项1的方法,其中所述反应在约0℃至约100℃范围内的温度下进行。
项5.项1的方法,其中所述反应是在包含与手性配体络合的镧系元素或过渡金属的催化剂存在下进行的。
项6.项5的方法,其中所述手性配体是
其中Ph是苯基。
项7.项1的方法,该方法在溶剂存在下进行。
项8.项7的方法,其中所述溶剂是极性非质子溶剂。
项9.项8的方法,其中所述溶剂是甲基-叔丁基-醚,二氯甲烷或它们的混合物。
项10.项1的方法,该方法在作为溶剂的过量的2,3-二氢呋喃存在下进行。
项11.项1的方法,其中所述催化剂包含Sc。
项12.项1的方法,其中所述催化剂包含Yb。
项13.项1的方法,该方法还包括:
(i)将所述式0的二呋喃醇与二碳酸二琥珀酰亚胺基酯混合,以形成式L1的化合物:
(ii)将所述式0的二呋喃醇与碳酸二(对硝基)苯基酯或对硝基苯酚氯代甲酸酯混合,以形成式L2的化合物:
或者
(iii)将所述式0的二呋喃醇与碳酸二吡啶基酯混合,以形成式L3的化合物:
项14.项13的方法,还包括将所述式L1,L2或L3的化合物与式N的化合物混合,
以形成式A的化合物,
其中Me是甲基。
项15.项14的方法,还包括将所述式A的化合物与式J的化合物混合,
以形成式I的化合物,
其中,
Me是甲基;
Et是乙基;和
Ph是苯基。
项16.项15的方法,还包括将所述式I的化合物与己二酸混合,以形成式IV的盐,
其中Me、Et和Ph各自独立地与项15中的定义相同。
项17.项14的方法,其中所述式N的化合物通过将式M的化合物去保护来制备:
项18.项17的方法,其中所述去保护通过将所述式M的化合物与去保护剂混合来实现,所述去保护剂选自三氟乙酸,盐酸,甲苯磺酸,甲磺酸,苯磺酸或氢溴酸。
项19.项17的方法,其中所述式M的化合物通过还原式C的化合物来制备:
项20.项19的方法,其中所述还原通过使所述式C的化合物与还原剂接触来完成,所述还原剂是氢化铝锂,硼氢化钠,硼氢化锂,三乙酸硼氢化钠,氰基硼氢化钠,三异丙氧基硼氢化钾或氢化二异丁基铝。
项21.项19的方法,其中所述式C的化合物通过将式F的化合物与式G的化合物混合来制备:
项22.项21的方法,其中所述式F的化合物通过将式E的化合物与一种胺混合来制备:
项23.项22的方法,其中所述胺是
项24.式C的化合物:
或其药物学可接受的盐。
项25.式M的化合物:
或其药物学可接受的盐。
项26.式N的化合物:
或其药物学可接受的盐。
项27.式IV的盐:
项28.包含项27的盐和赋形剂、稀释剂或载体的药物组合物。
项29.用于治疗或预防患者逆转录病毒感染的方法,该方法包括给予所述患者治疗有效量的项27的盐。
项30.项29的方法,其中所述逆转录病毒是人免疫缺陷病毒(HIV)。
项31.项29的方法,其中所述治疗有效量是约10mg至约2000mg。
项32.项29的方法,其中所述盐被在药物组合物中给药。
项33.项32的方法,其中所述药物组合物是片剂的单位剂量形式。
项34.项29的方法,其中所述盐被口服给药。
项35.一种装备盒,其包含:(1)项28的药物组合物;(2)处方信息;和(3)容器。
项36.项35的装备盒,其中所述药物组合物呈片剂的单位剂量形式。
项37.这里所公开的化合物、组合物或方法。
项38.项27的盐在制备用于抑制患者体内逆转录病毒蛋白酶活性的药物中的用途,包括给予所述患者治疗有效量的所述盐。
项39.项27的盐在制备用于治疗或预防患者体内逆转录病毒感染的药物中的用途,包括给予所述患者治疗有效量的所述盐。
项40.项38或39的用途,其中所述逆转录病毒是人免疫缺陷病毒(HIV)。
项41.项38或39的盐的用途,其中所述盐作为单一组合物给予所述患者。
项42.项38或39的盐的用途,其中所述盐通过口服给予所述患者。
项43.项42的用途,其中所述口服给药每天一次。
项44.项38或39的用途,其中所述患者还服用选自下组中的一种或多种治疗剂:司他夫定(stavudine),emtricitabine,替诺福韦(tenofovir),emtricitabine,阿巴卡韦(abacavir),拉米夫定(lamivudine),齐多夫啶(zidovudine),去羟肌苷(didanosine),扎西他滨(zalcitabine),phosphazide,依法韦仑(efavirenz),奈韦拉平(nevirapine),地拉韦啶(delavirdine),替拉那韦(tipranavir),沙奎那韦(saquinavir),茚地那韦(indinavir),atazanavir,奈非那韦(nelfinavir),氨普奈韦(amprenavir),samprenavir,洛匹那韦(lopinavir),利托那韦(ritonavir),enfuvirtide,福齐夫定替酯(Fozivudine tidoxil),Alovudine,Dexelvucitabine,Apricitabine,Amdoxovir,Elvucitabine(ACH126443),Racivir(外消旋的FTC,PSI-5004),MIV-210,KP-1461,fosalvudine tidoxil(HDP 99.0003),AVX756,DioxolaneThymine(DOT),TMC-254072,INK-20,4′-Ed4T,TMC-125(etravirine),Capravirine,TMC-278(rilpivirine),GW-695634,Calanolide A,BILR 355BS,和VRX 840773,以及它们的药物学可接受的盐。
项45.项38或39的用途,其中所述治疗有效量是约10mg至约2000mg。
项46.项38或39的用途,其中所述盐被在药物组合物中给药。
项47.项46的用途,其中所述药物组合物是片剂的单位剂量形式。
项48.项47的用途,其中所述盐被口服给药。
示例性实施方案的详细说明
定义
除非另外指明,下列术语和短语在本文中使用时意图具有如下含义:
当在本文中使用商标名时,申请人意图独立地包括所述商标名的产品和该商标名产品的活性药物成分。
“保护基团”是指化合物的结构部分,其掩蔽或改变一种官能团的性质或者化合物整体的性质。化学保护基团和保护/去保护的策略是本领域公知的。参见例如Protective Groups in Organic Chemistry,Theodora W.Greene,John Wiley & Sons,Inc.,New York,1991。保护基团经常被用于掩蔽某些官能团的反应性,以帮助希望的化学反应的效率,例如,以安排好的和计划的方式产生和切断化学键。化合物的官能团的保护除改变被保护的官能团的反应性外,还改变其它物理性质,例如极性,亲脂性(亲水性)和其它性质,这可以通过常见的分析工具测定。化学保护的中间体本身可以是生物活性的或非活性的。
术语“手性的”是指具有镜像配偶体的不可叠加性质的分子,而术语“非手性的”是指可叠加在其镜像配偶体上的分子。
术语“立体异构体”是指具有相同的化学构成但在原子或基团的空间排列方面不同的化合物。
“非对映异构体”是指具有两个或更多个手性中心的立体异构体,并且其分子不是彼此的镜像。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可以在高分辩分析程序如电泳和色普法中分离。
“对映体”是指一种化合物的两种立体异构体,它们是彼此不可叠加的镜像。
“镧系元素”是指下列元素和它们的离子:La,Ce,Pr,Nd,Pm,Sm,Eu,Gd,Tb,Dy,Ho,Er,Tm,Yb,Lu。
“过渡金属”是指下列元素和它们的离子:Sc,Ti,V,Cr,Mn,Fe,Co,Ni,Cu,Zn,Y,Zr,Nb,Mo,Tc,Ru,Rh,Pd,Ag,Cd,Hf,Ta,W,Re,Os,Ir,Pt,Au,Hg。
构成金属催化剂的配位体可以是手性的、非手性的或外消旋的。
路线和实施例
这些示例性方法的一般方面被描述在下面和实施例中。下列方法的产物中的每一种在用于后面的工艺中之前任选被分离、离析和/或纯化。
氧化和还原反应典型地在接近室温(约20℃)的温度下进行,但是对于金属氢化物还原反应,温度经常被降低到0℃至-100℃。对于还原反应,溶剂典型地是非质子的,并且对于氧化反应,溶剂可以是质子的或非质子的。反应时间被调整以实现希望的转化率。
缩合反应典型地在接近室温的温度下进行,但是对于非平衡的、动力学控制的缩合反应,降低的温度(0℃至-100℃)也是常见的。溶剂可以是质子的(在平衡反应中常用)或非质子的(在动力学控制的反应中常用)。
标准的合成技术如共沸去除反应副产物和无水反应条件(例如惰性气体环境)的使用是本领域中常见的,并且在适用时将使用。
当结合化学合成操作使用时,术语“处理的”,“处理(treating)”,“处理(treatment)”等是指接触、混合、反应、允许反应、使接触和用于指明一种或多种化学物质被以使其转化为一种或多种其它化学物质的方式处理的其它本领域常见的术语。这意味着“用化合物2处理化合物1”与“允许化合物1与化合物2反应”,“使化合物1与化合物2接触”,“使化合物1与化合物2反应”,和用于合理地指明化合物1被用化合物2“处理”,与化合物2“反应”,“允许与化合物2反应”等的其它有机合成领域常见表述是同义的。例如,处理预示了其中允许有机化学品反应的合理和常见的方式。除非另外指明,否则意图采用正常的浓度(0.01M至10M,典型地0.1M至1M),温度(-100℃至250℃,典型地-78℃至150℃,更典型地-78℃至100℃,更更典型地0℃至100℃),反应容器(典型地玻璃,塑料,金属),溶剂,压力,气氛(对于对氧和水不敏感的反应典型地是空气,或者对于对氧和水敏感的反应典型地是氮气或氩气)等。有机合成领域已知的类似反应的知识被用于选择用于给定方法中的“处理”的条件和装置。特别地,基于本领域的知识,有机合成领域的普通技术人员能够选择合理预期可以成功进行所描述的方法的化学反应的条件和装置。
在每个示例性的路线中,将反应产物彼此分离和/或与原料分离可能是有利的。每个步骤或一系列步骤的希望的产物被通过本领域常见的技术分离和/或纯化(下面称为分离)至希望的同质程度。典型地,这样的分离包括多相萃取、从溶剂或溶剂混合物中结晶、蒸馏、升华或色谱法。色谱法可以包括任意数目的方法,包括例如:反相和正相;尺寸排阻;离子交换;高、中和低压液相色谱法和设备;小规模的分析色谱;模拟移动床(SMB)和制备薄或厚层色谱,以及小规模薄层和快速色谱的技术。
另一类制备方法涉及用试剂处理混合物,选择所述试剂以与希望的产物、未反应的原料、反应副产物等结合或者使希望的产物、未反应的原料、反应副产物等可分离。这样的试剂包括吸附剂或吸收剂,例如活性炭、分子筛、离子交换介质等。或者,试剂可以是酸(在碱性物质的情况下)、碱(在酸性物质的情况下)、结合试剂如抗体、结合蛋白、选择性螯合剂如冠醚、液/液离子萃取试剂(LIX)等。
基本上不含其立体异构体的单一立体异构体,例如对映体,可以通过外消旋混合物的拆分来得到,所述拆分使用例如使用光学活性的拆分试剂形成非对映异构体的方法(Stereochemistry of Carbon Compounds,(1962),E.L.Eliel,McGraw Hill;Lochmuller,C.H.,(1975)J.Chromatogr.,113:(3)283-302)。本发明的手性化合物的外消旋混合物可以通过任何合适的方法分离和离析,所述方法包括:(1)与手性化合物形成离子性的非对映异构体盐,并通过分级结晶或其它方法分离;(2)与手性衍生化试剂形成非对映异构体化合物,分离非对映异构体,和转化成纯的立体异构体;和(3)直接在手性条件下分离基本上纯的或富集的立体异构体。
示例性实施方案
在一个实施方案中,本发明提供了式C的化合物和其药物学可接受的盐:
在另一个实施方案中,本发明提供了制备式M的化合物的方法,该方法包括:
a)用胺如1-氨基-2-甲基丙烷处理式E的化合物
以形成式F的化合物
b)用式G的化合物处理式F的化合物
以形成式C的化合物
c)用还原剂处理式C的化合物,以形成式M的化合物
可用于将腈结构部分转化为醛结构部分的典型的还原剂可以在Larock,Richard,C.“Comprehensive Organic Transformations 2nd Ed.1999John Wiley and Sons publisher,1271-1272页中找到。
在另一个实施方案中,本发明提供了式M的化合物:
在另一个实施方案中,本发明提供了制备式M的化合物的方法:
该方法包括
用还原剂处理式C的化合物,以形成式M的化合物
在另一个实施方案中,本发明提供了制备式M的化合物的方法,其中所述还原剂是氢化二异丁基铝。
在另一个实施方案中,本发明提供了制备式0的化合物的方法,还包括
用二碳酸二琥珀酰亚胺基酯(disuccinimidyl dicarbonate)处理式0的二呋喃醇,以形成式L1的化合物
在另一个实施方案中,本发明提供了制备式0的化合物的方法,该方法还包括
用碳酸二(对硝基苯基)酯或对硝基苯酚氯代甲酸酯处理式0的二呋喃醇,以形成式L2的化合物
在另一个实施方案中,本发明提供了制备式0的化合物的方法,该方法还包括
用碳酸二吡啶基酯处理式0的二呋喃醇,以形成式L3的化合物
在另一个实施方案中,本发明提供了式N的化合物和其药物学可接受的盐
在另一个实施方案中,本发明提供了式A的化合物和其药物学可接受的盐
在另一个实施方案中,本发明提供了制备氨基甲酸酯磺酰胺氨基膦酸酯的方法,该方法包括:
a)在Yb,Pr,Cu,Eu或Sc催化剂存在下向乙醇醛或乙醇醛二聚体中添加二氢呋喃,以形成式0的二呋喃醇
b)用二碳酸二琥珀酰亚胺基酯,碳酸二(对硝基苯基)酯,对硝基苯酚氯代甲酸酯,或碳酸二吡啶基酯处理步骤(a)的反应产物,以分别形成式L1,式L2,式L2,或式L3的化合物,
c)用胺处理式E的化合物
以形成式F的化合物
d)用式G的化合物处理式F的化合物
以形成式C的化合物
e)用还原剂处理式C的化合物,以形成式M的化合物
f)用三氟乙酸,盐酸,甲苯磺酸,甲磺酸,苯磺酸,氢溴酸或在Protective Groups in Organic Chemistry,Theodora W.Greene,John Wiley &Sons,Inc.,New York,1991中列出的另一种合适的酸将式M的化合物脱保护,以形成式N的化合物
g)用式L,L2,或L3的化合物处理式N的化合物,以形成式A的化合物
h)用式J的化合物处理式A的化合物
式J
以形成式I的化合物
式I
i)用己二酸处理式I的化合物,以形成式IV的盐
式IV。
在另一个实施方案中,本发明提供了式IV的盐:
式IV。
式IV的盐已经被制备,并且具有118℃-121℃的熔点。式IV的盐的游离碱是HIV蛋白酶抑制剂,其已经被制备和公开在WO 2003/090690中,该文件通过引用结合在本文中。式IV的盐也是HIV蛋白酶抑制剂,可用于治疗被HIV感染的患者。
表1:在二呋喃醇形成中的手性催化剂
DHF=二氢呋喃,DCM=二氯甲烷,MTBE=甲基-叔丁基醚。
1GC分析通过将二呋喃醇用三氟乙酸酐在DCM中衍生化成三氟乙酸酯来进行。
表2:钪(III)催化剂和手性配体的使用以直接获得(-)-1
TFT=三氟甲苯,DME=二甲氧基乙烷,DCM=二氯甲烷,MTBE=甲基-叔丁基醚,THF=四氢呋喃。
1GC分析通过将二呋喃醇用三氟乙酸酐在DCM中衍生化成三氟乙酸酯来进行。
表3.催化剂和手性配体的使用以直接获得(-)-1
1GC分析通过将二呋喃醇用三氟乙酸酐在DCM中衍生化成三氟乙酸酯来进行。
表4.用于(±)-二呋喃醇的对映体拆分的柱方法的使用
路线1:用于由二呋喃醇制备二呋喃碳酸酯的方法,使用用于合成二呋喃醇的新方法
路线2:氯代醇氨化成BOC(OBn)酪氨酸
路线3:在路线2中得到的产物与如路线1中所述得到的二呋喃碳酸酯的反应
路线4.
路线5.
路线6.
路线7.
现在通过以下非限制性实施例举例说明本发明。
路线8.二呋喃乙酸酯的动力学的脂肪酶诱导的水解
实施例
(3R,3aS,6aR)六氢呋喃并[2,3-b]呋喃-3-醇(1)的制备
向一个反应容器中加入乙醇醛二聚体(4.45kg),Yb(fod)3催化剂(0.29kg)和二氢呋喃(20.5kg)。搅拌内容物以进行混合,并加热到50℃,维持~5小时。浓缩反应内容物成粗油,溶解在饱和NaHCO3水溶液(60kg)中,并用二氯甲烷(6kg)洗涤。将二氯甲烷(58kg)、KBr(0.89kg)和TEMPO(0.116kg)加入到水层中,并冷却该混合物至0℃。向该混合物中缓慢添加次氯酸钠(NaOCl,~11%Cl,55kg)。在反应完成后,允许水层和有机层分离。用二氯甲烷(29kg)洗涤水层。合并有机层并用水、含KI的10%HCl和10%硫代硫酸钠洗涤。用硫酸钠干燥有机层,过滤掉固体物,并冷却滤液到0℃以下。添加硼氢化钠(0.36kg)在乙醇(7.1kg)中的溶液,同时维持反应内容物温度低于0℃。在反应完成后,添加乙酸(1.4kg)和水(13.4kg)进行猝灭。通过真空蒸馏浓缩混合物。向得到的粗油/半固体混合物中添加乙酸乙酯(31kg)。有机层用硫酸钠干燥,过滤掉固体,并通过真空蒸馏浓缩,以分离(±)-1,其为油状物。
酶拆分。将乙二醇二甲醚(DME,14.7kg)和乙酸酐(4.6kg)加入到所述粗产物油中。使该溶液流动通过填充了脂肪酶PS-C“Amano I”(0.36kg)和砂(6kg)的柱。在该对映体拆分结束后,通过真空蒸馏浓缩该溶液。添加水(18kg)以溶解产物并用二氯甲烷(28kg)洗涤该溶液。通过真空蒸馏浓缩含有产物的水层。将得到的油状物溶解在乙酸乙酯(16kg)中,并用硫酸钠干燥。通过用水反萃取二氯甲烷层数次,可以分离出附加的产物。通过真空蒸馏浓缩合并的水层。将得到的油状物溶解在乙酸乙酯中,用硫酸钠干燥,并过滤出固体。通过真空蒸馏浓缩合并的乙酸乙酯层,以给出产物(3R,3S,6R)六氢呋喃并[2,3-b]呋喃-3-醇,即(-)-1,其为油状物(1.6kg,97%ee,33%收率),含有大约15wt%的相应的乙酸盐。分析数据:1HNMR(DMSO-d6,300MHz)δ5.52(dd,1H),4.25-4.15(m,1H),3.85-3.75(m,2H),3.7-3.6(m,1H),3.3(t,1H),2.75-2.65(m,1H),2.23-2.13(m,1H),1.75-1.6(m,1H)。
(3R,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-基4-硝基苯基碳酸酯的制备
向一个反应容器中加入碳酸二(4-硝基苯基)酯(2.85kg)和二氯甲烷(33.4kg)。向该溶液中添加溶解在二氯甲烷(6.7kg)中的(3R,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-醇,即(-)-1(1.2kg,98.5%ee,含有~36%乙酸盐)。添加三乙胺(1.6kg),并在20-25℃搅拌得到的反应内容物。在反应完成后,用水(16.8kg)洗涤该内容物。分离各层,并通过真空蒸馏浓缩二氯甲烷层。将含有产物的油状物溶解在乙酸乙酯(21.2kg)中,并随后用水、碳酸钾水溶液和盐水洗涤。该乙酸乙酯层用硫酸钠干燥,过滤出固体,并通过真空蒸馏浓缩。将该浓缩的产物混合物溶解在乙酸乙酯(9.3kg)中并加热到45℃。缓慢添加己烷(6.7kg),并缓慢冷却该最终混合物至0℃。过滤得到的淤浆,以分离化合物12。用乙酸乙酯和己烷的溶液(1∶1v/v,5.3kg)洗涤固体滤饼。干燥产物至恒重,给出1.5kg的12(55%),其为灰白色固体。通过经真空蒸馏浓缩母液和重复结晶程序,可以得到附加的产物。分析数据:1H NMR(CDCl3,300MHz)δ8.3(d,2H),7.4(d,2H),5.8(d,1H),5.3-5.2(m,1H),4.2-4.1(m,1H),4.1-3.9(m,3H),3.25-3.1(m,1H),2.3-2.1(m,1H),2.1-1.9(m,1H);HPLC AN=98.5%。
式12的{(2S,3R)-1-(4-苄氧基苄基)-2-羟基-3-[异丁基-(4-甲氧基-苯磺酰基)-氨基]-丙基}-[3R,3aS,6aR]-氨基甲酸六氢呋喃并[2,3-b]呋喃-3-基酯的制备程序
式12
向烧瓶中加入式27的化合物(1.3Kg),然后添加式12的化合物(0.65Kg)和乙酸乙酯(7.2Kg)并搅拌,和添加三乙胺(0.65Kg)和二甲基氨基吡啶(24g)并在室温下搅拌数小时。将反应混合物相继用水(8Kg)、饱和NaHCO3水溶液(8L)、稀盐酸(8L)和盐水(8L)洗涤。向反应混合物中加入活性炭(0.13Kg),搅拌数小时,过滤通过硅藻土并用乙酸乙酯漂洗。添加庚烷(6L),将混合物搅拌数小时,并且产物通过过滤收集,用1∶1EtOAc/庚烷漂洗。将产物干燥至恒重,给出1Kg式12的化合物(70%),为灰白色固体,mp127.5℃,HPLC纯度98.4。1H NMR(CDCl3)7.7-7.75(d,2H),7.26-7.48(m,5H),7.12-7.20(d,2H),6.96-7.03(d,2H),6.85-6.94(d,2H),5.65(d,1H),5.3(宽的d,1H),5.01(s,2H),4.96-5.06(宽峰,1H),3.63-3.96(m,7H),3.84(s,3H),2.62-3.20(m,7H),1.8-1.95(m,1H),1.40-1.69(m,2H),0.95(dd,6H)。
式13的{[1S,2R}-2-羟基-1-(4-羟基-苄基)-3-[N-异丁基-(N-4-甲氧基苯磺酰基)-氨基]-丙基}-氨基甲酸六氢-[3R,3aS,6aR]-呋喃并[2,3-b]呋喃-3-基酯的制备程序
向烧瓶中加入式12的化合物(1Kg),并用氮气吹扫。添加湿的10wt%披钯活性炭(0.2Kg),将烧瓶用氮气吹扫,并添加乙酸乙酯(10L)。将混合物加热到50℃,并向反应混合物中通氢气2.5h,直到反应完成。向混合物中通氮气,然后在氮气气氛下通过硅藻土过滤,并用乙酸乙酯漂洗。将滤液浓缩至2.5L,并将庚烷(7.5L)添加到该温溶液中。将得到的淤浆在冰浴中冷却,收集,和用正庚烷洗涤并干燥至恒重,给出固态的式13的化合物0.82Kg,mp:在98.2和133.8℃的两个放热峰,HPLC纯度97.4%。1H NMR(CDCl3)7.61-7.75(d,2H),7.01-7.10(m,2H),6.91-6.99(d,2H),6.63-6.79(d,2H),5.62(d,2H),5.51(宽的s,1H),4.96-5.09(d,2H),3.81(s,3H),3.59-3.98(m,6H),2.62-3.18(m,7H),1.42-1.91(m,3H),0.78-0.95(dd,6H)。
式14的三氟甲磺酸4-(2S,3R)-{2-([2R,3S]-六氢呋喃并[2,3-b]呋喃-(3R)-3-基氧基羰基氨基)-3-羟基-4-[N-异丁基-(N-4-甲氧基苯磺酰基)-氨基]-丁基}-苯基酯的制备程序
将式13的化合物(0.82Kg)和二氯甲烷(8Kg)加入到烧瓶中,并温和加热以溶解式13的化合物。向另一个烧瓶中加入N-苯基三氟甲磺酰亚胺(N-phenyltriflimide)(0.61Kg)和二氯甲烷(2.6Kg),并温和加热以得到一种溶液。将所述三氟甲磺酰化试剂(trfilating agent)的溶液转移到含式13化合物的溶液中,并添加碳酸铯(0.55Kg),在室温下继续搅拌数小时,直到反应完成。添加水(4Kg),分离各层,将水层用二氯甲烷反萃取,并且将合并的有机层用无水硫酸钠干燥。将该溶液过滤并浓缩至小的体积,随后用甲基叔丁基醚(7L)和庚烷(16L)稀释,并在室温下搅拌以得到固体,将所述固体收集并干燥至恒重,给出固态的式14的化合物0.68Kg,mp 133.7℃,19F NMR(CDCl3)-73.5ppm,HPLC纯度97.2%。1H NMR(CDCl3)7.70-7.78(d,2H),7.29-7.38(d,2H),7.16-7.23(d,2H),6.96-7.06(d,2H),5.67(d,1H),4.95-5.04(m,2H),3.87(s,3H),3.64-4.01(m,7H),2.78-3.21(m,7H),1.51-1.90(m,3H),0.87-0.97(dd,6H)。
式15的{(1S,2R)-[1-(4-甲酰基-苄基)]-(2R)-2-羟基-3-[N-异丁基-(N-4-甲氧基-苯磺酰基)-氨基]-丙基}-氨基甲酸[3R,3aS,6aR]-六氢呋喃并[2,3-b]呋喃-3-基酯的制备程序
向烧瓶中加入式14的化合物(0.15Kg),接着加入Pd(OAc)2(0.06Kg),dppp.(0.1Kg),二甲基甲酰胺(1.9Kg),并随后抽真空和充氮气数次,然后在氮气气氛下加热至内部温度为60至65℃,并添加氯化锂(3g)。将该混合物在65-70℃加热,并且向混合物中通一氧化碳30分钟。向溶液中添加三乙胺(86g),接着缓慢添加三乙基硅烷(0.05Kg)。将反应在CO气氛下维持在65-70℃,直到反应完成。将反应混合物冷却到室温,用乙酸乙酯(1.8Kg)稀释和用水(4Kg)洗涤。将乙酸乙酯相用水(1Kg)反萃取,并将合并的水层用乙酸乙酯(0.5Kg)反萃取。将合并的乙酸乙酯萃取液用水洗涤数次,并将乙酸乙酯相过滤通过硅藻土,用乙腈(0.2Kg)稀释。添加HF(48%,在水中,0.23Kg)和饱和NaHCO3(3Kg),分离反应混合物并将水层丢弃。将有机层用无水硫酸钠干燥,过滤,并将滤液加热到50-55℃的温度,用三巯基三嗪(23g)处理数分钟,添加活性炭(10g),将混合物在50-55℃加热至少30分钟,冷却到室温并过滤通过硅藻土垫。将滤液用饱和NaHCO3(0.7Kg)洗涤,分离,用无水硫酸钠干燥,过滤并浓缩,并将残余物通过硅胶柱层析纯化,使用乙酸乙酯和庚烷的混合物洗脱。收集含有希望的式15化合物的级分并浓缩,给出一种白色固体,通过将该固体在升高的温度下溶解在乙二醇二甲基醚中并缓慢添加庚烷,然后冷却到室温,来将该固体重结晶。通过过滤收集固体,用庚烷漂洗并干燥至恒重,提供了为白色固体的式15的化合物,72%,0.125Kg,mp 140.2℃,HPLC纯度98.3%。1H NMR(CDCl3)9.98(s,1H),7.80-7.85(d,2H),7.67-7.76(d,2H),7.39-7.45(d,2H),6.95-7.04(d,2H),5.65(d,1H),4.96-5.12(m,2H),3.85(s,3H),3.64-4.02(m,7H),2.75-3.21(m,7H),1.72-1.89(m,1H),1.42-1.70(m,2H),0.84-0.98(dd,6H)。
式16的2-(N-苄氧基氨基甲酰基)-氨基乙基膦酸的制备程序
向烧瓶中加入去离子水(9Kg),惰性化,搅拌,并分批添加氢氧化钠(2.7Kg)以保持温度低于35℃。
将氨基乙基膦酸(AEP,3Kg)分批添加到烧瓶中。分数份添加氯代甲酸苄酯(5.6Kg),控制温度在大约40℃之间。允许该混合物在室温下反应数小时,直到反应完成。将混合物用乙酸乙酯(每次16Kg)萃取两次。水层用浓盐酸酸化至pH1.3并陈化数小时。收集固体并用乙腈(2.3Kg)洗涤。然后将该固体和甲醇(9.6Kg)加入到烧瓶中,并用预先用水和甲醇洗涤过的Dowex树脂(8.7Kg)处理。将混合物在环境温度下搅拌1h,过滤,并用甲醇(3Kg)漂洗。将滤液浓缩至粘稠的油状物,用乙腈稀释,并重复地用乙腈共沸蒸馏,直到残余甲醇被除去。然后将该溶液用乙腈稀释,加热以得到溶液,过滤,并允许其逐渐冷却至冰浴温度。收集固体并干燥至恒重,给出式16的化合物(CBZ-AEP)4.8Kg,77%,mp 107℃,31P NMR(D2O)26.6ppm。1HNMR(D2O)7.2-7.36(宽的s,5H),4.95(宽的s,2H),3.16-3.30(m,2H),1.78-1.94(m,2H)。
式17的2-(N-苄氧基氨基甲酰基)-氨基乙基膦酸苯酯的制备程序
将CBZ-AEP(2.5Kg)和乙腈(3.1Kg)搅拌并加热至60-65℃。在另一个烧瓶中,温热苯酚(4.5Kg)和乙腈(3.5Kg)以给出一种溶液,并将该溶液加入到所述CBZ-AEP混合物中和搅拌,直到得到溶液。向该溶液中添加4-二甲基氨基吡啶(DMAP,1.4Kg)在乙腈(3.1Kg)中的淤浆。向另一个烧瓶中添加乙腈(0.8Kg),并添加二环己基碳二亚胺(3Kg)。将该DCC溶液加入到所述温的AEP溶液中。一旦完成添加,将反应混合物回流数小时,直到反应完成。将反应混合物冷却到室温,过滤,将滤液浓缩并用水(20L)和NaOH水溶液稀释。将该溶液用乙酸乙酯(13.5L)萃取两次。通过添加6M HCl,将水相酸化至pH 1.0,收集产生的固体并重新在水(19L)中形成淤浆,并再次收集,干燥至恒重,给出式17的化合物2.47Kg,为白色固体,mp 124℃,HPLC纯度99.2%,31P NMR(CDCl3)29.8ppm(~90%)和28.6ppm(~10%)(由于氨基甲酸酯官能团的旋转异构体)。1H NMR(CDCl3)7.05-7.40(m,10H),5.10(宽的s,2H),3.41-3.59(m,2H),2.01-2.20(m,2H)。
式18的(乙基(S)-2-丙酰基)-2-(N-苄氧基氨基甲酰基)-氨基乙基膦酸苯酯的制备程序
将式17的化合物(4.8kg)与甲苯(24kg)和DMF(4g)一起加入到反应器中。将该混合物温热到70℃。用一定时间添加SOCl2,同时维持67-72℃的内容物温度,并将反应在75℃下搅拌,直到反应完成。将溶液冷却到45℃,并在真空下浓缩至大约一半体积。在另一个反应器中,制备(S)-乳酸乙酯(1.9kg)、甲苯(15kg)和吡啶(1.5kg)的干燥溶液并冷却到-1℃。缓慢添加所述氯化物溶液,同时维持内部温度为-3至3℃,然后将得到的溶液温热到20℃并搅拌,直到反应完成。将反应物加入到10%的柠檬酸水溶液(10kg)中,分离各层,并将有机层用10%NaH2PO4水溶液(10kg)洗涤。将有机层用无水硫酸钠(5kg)干燥,浓缩,并从乙酸乙酯(4kg)中蒸发至粘稠的油状物,通过使该油状物通过硅胶柱(9.2kg)来纯化该油状物,用乙酸乙酯和庚烷的混合物洗脱。合并含有式17化合物的级分并浓缩,给出一种油状物。通过与乙腈(2x3kg)一起蒸发两次来交换溶剂,给出一种稠的液体(4.7kg,80%),HPLC纯度为98%,为两种非对映异构体的混合物(对氯化苄修正的)。
将所述异构体的混合物在Chromasil硅胶上分离,使用乙酸乙酯和庚烷的混合物洗脱。希望的异构体式20化合物显示了如下物理数据:油状物,31P NMR(CDCl3)26.1(~90%)和25.4(~10%)(因氨基甲酸酯官能团的旋光异构体);1H NMR(CDCl3)7.24-7.4(m,8H),7.14-7.21(m,2H),5.65(宽的s,1H),5.1(s,2H),5.02-5.06(m,1H),4.12-4.17(q,2H),3.52-3.70(m,2H),2.15-2.36(m,2H),1.57(d,3H),1.22(t,3H)。
式19的(乙基(S)-2-丙酰基)-2-氨基乙基膦酸苯酯乙酸盐的制备程序
向烧瓶中加入湿的10wt%披钯活性炭(0.28Kg)、乙酸(0.15L)、式20的化合物(0.56Kg)和乙醇(5.6L),并向烧瓶中通氮气大约30分钟。向反应混合物中通氢气数小时,直到起始原料消耗完。向反应混合物中通氮气60分钟,并将反应混合物过滤通过硅藻土和用乙醇(2L)洗涤。将滤液在室温下浓缩至小的体积,用乙腈(5.6L)稀释,浓缩至一半体积,并用活性炭(0.3Kg)处理,过滤通过硅藻土,和用乙腈(2.5L)洗涤。将滤液在室温下蒸发,并用乙腈稀释和蒸发。将这种操作重复数次,以除去所有乙醇和水,并且最后将溶液浓缩至小的体积和在5℃保存。等分试样的蒸发提供了收率。油状物,90%,0.49Kg,31P NMR(CDCl3)25.2。所述材料不用进一步纯化而直接用于下一步。
式21的2-[(2S,3R)-4-[((4-甲氧基苯)磺酰基)(2-甲基丙基)氨基]-3-(羟基)丁基]-[[[[(苯氧基)(2-(2R)-丙酸乙酯)氧基]氧膦基]乙基氨基]苄基]-[氨基甲酸-(3R,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-基酯]己二酸盐(1∶1)的制备程序
向烧瓶中加入式15的化合物(0.5Kg),乙腈(1.6L),和式19的化合物(0.46Kg)在乙腈(1L)中的溶液,接着加入乙腈(2.4L)。将该混合物在室温下搅拌数小时。在室温下用一定时间分批添加NaBH(OAc)3(0.27Kg),以维持在室温。将反应混合物搅拌数小时,直到反应完成。添加硅藻土(0.24Kg),并将反应混合物过滤,并用乙腈和乙酸异丙酯洗涤。将滤液浓缩至小的体积,并用乙酸异丙酯(12.5L)稀释,随后用饱和NaHCO3洗涤3-4次(每次7.5L),用盐水(3.8L)洗涤,有机溶液用硫酸钠干燥,过滤,浓缩至小的体积,用乙酸异丙酯稀释,并共沸蒸馏除去残余水。将溶液用乙腈稀释,温热,并添加己二酸(0.13Kg)。将溶液逐渐冷却,并收集固体和用乙酸异丙酯漂洗,提供了固态的式21的化合物,0.69Kg,79%,mp 119℃,HPLC纯度95.3%。光谱数据与文献标准物的数据一致:31P NMR(丙酮-d6)27.6;13C NMR(丙酮-d6)ppm 173.4,170,162.6,155.0,150.4,137.9,137.4,130.7,129.3,129.2,129.1,127.6,124.5,120.4,113.9,108.9,72.7,72.6,70.4,70.4,68.6,60.7,57.8,55.6,54.9,52.8,52.3,45.1,42.1,34.9,32.6,26.5,26.5,25.4,24.0,19.2,18.6,13.1;1H NMR(丙酮d-6)ppm 7.80(d,2H),7.38(t,2H),7.29(d,2H),7.28(d,2H),7.26(d,2H),7.21(t,1H),7.12(d,2H),5.53(d,1H),5.04(dq,1H),4.95(ddd,1H),4.14(q,2H),3.92(s,3H),3.89(m,1H),3.88(dd,1H),3.84(m,1H),3.78(宽的s,2H),3.76(dd,1H),3.63(dd,1H),3.60(dd,1H),3.20(dd,1H),3.06(dd,1H),2.97(dt,2H),2.91(dd,1H),2.85(m,1H),2.70(dd,1H),2.33(m,2H),2.24(m,2H),2.04(m,1H),1.67(m,2H),1.51(m,2H),1.51(d,3H),1.21(t,3H),0.93(d,3H),0.89(d,3H);IR(KBr)cm-13354,3424,3300-2400(宽峰),2959,1755,1703,1599,1497,1308,1343,1152,991,950。
式21b的2-[(2S,3R)-4-[((4-甲氧基苯)磺酰基)(2-甲基丙基)氨基]-3-(羟基)丁基]-[[[[(苯氧基)(2-(2R)-丙酸乙酯)氧基]氧膦基]乙基氨基]苄基]-[氨基甲酸-(3R,3aS,6aR)-六氢呋喃并[2,3-b]呋喃-3-基酯]丁二酸盐(1∶1)的制备程序
制备如下:通过在热的乙酸异丙酯(~200mL)中搅拌而将7.8g游离碱形式的式29化合物溶解,添加琥珀酸(1当量),并且在得到溶液后,将该溶液逐渐冷却到室温,然后在冰浴中冷却数分钟,收集产物并用乙酸异丙酯漂洗和干燥至恒重,提供了式21b的琥珀酸盐,7.7g,86%,HPLC纯度98.6%,mp 106.5℃。13C NMR(CDCl3)129.8,129.4,129.2,124.9,120.3,114.1,109.0,70.9,72.7,71.4,70.33,70.28,69.34,69.30,61.3,56.51,56.47,55.3,54.95,52.24,52.22,51.74,51.72,44.93,42.42,30.65,24.84,24.79,26.48,25.42,19.7,19.6,19.24,13.7。1H NMR(CDCl3)7.75-7.79(d,2H),7.38-7.43(d,2H),7.33-7.36(m,2H),7.24-7.29(d,2H),7.15-7.20(t,1H),6.98-7.05(4H),5.63(d,1H),5.00-5.08(m,1H),5.84-4.92(m,1H),4.09-4.18(m,3H),3.93-3.98(m,1H),3.91(s,3H),3.79-3.92(m,4H),3.66-3.74(m,1H),3.22-3.56(m,4H),2.96-3.02(m,2H),2.51-2.83(m,10H),1.74-1.82(m,2H),1.6(d,3H),1.46-2.01(3H),1.21(t,3H),1.83(d,3H),1.63(d,3H)。
式22的制备程序
向烧瓶中加入14.8g碳酸二琥珀酰亚胺基酯,CH2Cl2(25mL),5.0g式10化合物(以在CH2Cl2(20mL)中的溶液的形式),和吡啶(7.8mL)。将该溶液在温和回流条件下加热数小时,直到反应完成。撤掉加热,并添加水(35mL),将混合物搅拌数分钟,分离各层。将有机相相继用水(35mL)和盐水(30mL)洗涤。将有机相用硫酸钠干燥,过滤并浓缩。残余物在加热下重新溶解在二氯甲烷CH2Cl2(13mL)中,并将庚烷(10mL)添加到该温的溶液中。将混合物逐渐冷却到大约10℃,过滤出固体,用庚烷漂洗并干燥至恒重,提供了~8.9g,87.5%。
向烧瓶中加入粗的式22的化合物(106g)、活性炭(23g)和甲苯(5.7Kg)。在搅拌2h后,将混合物过滤通过硅藻土,并将滤液蒸发,以给出100g(94.3%回收率)的式22化合物,为灰白色固体。
向烧瓶中加入式22的化合物(12g)和丙酮(24g),并加热至52℃,得到一种溶液。将庚烷(60g)在搅拌下添加到该温的溶液中。将混合物用2小时冷却到大约10℃,收集固体,用3∶1丙酮∶庚烷洗涤,并干燥至恒重,提供了式22的化合物,11.4g,95%回收率,为白色固体。1H NMR(CDCl3)5.75(d,1H),5.21-5.30(dd,1H),3.90-4.16(m,4H),3.07-3.18(m,1H),2.85(s,4H),2.10-2.22(m,1H),1.92-2.06(m,1H)。
式24的制备
向烧瓶中加入式24的化合物(10g),饮用水(7.5g,13.5当量)和异丁基胺(22.08g,9.8当量),将该稠的混合物加热到~60℃,并在该温度下搅拌,直到反应完成。用~30分钟向反应混合物中添加100mL饮用水,同时维持内部温度>55℃。将混合物用1.5小时冷却到5℃,并在该温度下再维持30分钟。将淤浆过滤,用20mL饮用水洗涤,并干燥至恒重,给出式23的化合物10.94g;98.4%,HPLC纯度97.9%。1H NMR(CDCl3)7.55-7.62(d,2H),7.32-7.38(d,2H),4.62-4.72(宽的s,1H),3.78-3.90(宽的m,1H),3.42-3.50(m,1H),3.08-3.16(dd,1H),2.63-2.90(m,3H),2.42(d,2H),1.65-1.81(m,1H),1.35(s,9H),0.93(d,6H)。
式25的制备
向烧瓶中加入式23的化合物(10.5g),二氯甲烷(63mL)和三乙胺(3.1g,1.05当量),并用~10分钟的时间添加4-甲氧基苯磺酰氯(6.1g,1.02当量)在二氯甲烷(18mL)中的溶液,在添加过程中维持内部温度<25℃。在反应结束后(在室温~2h),添加1M盐酸(5mL),搅拌5min,并分离各层。将1M NaHCO3水溶液(5mL)添加到有机相中,并将混合物搅拌5min,分离各层,并且有机相浓缩至泡沫体。将粗产物在65℃溶解在200mL EtOH中,用~45分钟时间添加水(120mL),同时维持内部温度>57℃,并且将混合物d,2H),7.36-7.43(d,2H),6.96-7.04(d,2H),4.63-4.72(宽的s,1H),3.88(s,3H),3.72-3.90(m,2H),3.04-3.18(m,3H),2.79-3.01(m,3H),1.78-1.92(m,1H),1.62(宽的s,1H),用大约4.5小时逐渐冷却到10℃。将淤浆过滤和用50mL 30%EtOH水溶液洗涤,产物干燥至恒重,给出14.5g,94%,HPLC纯度99.86%。1H NMR(CDCl3)7.70-7.76(d,2H),7.55-7.64(1.35(s,9H),0.85-0.95(dd,6H)。
式26的制备程序
向烧瓶中加入式25的化合物(35g),甲苯(525mL),惰性化,并冷却到-20℃。逐渐添加1.5M DIBAL-H在甲苯中的溶液(154mL,1.5M,3.5当量),保持温度低于-10℃。将反应在该温度下搅拌数小时,直至完成。逐渐添加甲醇(9.3mL,3.5当量),然后添加THF(88mL),并将混合物温热到0℃以上。用5分钟添加柠檬酸水溶液(用130ml水稀释的220ml 40%(w/w)的柠檬酸,7当量),然后将混合物温热到~60℃,维持大约1小时。将混合物冷却到室温,分离各层,并且将有机层添加到175ml 1M HCl和35ml水中。用105ml THF漂洗分液漏斗。将得到的混合物在室温下搅拌大约1小时,用THF(35mL)稀释,分离,将有机层与35ml 1M NaHCO3合并并搅拌30分钟。分离各层,过滤通过无水硫酸镁层(大约2g),并用甲苯(35mL)漂洗。将该溶液浓缩,并用甲苯共沸蒸馏三次,以减少残余的THF。将最终体积调节到大约275mL,并且将淤浆加热到~65℃以得到溶液。逐渐添加庚烷(132mL),然后将混合物用4小时逐渐冷却到室温。将产物过滤,用2∶1甲苯∶庚烷洗涤,并干燥至恒重,提供了式26的化合物,31g,88%,mp 120.5℃,HPLC纯度99.6%。1H NMR(CDCl3)10.0s,1H),7.80-7.85(m,4H),7.27-7.50(d,2H),7.09-7.10(d,2H),5.99-6.07(宽的d,1H),3.91(s,3H),3.78-3.93(m,3H),3.41-3.51(dd,1H),3.24-3.34(dd,1H),2.79-3.05(m,5H),1.29(s,9H),0.87-0.93(dd,6H)。
式15的{(1S,2R)-[1-(4-甲酰基-苄基)]-(2R)-2-羟基-3-[N-异丁基-(N-4-甲氧基-苯磺酰基)-氨基]-丙基}-氨基甲酸[3R,3aS,6aR]-六氢呋喃并[2,3-b]呋喃-3-基酯的制备程序
向烧瓶中加入式26的化合物(2.0g)和20mLTHF。向溶液中滴加甲磺酸。将该溶液温热至40℃,直到脱保护反应完成。将该溶液冷却到20℃,并向反应器中添加N-甲基咪唑(2.39g)。然后添加式22的化合物(1.52g),并将反应温热至50℃,直到反应完成。添加乙酸乙酯(150mL),并且将溶液相继用0.5M柠檬酸水溶液(20g),10%NaH2PO4水溶液(20g),饱和NaHCO3水溶液(20g),和10%NaH2PO4水溶液(20g)洗涤。将有机层用无水硫酸钠(2g)干燥,过滤,并浓缩至粘稠的油状物,将该油状物通过硅胶柱层析纯化,使用乙酸乙酯和庚烷的混合物洗脱。合并含希望的式15化合物的级分并浓缩,给出一种白色固体,95%,2.13g,HPLC纯度97%。
提及了本发明的某些实施方案,结合说明、结构和式子举例说明了所述实施方案的实例。尽管已经结合列举的实施方案描述了本发明,应该明白,它们并不是意图将本发明限制到这些实施方案。相反,本发明意图涵盖可以被包括在由项定义的本发明的范围内的所有可选择的方案、修改和等价物。
Claims (11)
6.权利要求5的方法,其中所述去保护通过将所述式M的化合物与去保护剂混合来实现,所述去保护剂选自三氟乙酸,盐酸,甲苯磺酸,甲磺酸,苯磺酸或氢溴酸。
8.权利要求7的方法,其中所述还原通过使所述式C的化合物与还原剂接触来完成,所述还原剂是氢化铝锂,硼氢化钠,硼氢化锂,三乙酸硼氢化钠,氰基硼氢化钠,三异丙氧基硼氢化钾或氢化二异丁基铝。
9.式C的化合物的制备方法,其中式C的化合物通过将式F的化合物与式G的化合物混合来制备:
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ATE401298T1 (de) | 1999-12-23 | 2008-08-15 | Ampac Fine Chemicals Llc | Verbessertes verfahren zur herstellung von 2s,3s- n-isobutyl-n-(2-hydroxy-3-amino-4-phenylbutyl)- - nitrobenzenesulfonylamid hydrochlorid und anderen derivaten von 2-hydroxy-1,3-diamin |
JP2004536546A (ja) | 2001-07-20 | 2004-12-02 | コーニンクレッカ フィリップス エレクトロニクス エヌ ヴィ | 発振回路、斯かる発振回路を有するコンバータ、及び斯かるコンバータを有するプレコンディショニング装置 |
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