CN1190956A - 制备非晶性[R－(R*,R*)]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基羰基]－1H－吡咯－1－庚酸钙盐(2∶1)的新方法 - Google Patents
制备非晶性[R－(R*,R*)]－2－(4－氟苯基)－β,δ－二羟基－5－(1－甲基乙基)－3－苯基－4－[(苯氨基羰基]－1H－吡咯－1－庚酸钙盐(2∶1)的新方法 Download PDFInfo
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Abstract
本发明提供了制备非晶性阿特沃斯汀的新方法,包括将Ⅰ型结晶阿特沃斯汀溶于非羟基溶剂中,随后除去溶剂,得到非晶性阿特沃斯汀。
Description
本发明涉及可用作药物的非晶性阿特沃斯汀(atorvastatin)的新制备方法[其化学名称为[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐]。阿特沃斯汀适于用作3-羟基-3-甲基戊二酰辅酶A还原酶(HMG-CoA还原酶)的抑制剂，因而适用作血清脂质减少和血胆固醇过少药。
美国专利4,681,893(此文献在此并入本文用作参考)公开了一些反式-6-[2-(3-或4-甲酰氨基取代的-吡咯-1-基)烷基]-4-羟基-吡喃-2-酮类化合物，包括反式(±)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-甲酰胺化合物。
美国专利5,27 3,955(此文献在此并入本文用作参考)公开了反式-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[(2-四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-甲酰胺的开环酸的R构型对映体，即[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸。
美国专利5,003,080；5,097,045；5,103,024；5,124,482；5,149,837；5,155,251；5,216,174；5,245,047；5,248,793；5,280,126；5,397,792；和5,342,952(所有这些文献在此均并入本文用作参考)公开了制备阿特沃斯汀的各种方法和关键中间体。
阿特沃斯汀以其钙盐形式制备，即[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸钙盐(2∶1)。钙盐是比较理想的，这是由于它们能使阿特沃斯汀很方便地配制成例如片剂，胶囊，锭剂，粉剂等口服用制剂。
本申请人同时递交的题为“结晶[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸钙盐(2∶1)”和“III型结晶[R*，(R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-(苯氨基)羰基]-1H-吡咯-1-庚酸钙盐(2∶1)”的申请[代理人案卷号PD-5250-01-FJT，申请号＿＿＿，和PD-5333-01-FJT，申请号＿＿＿，]中公开了被称为I型，II型，III型和IV型的不同新晶型阿特沃斯汀。
上述美国专利中公开的阿特沃斯汀为非晶性固体。我们发现，在结晶阿特沃斯汀出现之后，用上述公开方法生产非晶性阿特沃斯汀不能重复再现。
文献(Konno T.，Chem.Pharm.Bull.，1990；38：2003-2007)中报道了与结晶形式相比，许多药物中的非晶性形式显示出溶解特性，并在某些情况显示出不同的生物利用模式。对于某些治疗指症，某种生物利用模式可能比另一种更有利。因此，最好是存在有将结晶性药物转化成非晶性形式的方法。
本发明的目的是提供一种适合大规模生产用的转化I型结晶阿特沃斯汀成非晶性阿特沃斯汀的方法。
我们惊奇且出人意料地发现，在非羟基溶剂中溶解阿特沃斯汀，随后除去溶剂，能够得到非晶性阿特沃斯汀。
因此，本发明提供了制备非晶性阿特沃斯汀及其水合物的新方法，包括：
(a)在非羟基溶剂中溶解I型结晶阿特沃斯汀；和
(b)除去溶剂，得到非晶性阿特沃斯汀。
在本发明的优选实施方案中，非羟基溶剂选自：四氢呋喃，和四氢呋喃与甲苯的混合物。
在本发明的另一优选实施方案中，溶剂用真空干燥器除去。
本发明用下列非限制性实施例并参照附图1，2和3进一步说明。有关附图的详细内容简述如下：
图1
I型阿特沃斯汀粉末的2分钟衍射图(Y-轴＝0至最大强度3767.50每秒计数(Cps))。图2
非晶性阿特沃斯汀的衍射图(Y-轴＝0至1455.00cps最大强度)。图3
I型阿特沃斯汀的具有星号标记的旋转拘带的固态13C核磁共振谱。
I型结晶阿特沃斯汀可以由其X-射线粉末衍射图和/或其固态核磁共振光谱(NMR)表征。
X-射线粉末衍射非晶性和I型阿特沃斯汀
非晶性和I型阿特沃斯汀用它们的X-射线粉末衍射图表征。例如，非晶性和I型阿特沃斯汀的X-射线衍射图用Siemens D-500衍射仪(CuKa辐射)测量。仪器
具有IBM兼容界面，软件＝DIFFRAC AT(SOCABIM 1986，1992)的Siemens D-500 Diffractometer-Kristalloflex。CuKa辐射(20mA，40kV，λ＝1.5406A，狭缝I和II/1°)，经PsiPeltier CooledSilicon[Si(Li)]检测器用电子学方法过滤。(狭缝：III(1°)和IV(0.15°))。方法
每天运行硅标准以检测X-射线管的的列线。
连续θ/2θ偶联扫描：以2θ扫描4.00°-40.00°，扫描速率6°/分钟：0.4秒/0.04°级(对于非晶性阿特沃斯汀，扫描速率3°/分钟：0.8秒/0.04级)。
将样品从小瓶内敲打出并压制到铝支架上的零点本底(zero-background)石英上。样宽13-15mm(对于非晶性阿特沃斯汀，样宽-16cm)。样品在室温下保存和测试。研磨
利用研磨将本发明所公开的I型阿特沃斯汀的衍射图的强度偏差降到最低程度。然而，如果研磨明显改变了衍射图或增加了样品的非晶性含量，则使用未研磨样品的衍射图。
表1列出了I型结晶阿特沃斯汀的未研磨样品的2θ，d-间距和相对强度大于20％的所有谱线的相对强度。表1还列出了在研磨2分钟后所测衍射图中相同谱线的相对强度。研磨2分钟样品的强度更能反映出无择优取向的衍射图。应当注意的是此表中列出的是由计算机产生的未四舍五入的数值。
表1：强度大于20％的I型阿特沃斯汀的所有衍射谱线的强度和峰位置2θ d 相对强度(＞20％) 相对强度(＞20％)*
未研磨 研磨2分钟9.150 9.6565 37.42 42.609.470 9.3311 46.81 41.9410.266 8.6098 75.61 55.6710.560 8.3705 24.03 29.3311.853 7.4601 55.16 41.7412.195 7.2518 20.03 24.6217.075 5.1887 25.95 60.1219.485 4.5520 89.93 73.5921.626 4.1059 100.00 100.0021.960 4.0442 58.64 49.4422.748 3.9059 36.95 45.8523.335 3.8088 31.76 44.7223.734 3.7457 87.55 63.0424.438 3.6394 23.14 21.1028.915 3.0853 21.59 23.4229.234 3.0524 20.45 23.36*第二相对强度栏给出了在研磨2分钟后原始衍射图中衍射谱线的相对强度。
固态核磁共振(NMR)方法
所有固体13C NMR测量利用Bruker AX-250，250Mhz NMR光谱仪完成。在大约5kHz下采用大功率质子去耦和具有魔角自旋(MAS)的交叉极化(CP)，得到高分辨光谱。按Frye和Maciel(Frye J.S和Maciel G.E.，J.Mag.Res.，1982；48：125)所述，通过检测侧带，利用KBr的Br信号调节魔角。对于每一试验，使用大约300至450mg(装在罐性旋转管(cani ster-design rotor)内)。化学位移参照外标四(三甲基甲硅烷基)硅烷(甲基信号在3.50ppm处)(Muntean J.V.和L.M.，J.Mag.Res.，1988；76：54)。
表2示出了I型结晶阿特沃斯汀的固态光谱。
表2.I型阿特沃斯汀的碳原子分布和化学位移分布(7Khz) 化学位移C12或C25 182.8C12或C25 178.4C16 166.7(宽)
和159.3芳族碳C2-C5，C13-C18，C19-C24，C27-C32 137.0
134.9
131.1
129.5
127.6
123.5
120.9
118.2
113.8C8 ，C10 73.1
70.5
68.1
64.9亚甲基碳C6，C7， C9，C11 47.4
41.9
40.2C33 26.4
25.2C34 21.3本发明的非晶性阿特沃斯汀不仅可以无水形式存在，而且还能以水合形式存在。一般地，与无水形式一样，其水合形式也包括在本发明范围之内。
如前所述，非晶性阿特沃斯汀适于用作HMG-CoA还原酶抑制剂，因而适用作血清脂质减少和血胆固醇过少药。
本发明提供了工业制备非晶性阿特沃斯汀的方法。
例如，将I型结晶阿特沃斯汀溶于非羟基溶剂如四氢呋喃，四氢呋喃和甲苯的混合物等中，其浓度为约25％至约40％。优选将I型结晶阿特沃斯汀溶于含有高至约50％甲苯作为助溶剂的四氢呋喃中，其浓度为约25％至约40％。采用如干燥技术，象真空干燥，喷雾干燥等技术除去溶剂。优选干燥步骤采用搅拌型盘式烘干器如Comber Turbodry Vertical盘式烘干器等进行。干燥在约5mmHg至约25mmHg真空下先在约20℃至约40℃，随后在约70℃至约90℃下进行约3至约5天。优选干燥在约5mmHg至约25mmHg下先在约35℃，随后于约85℃进行约5天。将初始溶液干燥成脆泡沫，通过机械搅拌打碎，得到非晶性阿特沃斯汀。
下列非限制性实施例进一步说明了制备本发明化合物的优选方法。
实施例1[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐](I型阿特沃斯汀)
将(2R-反式)-5-(4-氟苯基)-2-(1-甲基乙基)-N，4-二苯基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1H-吡咯-3-甲酰胺(阿特沃斯汀内酯)(美国专利5,27 3,995)(75kg)，甲基叔丁基醚(MTBE)(308kg)，甲醇(190L)的混合物与氢氧化钠水溶液(5.72kg/950L)在48-50℃下反应40至60分钟，形成开环钠盐。冷却至25-35℃后，弃去有机层，将水层用MTBE(230kg)再提取。弃去有机层，并将钠盐的MTBE饱和水溶液加热至47-52℃。在至少30分钟内，将乙酸钙半水合物(11.94kg)的水(410L)溶液加入到上述溶液内。在加入乙酸钙溶液后不久，混合物用I型结晶阿特沃斯汀d的浆状物(1.1kg/11L水和5L甲醇)引晶。然后将混合物加热至51-57℃反应至少10分钟，随后冷却至15-40℃。过滤混合物，先用水(300L)和甲醇(150L)洗涤，随后用水(450L)洗涤。固体在60-70℃下真空干燥3至4天，得到I型结晶阿特沃斯汀(72.2kg)。
实施例2[R-(R*，R*)]-2-(4-氟苯基)-β，δ-二羟基-5-(1-甲基乙基)-3-苯基-4-[(苯氨基)羰基]-1H-吡咯-1-庚酸半钙盐](非晶性阿特沃斯汀)
氮气氛及搅拌下，将I型结晶阿特沃斯汀(实施例1)(30kg)在室温下溶于四氢呋喃(75L)。溶液形成之后缓慢加入49.4L甲苯。随后将溶液通过0.45目Pall滤器转至200L Comber Turbody Vertical Pan Dryer内。传送系统用另外的四氢呋喃(4.5L)冲洗到烘干器内。施用完全真空，并在于35℃下伴随温和搅拌浓缩溶液。在浓缩步骤即将结束时，将搅拌器升起。产物变成易脆玻璃状泡沫。逐渐放下搅拌器，将脆泡沫打碎成自由流动性粉末。搅动粉末并在真空(6至8mmHg)下将温度升至85℃以减少残留溶剂水平。干燥4天后，达到所希望的残留溶剂水平：0.01％四氢呋喃和0.29％甲苯。从烘干器中卸出自由流动的白色粉末(27.2kg)。X-射线衍射证明产物为非晶性。
Claims (8)
1.制备非晶性阿特沃斯汀及其水合物的方法，该方法包括：
(a)将I型结晶阿特沃斯汀溶于非羟基溶剂中，和
(b)除去溶剂，得到非晶性阿特沃斯汀。
2.根据权利要求1的方法，其中步骤(a)中所用的非羟基溶剂选自：四氢呋喃，和四氢呋喃与甲苯的混合物。
3.根据权利要求2的方法，其中所述溶剂为四氢呋喃与甲苯的混合物。
4.根据权利要求1的方法，其中步骤(b)中的溶剂通过真空干燥或喷雾干燥除去。
5.根据权利要求4的方法，其中步骤(b)中的溶剂通过真空干燥除去。
6.根据权利要求5的方法，其中真空干燥是在约5mmHg至约25mmHg真
空下先在约20℃至约40℃，随后于约70℃至约90℃下进行。
7.根据权利要求6的方法，其中真空干燥是在约5mmHg至约25mmHg真
空下先在约35℃，随后于约85℃进行。
8.根据权利要求5的方法，其中干燥后所得的物质为机械搅动能打碎的脆泡沫。
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| US145395P | 1995-07-17 | 1995-07-17 | |
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| NO (1) | NO309322B1 (zh) |
| NZ (1) | NZ313008A (zh) |
| PE (1) | PE1698A1 (zh) |
| PL (1) | PL191017B1 (zh) |
| PT (1) | PT839132E (zh) |
| RO (1) | RO120069B1 (zh) |
| SI (1) | SI0839132T1 (zh) |
| SK (1) | SK283204B6 (zh) |
| UA (1) | UA50743C2 (zh) |
| UY (1) | UY24286A1 (zh) |
| WO (1) | WO1997003960A1 (zh) |
| ZA (1) | ZA966043B (zh) |
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| FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
| IN191236B (zh) * | 1999-05-25 | 2003-10-11 | Ranbaxy Lab Ltd | |
| US6646133B1 (en) | 2000-10-17 | 2003-11-11 | Egis Gyogyszergyar Rt. | Process for the preparation of amorphous atorvastatin calcium |
| HU226640B1 (en) * | 1999-10-18 | 2009-05-28 | Egis Gyogyszergyar Nyilvanosan | Process for producing amorphous atorvastatin calcium salt |
| US7411075B1 (en) | 2000-11-16 | 2008-08-12 | Teva Pharmaceutical Industries Ltd. | Polymorphic form of atorvastatin calcium |
| SI20425A (sl) * | 1999-12-10 | 2001-06-30 | LEK tovarna farmacevtskih in kemi�nih izdelkov d.d. | Priprava amorfnega atorvastatina |
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| US7501450B2 (en) * | 2000-11-30 | 2009-03-10 | Teva Pharaceutical Industries Ltd. | Crystal forms of atorvastatin hemi-calcium and processes for their preparation as well as novel processes for preparing other forms |
| IL156055A0 (en) | 2000-11-30 | 2003-12-23 | Teva Pharma | Novel crystal forms of atorvastatin hemi calcium and processes for their preparation as well as novel processes for preparing other forms |
| MXPA03005879A (es) | 2000-12-27 | 2003-09-10 | Ciba Sc Holding Ag | Formas cristalinas de atorvastatina. |
| WO2002057228A1 (en) * | 2001-01-17 | 2002-07-25 | Biocon India Limited | Atorvastatin calcium |
| WO2002057229A1 (en) | 2001-01-19 | 2002-07-25 | Biocon India Limited | FORM V CRYSTALLINE [R-(R*,R*)]-2-(4-FLUOROPHENYL)-ß,$G(D)-DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1- HEPTANOIC ACID HEMI CALCIUM SALT. (ATORVASTATIN) |
| SI20814A (sl) * | 2001-01-23 | 2002-08-31 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Priprava amorfnega atorvastatina |
| SI20848A (sl) * | 2001-03-14 | 2002-10-31 | Lek, Tovarna Farmacevtskih In Kemijskih Izdelkov, D.D. | Farmacevtska formulacija, ki vsebuje atorvastatin kalcij |
| IN190564B (zh) * | 2001-04-11 | 2003-08-09 | Cadila Heathcare Ltd | |
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| US7361772B2 (en) | 2001-08-16 | 2008-04-22 | Biocon Limited | Process for the production of atorvastatin calcium |
| CA2456095C (en) | 2001-08-31 | 2010-05-11 | Morepen Laboratories Ltd. | An improved process for the preparation of amorphous atorvastatin calcium salt (2:1) |
| UA77990C2 (en) * | 2001-12-12 | 2007-02-15 | Crystalline calcium salt of (2:1) [r-(r*,r*)]-2-(4-fluorophenyl)-?,?-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrroleheptanic acid | |
| CZ296967B6 (cs) | 2002-02-01 | 2006-08-16 | Zentiva, A.S. | Zpusob výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) |
| CA2479005C (en) | 2002-03-18 | 2012-05-22 | Biocon Limited | Amorphous atorvastatin calcium or pravastatin sodium hmg-coa reductase inhibitors of desired particle size |
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| ATE425132T1 (de) | 2003-04-22 | 2009-03-15 | Biocon Ltd | Neues verfahren zur stereoselektiven reduktion von beta-ketoestern |
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| US20050271717A1 (en) * | 2003-06-12 | 2005-12-08 | Alfred Berchielli | Pharmaceutical compositions of atorvastatin |
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| WO2005026107A1 (en) | 2003-09-18 | 2005-03-24 | Biocon Limited | Novel process for the preparation of tert-butyl 6-cyano-5-hydroxy-3-oxohexanoate |
| CA2456430A1 (en) * | 2004-01-28 | 2005-07-28 | Brantford Chemicals Inc. | Improved process for the preparation of amorphous atorvastatin calcium |
| CZ298382B6 (cs) * | 2004-03-10 | 2007-09-12 | Zentiva, A. S. | Zpusob prípravy amorfní formy hemivápenaté soli atorvastatinu a její stabilizace |
| DK1727795T3 (da) * | 2004-03-17 | 2012-04-16 | Ranbaxy Lab Ltd | Fremgangsmåde til fremstillingen af atorvastatin-calcium i amorf form |
| EP3581564A1 (en) | 2004-05-05 | 2019-12-18 | Pfizer Products Inc. | Diethylamine salt forms of [r-(r*,r*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid |
| SI1771455T1 (sl) * | 2004-07-16 | 2016-09-30 | Lek Pharmaceuticals D.D. | Oksidacijski razgradni produkti atorvastatin kalcija |
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| EP1793815A4 (en) * | 2004-09-30 | 2010-12-29 | Reddys Lab Ltd Dr | AMORPHES ATORVASTATINCALCIUM |
| US20060106230A1 (en) * | 2004-10-18 | 2006-05-18 | Michael Pinchasov | Processes for preparing amorphous atorvastatin hemi-calcium |
| WO2006046109A1 (en) * | 2004-10-28 | 2006-05-04 | Warner-Lambert Company Llc | Process for forming amorphous atorvastatin |
| AU2005305460B2 (en) * | 2004-11-22 | 2011-04-21 | Dexcel Pharma Technologies Ltd. | Stable atorvastatin formulations |
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| US20080108664A1 (en) * | 2005-12-23 | 2008-05-08 | Liu Belle B | Solid-state form of AMG 706 and pharmaceutical compositions thereof |
| EP1810667A1 (en) | 2006-01-20 | 2007-07-25 | KRKA, tovarna zdravil, d.d., Novo mesto | Pharmaceutical composition comprising amorphous atorvastatin |
| MX2007013612A (es) * | 2006-03-01 | 2007-12-10 | Teva Pharma | Proceso para preparar una forma cristalina de hemi-calcio de atorvastatina. |
| US20100113802A1 (en) * | 2006-11-02 | 2010-05-06 | Cadila Pharmaceuticals Limited | Process for preparing amorphous atorvastatin hemi calcium salt and its itermediate |
| US7834195B2 (en) | 2007-01-24 | 2010-11-16 | Apotex Pharmachem Inc. | Atorvastatin calcium propylene glycol solvates |
| US20100260851A1 (en) * | 2007-07-11 | 2010-10-14 | Actavis Group Ptc Ehf | Novel Polymorph of Atorvastatin Calcium and Use Thereof for the Preparation of Amorphous Atorvastatin Calcium |
| US20090124817A1 (en) * | 2007-11-09 | 2009-05-14 | The Industry & Academic Cooperation In Chungnam National University | Process for Preparing Amorphous Atorvastatin Calcium Nanoparticles |
| EP2075246A1 (en) | 2007-12-27 | 2009-07-01 | M. J. Institute of Research | A process for preparation of amorphous form of atorvastatin hemi-calcium salt |
| WO2010066846A2 (en) * | 2008-12-11 | 2010-06-17 | Dsm Ip Assets B.V. | Method for the isolation of atorvastatin |
| WO2010069593A1 (en) | 2008-12-19 | 2010-06-24 | Krka, D. D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| EP2327682A1 (en) | 2009-10-29 | 2011-06-01 | KRKA, D.D., Novo Mesto | Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates |
| CZ201039A3 (cs) | 2010-01-19 | 2011-07-27 | Zentiva, K. S | Zpusob prumyslové výroby amorfní formy hemivápenaté soli (3R,5R) 7-[3-fenyl-4-fenylkarbamoyl-2-(4-fluorfenyl)-5-isopropylpyrrol-1-yl]-3,5-dihydroxyheptanové kyseliny (atorvastatinu) s vysokým specifickým povrchem a jeho použití v lékové forme |
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| US4681893A (en) | 1986-05-30 | 1987-07-21 | Warner-Lambert Company | Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one inhibitors of cholesterol synthesis |
| US5003080A (en) | 1988-02-22 | 1991-03-26 | Warner-Lambert Company | Process for trans-6-(2-(substituted-pyrrol-1-yl)alkyl)pryan-2-one inhibitors of cholesterol synthesis |
| US5097045A (en) | 1989-02-01 | 1992-03-17 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US5149837A (en) | 1988-02-22 | 1992-09-22 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US5216174A (en) | 1988-02-22 | 1993-06-01 | Warner-Lambert Co. | Process for trans-6-[12-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US5245047A (en) | 1988-02-22 | 1993-09-14 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| US5124482A (en) | 1988-02-22 | 1992-06-23 | Warner-Lambert Company | Process for trans-6-(2-substituted-pyrrol-1-yl)alkyl)pyran-2-one inhibitors of cholesterol synthesis |
| FI94339C (fi) | 1989-07-21 | 1995-08-25 | Warner Lambert Co | Menetelmä farmaseuttisesti käyttökelpoisen /R-(R*,R*)/-2-(4-fluorifenyyli)- , -dihydroksi-5-(1-metyylietyyli)-3-fenyyli-4-/(fenyyliamino)karbonyyli/-1H-pyrroli-1-heptaanihapon ja sen farmaseuttisesti hyväksyttävien suolojen valmistamiseksi |
| US5248793A (en) | 1990-10-17 | 1993-09-28 | Warner-Lambert Company | Process for the synthesis of (4R-cis)-1,1-dimethylethyl 6-iodomethyl or 6-(phenyl-substituted)sulfonyloxymethyl-2,2-dimethyl-1,3-dioxane-4-acetate |
| US5103024A (en) | 1990-10-17 | 1992-04-07 | Warner-Lambert Company | Process for the synthesis of (4r-cis)-1,1-dimethylethyl 6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate |
| US5155251A (en) | 1991-10-11 | 1992-10-13 | Warner-Lambert Company | Process for the synthesis of (5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate |
| US5298627A (en) | 1993-03-03 | 1994-03-29 | Warner-Lambert Company | Process for trans-6-[2-(substituted-pyrrol-1-yl)alkyl]pyran-2-one inhibitors of cholesterol synthesis |
| WO1997003959A1 (en) | 1995-07-17 | 1997-02-06 | Warner-Lambert Company | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole-1-heptanoic acid hemi calcium salt (atorvastatin) |
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1996
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