CN103274926A - 一种制备Remodulin中的活性成分曲前列素的改良方法 - Google Patents
一种制备Remodulin中的活性成分曲前列素的改良方法 Download PDFInfo
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- CN103274926A CN103274926A CN2013102177181A CN201310217718A CN103274926A CN 103274926 A CN103274926 A CN 103274926A CN 2013102177181 A CN2013102177181 A CN 2013102177181A CN 201310217718 A CN201310217718 A CN 201310217718A CN 103274926 A CN103274926 A CN 103274926A
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- 238000000034 method Methods 0.000 title claims abstract description 40
- 230000008569 process Effects 0.000 title abstract description 4
- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title abstract 5
- 229960005032 treprostinil Drugs 0.000 title abstract 4
- 229940118867 remodulin Drugs 0.000 title description 3
- 239000004480 active ingredient Substances 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims description 60
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 31
- -1 2-(2-furyl) ethyl Chemical group 0.000 claims description 29
- 239000003513 alkali Substances 0.000 claims description 25
- 239000011737 fluorine Substances 0.000 claims description 15
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- 238000006460 hydrolysis reaction Methods 0.000 claims description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- 239000000460 chlorine Substances 0.000 claims description 9
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- 230000029936 alkylation Effects 0.000 claims description 8
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- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims description 7
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- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- 235000010755 mineral Nutrition 0.000 claims description 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 claims description 6
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- 235000014852 L-arginine Nutrition 0.000 claims description 6
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- 229930195722 L-methionine Natural products 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- HCBIBCJNVBAKAB-UHFFFAOYSA-N Procaine hydrochloride Chemical compound Cl.CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 HCBIBCJNVBAKAB-UHFFFAOYSA-N 0.000 claims description 6
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
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- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 6
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- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- 125000003118 aryl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
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- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- A61K31/19—Carboxylic acids, e.g. valproic acid
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- C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
- C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
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- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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- C07C59/72—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
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- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/10—Aromatic or araliphatic carboxylic acids, or thio analogues thereof; Derivatives thereof
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- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
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- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
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- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
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- C07C39/17—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic with no unsaturation outside the aromatic rings containing other rings in addition to the six-membered aromatic rings, e.g. cyclohexylphenol
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Indole Compounds (AREA)
Abstract
本发明涉及制备前列环素衍生物的改良方法。一种实施方式提供通过曲前列素的盐将苯并茚三元醇转化为曲前列素的改良方法并且提供纯化曲前列素的改良方法。
Description
本申请为2010年6月17日进入中国国家阶段、申请号为200880121181.6、申请日为2008年12月12日、发明名称为“一种制备Remodulin中的活性成分曲前列素的改良方法”的发明专利申请的分案申请。
相关申请的交叉引用
本申请要求2007年12月17日提交的美国临时专利申请第61/014,232号的优先权,该临时专利申请的全部内容在此通过引用并入本文。
背景技术
本发明涉及用于生产前列环素衍生物的方法以及在所述方法中有用的新型中间体化合物。
前列环素衍生物是具有活性的有用药物化合物,所述活性例如抑制血小板聚集、降低胃分泌、抑制病变以及支气管扩张。
中的活性成分曲前列素在美国专利第4,306,075号中被首次描述。曲前列素和其他前列环素衍生物已按照Moriarty等人在J.Org.Chem.2004,69,1890-1902、Drug of the Future,2001,26(4),364-374,美国专利第6,441,245号、第6,528,688号、第6,765,117号、第6,809,223号和第6,756,117号中所描述的来制备。他们的教导通过引用并入本文以说明如何实施本发明的实施方式。
美国专利第5,153,222号描述了使用曲前列素治疗肺动脉高压。曲前列素被批准用于静脉进入和皮下进入,后者避免了与持续静脉内置管有关的败血症事件。美国专利第6,521,212号和第6,756,033号描述了通过吸入服用曲前列素治疗肺动脉高压、外周血管疾病和其他疾病及病症。美国专利第6,803,386号公开了服用曲前列素治疗癌症,所述癌症例如肺癌、肝癌、脑癌、胰腺癌、肾癌、前列腺癌、乳腺癌、结肠癌以及头颈癌。美国专利申请公开第2005/0165111号公开了曲前列素治疗缺血性病变。美国专利第7,199,157号公开了曲前列素治疗改善肾功能。美国专利申请公开第2005/0282903号公开了曲前列素治疗神经性足部溃疡。2008年2月8日提交的美国申请第12/028,471号公开了曲前列素治疗肺纤维化。美国专利第6,054,486号公开了用曲前列素治疗外周血管疾病。2007年10月17日提交的美国专利申请第11/873,645号公开了包括曲前列素的联合疗法。美国申请公开第2008/0200449号公开了使用计量剂量吸入器递送曲前列素。美国申请公开第2008/0280986号公开了用曲前列素治疗间质性肺病。2008年2月8日提交的美国申请第12/028,471号公开了用曲前列素治疗哮喘。美国专利第7,417,070号、第7,384,978号和美国申请公开第2007/0078095号、第2005/0282901号和第2008/0249167号描述了曲前列素和其他前列环素的类似物的口服剂型。
因为曲前列素和其他前列环素衍生物从医学角度而言极为重要,需要适于商业生产的大规模合成这些化合物的有效方法。
发明内容
在一种实施方式中,本发明提供用于制备通式I的化合物及其水合物、溶剂化物、前药或药学上可接受的盐的方法。
所述方法包括下列步骤:
(a)用烷基化剂烷基化结构II的化合物以生成通式III的化合物,
其中
w=1、2或3;
Y1是反式-CH=CH-,顺式-CH=CH-,-CH2(CH2)m-或-C≡C-;m为1、2或3;R7是
(1)-CpH2p-CH3,其中p为选自1至5的整数,所述整数的范围包括1和5,
(2)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基任选地取代的苯氧基,条件是不超过两个取代基是非烷基,条件是仅当R3和R4是氢或甲基(相同或不同)时,R7是苯氧基或取代苯氧基,
(3)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基在芳香环上任选地取代的苯基、苄基、苯乙基或苯基丙基,条件是不超过两个取代基是非烷基,
(4)顺式-CH=CH-CH2-CH3,
(5)-(CH2)2-CH(OH)-CH3,或
(6)-(CH2)3-CH=C(CH3)2;
其中,合并在一起的-C(L1)-R7为
(1)由1个至3个(C1-C5)烷基任选地取代的(C4-C7)环烷基;
(2)2-(2-呋喃基)乙基,
(3)2-(3-噻嗯基)乙氧基,或
(4)3-噻嗯氧基甲基(3-thienyloxymethyl);
M1是α-OH:β-R5或α-R5:β-OH或α-OR1:β-R5或α-R5:β-OR2,其中R5是氢或甲基,R2是醇保护基团(alcohol protecting group),并且
L1是α-R3:β-R4、α-R4:β-R3或α-R3:β-R4和α-R4:β-R3的混合物,其中R3和R4是氢、甲基或氟(相同或不同),条件是仅当R3和R4中一个为氢或氟时,R3和R4中另一个是氟。
(b)用碱水解(a)步骤的产物,
(c)使(b)步骤的产物与碱B接触以形成通式Is的盐,
(d)使(c)步骤的所述盐和酸反应以形成通式I的化合物。
在另一实施方式中,本发明提供用于制备通式IV的化合物的方法。
所述方法包括下列步骤:
(a)用烷基化剂烷基化结构V的化合物以生成通式VI的化合物,
(b)用碱水解(a)步骤的产物,
(c)使(b)步骤的产物与碱B接触以形成通式IVs的盐,以及
(d)使(b)步骤的盐与酸反应以形成通式IV的化合物。
具体实施方式
在本文描述的方法中单独地或结合地使用的各种术语在下面予以定义。
词语“包括”意思是“包括但不限于”。因此,其他未提及的物质、添加剂、载体或步骤可能存在。除非另有说明,不指明具体数目是指一种或一种以上。
C1-3-烷基是含有1个至3个碳原子的直链或支链烷基基团。典型的烷基基团包括甲基、乙基、n-丙基和异丙基。
C1-3-烷氧基是含有1个至3个碳原子的直链或支链烷氧基基团。典型的烷氧基基团包括甲氧基、乙氧基、丙氧基和异丙氧基。
C4-7-环烷基是含有4个至7个碳原子的、任选地取代的单环、双环或三环烷基基团。典型的环烷基基团包括但不限于环丁基、环戊基、环己基和环庚基。
本发明预想的取代基和可变物的组合仅仅是那些导致形成稳定化合物的组合。本文使用的术语“稳定的”是指化合物具有足以进行生产的稳定性,并且所述稳定性使所述化合物的完整性保持足够的时间以对本文详细描述的目的有用。
本文使用的术语“前药”意指化合物的衍生物,所述化合物的衍生物在生物学条件下(在体外或在体内)可水解、氧化或发生别的反应以提供活性化合物。前药的例子包括但不限于化合物的衍生物,该化合物的衍生物包括可生物水解(biohydrolyzable)基团,例如可生物水解酰胺、可生物水解酯、可生物水解氨基甲酸酯、可生物水解碳酸酯、可生物水解酰脲以及可生物水解磷酸盐类似物(例如,单磷酸盐、二磷酸盐或三磷酸盐)。
本文使用的“水合物”是一种化合物形式,其中水分子以一定比例被结合为化合物的结构复合物的不可或缺的部分。
本文使用的“溶剂化物”是一种化合物形式,其中溶剂分子以一定比例被结合为化合物的结构复合物的不可或缺的部分。
本文中“药学上可接受的”意思是在制备药物组合物方面有用,所述药物组合物通常是安全的、无毒的并且既不是生物学上的也不是别的不理想的,并且所述药物组合物包括对于兽医使用和人类药物使用是有用的。
“药学上可接受的盐”意思是如上定义的药学上可接受的盐,并且所述盐具有期望的药学活性。这些盐包括用有机酸和无机酸形成的酸加成盐,所述有机酸和无机酸例如氯化氢、溴化氢、碘化氢、硫酸、磷酸、醋酸、乙醇酸、马来酸、丙二酸、草酸、甲磺酸、三氟乙酸、富马酸、琥珀酸、酒石酸、柠檬酸、苯甲酸、抗坏血酸等。用有机碱和无机碱可形成碱加成盐,所述有机碱和无机碱例如钠、铵、钾、钙、乙醇胺、二乙醇胺、N-甲基葡糖胺、胆碱等。本发明所包括的是药学上可接受的盐或本文的任何通式化合物。
基于它的结构,本文使用的词组“药学上可接受的盐”是指药学上可接受的有机或无机的化合物的酸式盐或碱式盐。代表性的药学上可接受的盐包括,例如,碱金属盐、碱土金属盐、铵盐、水溶性盐或水不溶性盐,例如醋酸盐、氨芪磺酸盐(amsonate)(4,4-二氨基二苯乙烯-2,2-二磺酸盐)、苯磺酸盐、苯甲酸盐、重碳酸盐、硫酸氢盐、酒石酸氢盐、硼酸盐、溴化物、酪酸盐、钙、依地酸钙、右旋樟脑磺酸、碳酸盐、氯化物、柠檬酸盐、克拉维酸盐(clavulariate)、二氢氯化物、依地酸盐、乙二磺酸盐、丙酸酯十二烷基硫酸盐(estolate)、乙磺酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、对羟基乙酰氨基苯胂酸盐、六氟磷酸盐、己基间苯二酚化物(hexylresorcinate)、海巴明(hydrabamine)、氢溴酸盐、盐酸盐、羟萘甲酸盐、碘化物、异硫代化物(isothionate)、乳酸盐、乳糖醛酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基溴化物、甲基硝酸盐、甲基硫酸盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺铵盐(N-methylglucamineammonium salt)、3-羟基-2-萘甲酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐(1,1-亚甲基-双-2-羟基-3-萘甲酸盐,双羟萘酸盐(einbonate))、泛酸盐、磷酸盐/二磷酸盐、苦味酸盐、聚半乳糖醛酸盐、丙酸盐、p-甲苯磺酸盐、水杨酸盐、硬脂酸盐、碱式醋酸盐、琥珀酸盐、硫酸盐、磺基水杨酸盐、苏拉明酸盐(suramate)、单宁酸盐、酒石酸盐、8-氯茶碱盐、甲苯磺酸盐、三乙基碘化物以及戊酸盐。
本发明提供用于生产曲前列素以及其他前列环素衍生物的方法以及在所述方法中有用的新型中间体化合物。根据本发明,所述方法提供了相对于现有方法在大规模合成方面的优势。例如,通过柱层析的纯化被省去,因此,可燃性溶剂所需量和产生的废弃物大大减少。此外,形成盐是比柱层析容易得多的操作。而且,发现根据本发明的方法制备的产物具有更高的纯度。因此,本发明提供了更经济、更安全、更快速、更易于操作的方法并且本发明提供了更高的纯度。
本发明的一种实施方式是用于制备通式I的化合物或其水合物、溶剂化物、前药或药学上可接受的盐的方法。
所述方法包括下列步骤:
(a)用烷基化剂烷基化通式II的化合物以生成通式III的化合物,
其中
w=1、2或3;
Y1是反式-CH=CH-、顺式-CH=CH-、-CH2(CH2)m-或-C≡C-;m为1、2或3;
R7是
(1)-CpH2p-CH3,其中p是选自1至5的整数,所述整数的范围包括1和5,
(2)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基任选地取代的苯氧基,条件是不超过两个取代基是非烷基,条件是仅当R3和R4是氢或甲基(相同或不同)时,R7是苯氧基或取代苯氧基,
(3)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基在芳香环上任选地取代的苯基、苄基、苯乙基或苯基丙基,条件是不超过两个取代基是非烷基。
(4)顺式-CH=CH-CH2-CH3,
(5)-(CH2)2-CH(OH)-CH3,或
(6)-(CH2)3-CH=C(CH3)2;
其中,合并在一起的-C(L1)-R7为
(1)由1个至3个(C1-C5)烷基任选地取代的(C4-C7)环烷基;
(2)2-(2-呋喃基)乙基,
(3)2-(3-噻嗯基)乙氧基,或
(4)3-噻嗯氧基甲基;
M1是α-OH:β-R5或α-R5:β-OH或α-OR1:β-R5或α-R5:β-OR2,其中R5是氢或甲基,R2是醇保护基团,并且
L1是α-R3:β-R4、α-R4:β-R3或α-R3:β-R4和α-R4:β-R3的混合物,其中R3和R4是氢、甲基或氟(相同或不同),条件是仅当R3和R4中一个是氢或氟时,R3和R4中另一个是氟。
(b)用碱水解(a)步骤的产物,
(c)使(b)步骤的产物与碱B接触以形成通式Is的盐,
(d)使(c)步骤的所述盐与酸反应以形成通式I的化合物。
在一种实施方式中,通式I的化合物为至少90.0%、95.0%、99.0%。
通式II的化合物可从通式XI的化合物来制备,通式XI的化合物是如美国专利第6,441,245中描述的通式X的化合物的环化产物。
其中,n为0、1、2或3。
可选地,通式II的化合物可从通式XIII的化合物来制备,通式XIII的化合物是如美国专利第6,700,025中描述的通式XII的化合物的环化产物。
本发明的一种实施方式是用于制备具有通式IV的化合物及其水合物、溶剂化物或药学上可接受的盐的方法。
所述方法包括
(a)用诸如ClCH2CN之类的烷基化剂烷基化结构V的化合物以生成通式VI的化合物,
(b)用诸如KOH之类的碱水解(a)步骤的产物,
(c)使(b)步骤的产物与诸如二乙醇胺之类的碱B接触以形成下述结构的盐,以及
(d)使(b)步骤的盐与诸如HCl之类的酸反应以形成通式IV的化合物。
在一种实施方式中,通式IV的化合物的纯度为至少90.0%、95.0%、99.0%、99.5%。
在一种实施方式中,所述方法还包括分离通式IVs的盐的步骤。
在一种实施方式中,(c)步骤中的碱B可以是铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇(tromethanine)、镁、L-赖氨酸、L-精氨酸或三乙醇胺。
下列缩写被用于说明书和/或所附的权利要求书,并且它们具有下列含义:
“MW”意思是分子量。
“Eq.”意思是相等。
“TLC”意思是薄层色谱。
“HPLC”意思是高效液相色谱。
“PMA”意思是磷钼酸。
“AUC”意思是曲线下面积。
根据前述考虑因素以及下面的具体实施例,本领域技术人员可以理解的是在实施本发明时如何选择必需的试剂和溶剂。
本发明通过下列实施例予以描述。这些实施例不被认为是限制本发明的范围,而仅仅作为示例。
实施例
实施例1苯并茚三元醇的烷基化
将苯并茚三元醇(1250g)、丙酮(19L)和K2CO3(粉末)(1296g)、氯乙腈(567g)、四丁基溴化铵(36g)装入配有机械搅拌器和热电偶的50-L三颈圆底烧瓶。在室温下(23±2℃)用力搅拌反应混合物16小时至72小时。所述反应的进行通过TLC来监测。(甲醇/CH2Cl2;1:9并且由PMA的10%乙醇溶液来显色(develop))。反应完全之后,所述反应混合物用/不用硅藻土垫过滤。滤饼用丙酮(10L)洗涤。在50℃至55℃条件下,真空浓缩滤液,得到浅棕色粘性液体苯并茚腈。苯并茚腈粗产物就这样用于下一个步骤而无需进一步纯化。
实施例2苯并茚腈的水解
名称 | MW | 数量 | Mol. | Eq. |
苯并茚腈 | 371.52 | 1397g* | 3.76 | 1.0 |
KOH | 56.11 | 844g | 15.04 | 4.0 |
甲醇 | -- | 12L | -- | -- |
水 | -- | 4.25L | -- | -- |
*注:该重量是基于来自前一步骤的100%产率。这不是分离的产率。
将溶于甲醇的苯并茚腈溶液(12L)和KOH溶液(844g KOH溶于4.25L水)装入配有加热/冷却系统、机械搅拌器、冷凝器和热电偶的50-L圆柱形反应器。搅拌反应混合物并加热至回流(温度72.2℃)。反应的进行通过TLC来监测(为了观测TLC,用3M HCl酸化1mL至2mL反应混合物至pH为1至2并且用乙酸乙酯萃取。乙酸乙酯萃取物被用于TLC;洗脱剂:甲醇/CH2Cl2;1:9并由PMA的10%乙醇溶液显色)。反应完全(约5小时)之后,将反应混合物冷却至-5℃至10℃并在搅拌时用盐酸溶液(3M,3.1L)淬灭反应混合物。在50℃至55℃条件下,真空浓缩所述反应混合物以获得大约12L至14L浓缩物。将所述浓缩物丢弃。
用水(7L至8L)稀释水层并用乙酸乙酯(2×6L)萃取水层以除去溶于乙酸乙酯的杂质。向水层加入乙酸乙酯(22L)并通过在搅拌时加入3M HCl(1.7L)将反应混合物的pH调节为1至2。分离有机层并用乙酸乙酯(2×11L)萃取水层。用水(3×10L)洗涤合并的有机层并随后用NaHCO3溶液(30gNaHCO3溶于12L水中)洗涤合并的有机层。再用饱和NaCl溶液(3372g NaCl溶于水(12L)中)进一步洗涤所述有机层并通过无水Na2SO4(950g至1000g)干燥所述有机层,过滤一次。
将滤液转移至配有机械搅拌器、冷凝器和热电偶的72-L反应器中。将活性碳(110g至113g)加至反应器中的曲前列素溶液中。将悬浮液加热至回流(温度为68℃至70℃)至少一小时。使用乙酸乙酯在烧结玻璃漏斗中制备用于过滤的545(300g至600g)。通过545垫过滤热悬浮液。用乙酸乙酯洗涤545直至在洗涤物的TLC上看不到化合物。
在50℃至55℃条件下,通过真空蒸发将滤液(浅黄色)体积减小至35L至40L直接用于下一步骤。
实施例3曲前列素转化为曲前列素二乙醇胺盐(1:1)
名称 | MW | 数量 | Mol | Eq |
曲前列素 | 390.52 | 1464g* | 3.75 | 1.0 |
二乙醇胺 | 105.14 | 435g | 4.14 | 1.1 |
乙醇 | -- | 5.1L | -- | -- |
乙酸乙酯 | -- | 35L** | -- | -- |
曲前列素二乙醇胺盐(晶种) | -- | 12g | -- | -- |
*注:这个重量是基于来自苯并茚三元醇的100%产率。它不是分离产率。曲前列素保留在前一步骤的乙酸乙酯溶液中并就这样用于这个步骤。
**注:乙酸乙酯的总体积应为35L至36L(它应当是所用的乙醇的体积的7倍)。大约35L乙酸乙酯从前一步骤中保留下来并且添加的1.0L乙酸乙酯被用于冲洗烧瓶。
将曲前列素的乙酸乙酯溶液(从前一步骤得到35L至40L)、无水乙醇(5.1L)和二乙醇胺(435g)装入配有加热/冷却系统、机械搅拌器、冷凝器和热电偶的50-L圆柱形反应器。搅拌时,将反应混合物加热至60℃至75℃达0.5小时至1.0小时以获得透明溶液。将该透明溶液冷却至55±5℃。在该温度下,将曲前列素二乙醇胺盐的多晶型物B的晶种(约12g)加至透明溶液。在该温度下搅拌多晶型物B的悬浮液一小时。将该悬浮液冷却至20±2℃过夜(经过16小时至24小时)。使用配有滤布的Aurora过滤器通过过滤收集曲前列素二乙醇胺盐并用乙酸乙酯(2×8L)洗涤固体。将曲前列素二乙醇胺盐转移至HDPE/玻璃容器中罩内风干,随后在50±5℃、高真空条件下在真空烘箱中干燥。
在这个阶段,如果曲前列素二乙醇胺盐的熔点高于104℃,认为它是多晶型物B。不需要重结晶。如果曲前列素二乙醇胺盐的熔点低于104℃,在EtOH-EtOAc中重结晶曲前列素二乙醇胺盐以提高熔点。
曲前列素二乙醇胺盐(1:1)的数据
*注:在这批中,在碳处理之前,大约1200mL曲前列素的乙酸乙酯溶液被取出用于R&D碳处理实验。
**注:这批被重结晶,由于这个原因产率较低。
实施例4.曲前列素二乙醇胺盐(1:1)的庚烷浆料
名称 | 批号 | 数量 | 比例 |
曲前列素二乙醇胺盐 | 1 | 3168g | 1 |
庚烷 | -- | 37.5L | 12 |
名称 | 批号 | 数量 | 比例 |
曲前列素二乙醇胺盐 | 2 | 3071 g | 1 |
庚烷 | -- | 36.0 L | 12 |
将曲前列素二乙醇胺盐在庚烷中的浆料(35 L至40 L)装入配有加热/冷却系统、机械搅拌器、冷凝器和热电偶的50-L圆柱形反应器。将该悬浮液加热至70℃至80℃达16小时至24小时。将该悬浮液冷却至20 ± 2℃经过1小时至2小时。使用Aurora过滤器通过过滤收集盐。用庚烷(15 L至30 L)洗涤滤饼并在Aurora过滤器中干燥材料1小时。将该盐转移至托盘用于罩内风干过夜直至得到恒重的曲前列素二乙醇胺盐。在50℃至55℃、高真空条件下在烘箱中干燥该材料2小时至4小时。
曲前列素二乙醇胺盐(1:1)的分析数据
实施例5.曲前列素二乙醇胺盐(1:1)转化为曲前列素
将曲前列素二乙醇胺盐(4g)和水(40mL)装入配有机械搅拌器的250-mL圆底烧瓶。搅拌混合物以获得透明溶液。将乙酸乙酯(100mL)加至透明溶液。在搅拌时,缓慢加入3M HCl(3.2mL)直至达到pH约为1。搅拌混合物10分钟并分离有机层。用乙酸乙酯(2×100mL)萃取水层。用水(2×100mL)、盐水(1×50mL)洗涤合并的有机层并通过无水Na2SO4干燥所述有机层。曲前列素的乙酸乙酯溶液被过滤并在50℃、真空下浓缩滤液以得到灰白色固体。曲前列素粗产物从50%乙醇的水溶液(70mL)中重结晶。通过过滤在Buchner漏斗中收集纯的曲前列素并且用冷的20%乙醇水溶液洗涤滤饼。将曲前列素的滤饼风干过夜并在50℃、高真空条件下在真空烘箱中进一步干燥以得到2.9g曲前列素(产率91.4%,纯度(HPLC,AUC)99.8%)。
由曲前列素二乙醇胺盐(1:1)生成曲前列素的曲前列素分析数据
实施例6.在先方法与根据本发明的方法的实施例的比较
根据本发明生产的曲前列素的性质优良。省去了通过柱层析纯化苯并茚腈。从中间步骤(即三元醇的烷基化和苯并茚腈的水解)保留下来的杂质在碳处理和盐形成步骤过程中除去。该方法额外的优势是:(a)曲前列素盐粗产物可作为原料在室温下保存并可通过用稀盐酸简单地酸化转化为曲前列素,以及(b)曲前列素盐可从曲前列素的溶液合成而无需分离。该方法提供更优质的最终产物并且节约大量溶剂和中间体纯化方面的人力。
虽然前述内容涉及具体的优选实施方式,但人们理解本发明并不限于此。本领域技术人员将会想到可对公开的实施方式作出各种修改,并且这些修改应属于本发明的范围。
在本说明书中列举的所有公开出版物、专利申请和专利的全部内容通过引用并入本文。
Claims (31)
1.一种含有通式I的化合物或其药学上可接受的盐的产品
所述产品通过下列方法制备:
(a)用烷基化剂烷基化结构II的化合物以生成通式III的化合物,
其中
w=1、2或3;
Y1是反式-CH=CH-、顺式-CH=CH-、-CH2(CH2)m-或-C≡C-;m为1、2或3;
R7是
(1)-CpH2p-CH3,其中p是选自1至5的整数,所述整数的范围包括1和5,
(2)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基任选地取代的苯氧基,条件是不超过两个取代基是非烷基,条件是仅当R3和R4是氢或甲基,R3和R4相同或不同时,R7是苯氧基或取代苯氧基,
(3)由一个、两个或三个氯、氟、三氟甲基、(C1-C3)烷基或(C1-C3)烷氧基在芳香环上任选地取代的苯基、苄基、苯基乙基或苯基丙基,条件是不超过两个取代基是非烷基,
(4)反式-CH=CH-CH2-CH3,
(5)-(CH2)2-CH(OH)-CH3,或
(6)-(CH2)3-CH=C(CH3)2;
合并在一起的-C(L1)-R7为
(1)由1个至3个(C1-C5)烷基任选地取代的(C4-C7)环烷基;
(2)2-(2-呋喃基)乙基,
(3)2-(3-噻嗯基)乙氧基,或
(4)3-噻嗯氧基甲基;
M1是α-OH:β-R5或α-R5:β-OH或α-OR1:β-R5或α-R5:β-OR2,其中,R5是氢或甲基,R2是醇保护基团,并且
L1是α-R3:β-R4、α-R4:β-R3或α-R3:β-R4和α-R4:β-R3的混合物,其中,R3和R4是氢、甲基或氟,R3和R4相同或不同,条件是仅当R3和R4中的一个是氢或氟时,R3和R4中另一个是氟。
(b)用碱水解(a)步骤的通式III的产物,
(c)使(b)步骤的产物与碱B接触以形成通式Is的盐,
(d)可选地,使(c)步骤所述盐与酸反应以形成通式I的化合物。
2.如权利要求1所述的产品,其中,通式I的化合物的纯度为至少99.5%。
3.如权利要求1所述的产品,其中,所述烷基化剂为Cl(CH2)wCN、Br(CH2)wCN或I(CH2)wCN。
4.如权利要求1所述的产品,其中,(b)步骤中所述碱是KOH或NaOH。
5.如权利要求1所述的产品,其中,(c)步骤中所述碱B选自:铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇、镁、L-赖氨酸、L-精氨酸、三乙醇胺和二乙醇胺。
6.如权利要求1所述的产品,其中,(d)步骤中所述酸是HCl或H2SO4。
7.如权利要求1所述的产品,其中,Y1是-CH2CH2-;M1是α-OH:β-H或α-H:β-OH;合并在一起的-C(L1)-R7为-(CH2)4CH3;并且w为1。
9.如权利要求1所述的产品,其中所述的方法不包括纯化步骤(a)产生的通式III的化合物的步骤。
10.如权利要求1所述的产品,其中,(b)步骤中所述碱为KOH或NaOH;并且其中(c)步骤中所述碱B选自:铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇、镁、L-赖氨酸、L-精氨酸、三乙醇胺和二乙醇胺。
11.如权利要求1所述的产品,其中,执行(d)步骤。
12.如权利要求11所述的产品,其中所述产品包括来自(d)步骤的产品形成的药学上可接受的盐。
14.如权利要求13所述的产品,其中,(d)步骤生产的产品的纯度为至少99.5%。
15.如权利要求13所述的产品,其中,所述烷基化剂为ClCH2CN。
16.如权利要求13所述的产品,其中,(b)步骤中所述碱为KOH。
17.如权利要求13所述的产品,其中,(c)步骤中所述碱B选自:铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇、镁、L-赖氨酸、L-精氨酸、三乙醇胺和二乙醇胺。
18.如权利要求13所述的产品,其中,所述碱B是二乙醇胺。
19.如权利要求13所述的方法,其中,(d)步骤中所述酸是HCl。
20.如权利要求13所述的产品,其中所述的方法不包括纯化步骤(a)产生的通式VI的化合物的步骤。
21.如权利要求20所述的产品,其中,(c)步骤中所述碱B选自:铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇、镁、L-赖氨酸、L-精氨酸、三乙醇胺和二乙醇胺。
22.如权利要求21所述的产品,其中,所述碱B是二乙醇胺。
23.如权利要求13所述的产品,其中,(b)步骤中所述碱为KOH或NaOH;并且其中(c)步骤中所述碱B选自:铵、N-甲基葡糖胺、普鲁卡因、氨基丁三醇、镁、L-赖氨酸、L-精氨酸、三乙醇胺和二乙醇胺。
24.一种制备含有曲前列素或其药学上可接受的盐的药物产品的方法,所述方法包括将曲前列素溶液与碱接触形成曲前列素药学上可接受的盐,其中所述溶液中的曲前列素之前未曾被分离过。
25.如权利要求24所述的方法,还包括分离所述曲前列素药学上可接受的盐并且加入药学上可接受的载体以形成药学产品。
26.如权利要求25所述的方法,其中所述的碱是无机碱。
27.如权利要求26所述的方法,其中通过所述无机碱形成的所述盐是一种曲前列素的钠盐。
28.如权利要求26所述的方法,其中通过所述无机碱形成的所述盐是一种曲前列素的钾盐。
30.如权利要求29所述的方法,其中所述形成的盐是是曲前列素的二乙醇胺盐。
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