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CN1164591C - 盐酸齐哌特罗单水合物 - Google Patents

盐酸齐哌特罗单水合物 Download PDF

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CN1164591C
CN1164591C CNB021030898A CN02103089A CN1164591C CN 1164591 C CN1164591 C CN 1164591C CN B021030898 A CNB021030898 A CN B021030898A CN 02103089 A CN02103089 A CN 02103089A CN 1164591 C CN1164591 C CN 1164591C
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hydrochloride
zipterol
crystals
water
trihydrate
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CN1396165A (zh
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Y·塞夫里蒙
J·－V·戈达
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Intervet International BV
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HESTER KOUSSEL WITT SA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/137—Heterocyclic compounds containing two hetero atoms, of which at least one is nitrogen
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S426/00—Food or edible material: processes, compositions, and products
    • Y10S426/807—Poultry or ruminant feed

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Abstract

本发明涉及盐酸齐哌特罗单水合物，该化合物可以用于制备结晶的盐酸齐哌特罗。盐酸齐哌特罗的特征是它含有少于5%的粒度小于15微米的结晶，其余结晶的粒度小于250微米，盐酸齐哌特罗可用作饲料添加剂，以提高饲养动物的体重。

Description

盐酸齐哌特罗单水合物
相关申请
本申请为1996年6月12日提交的发明名称为“特殊晶型的盐酸齐哌特罗，其制备方法吸所用的中间产物”、申请号为96110424.4的申请的分案申请，原申请要求其在法国专利局的申请日1995年6月13日作为优先权日。
技术领域
本发明涉及特殊晶型的盐酸齐哌特罗(zilpaterol hydrochloride)、其制备方法及所用的中间产物。
背景技术
齐哌特罗在美国专利4585770中被介绍，其立体化学结构如下：
盐酸齐哌特罗产品的生物性质是已知的，它可用于喂养动物，如法国专利2608046所述。
盐酸齐哌特罗能够增加饲养动物(如牛和猪)的体重并改善肉的质量。
可将盐酸齐哌特罗加入到动物饲料中。
可先制备预混物，然后将其加入到饲料中。
可利用的预混物的制备方法包括在玉米棒上吸附盐酸齐哌特罗，例如可使用欧洲专利申请197188描述的方法。
活性成分的粒度必须比载体的粒度小。
为了吸附在粒度为300微米至800微米之间的玉米棒上，要求活性成分的所有颗粒的粒度小于300微米且大多数粒度在50微米至200微米之间。如果还要求避免粉尘问题，活性成分的颗粒也不能太细。
当活性成分的颗粒太细并以粉尘的形式出现时，对使用者来说存在卫生问题，例如当活性成分被吸入肺泡时，使用者可能被刺激，甚至中毒。另外，对环境存在严重问题。
因此，需要按照上述规范得到适当颗粒形式的盐酸齐哌特罗。
发明内容
本发明的目的是结晶形式的无水盐酸齐哌特罗，其特征是它含有少于5％的粒度小于15微米的结晶，其余结晶粒度小于250微米。
本发明的另一目的是制备方法，其特征是
1.在温度高于50℃，制备在水中或在水/乙醇混合物中的盐酸齐哌特罗过饱和溶液；
2.将这样制得的溶液冷却，得到单水合物结晶；
3.将温度降至低于20℃得到三水合物结晶；
4.进行干燥，于是得到无水形式的微晶产品。
本发明的另一目的是该制备方法的变化形式，其特征是无水盐酸齐哌特罗在低于30℃时溶于水，得到无水盐酸齐哌特罗的饱和溶液，它以三水合物的形式自发重结晶。
此外，本发明包括上述操作方法的变化形式，其特征是将盐酸齐哌特罗溶于最小体积的热水(60℃至100℃)，将此溶液倒入盐酸齐哌特罗在水和乙醇混合物中的饱和溶液中，在低于20℃搅拌并先加入三水合物晶种，于是得到三水合物，将其干燥以得到所需的产品。
后文中的实验部分表明本发明方法的优选条件。
盐酸齐哌特罗的一水合物是新产品并且它本身就是本发明的一个主题。
盐酸齐哌特罗的三水合物也是新产品并因此其本身作为本发明的主题。
具体实施方式
以下实施例用于说明本发明，但不是对本发明的限制。
制备方法1
将400g盐酸齐哌特罗、480ml水和240ml乙醇一次加入到反应器中。将混悬液加热至70℃，15分钟后全部溶解。然后将溶液冷却至45℃，出现一水合物结晶后在此温度保持30分钟。针状结晶，其特征为一水合物，可简单地通过光学显微镜鉴定。然后，将混悬液在35分钟内持续冷却至10℃。向这样得到的浓混悬液中加入0.2g降低颗粒体积的三水合物晶种(H2O＝13％，97％的颗粒＜10μ)。
在10℃搅拌混悬液，直到完成一水合物向三水合物的转化。用光学显微镜可证实颗粒状结晶且无针状结晶。转化时间为5至17小时。然后，将混悬液加热至30℃，保持16小时后，在2小时内稳恒地冷却至0℃。在0℃反应2小时后，将产品分离并用含33％乙醇的100ml水洗涤。将该结晶在20℃减压(15托)干燥16小时，然后仍在减压条件下在钾盐颗粒沉淀的存在下在60℃保持24小时。然后将干燥的产品通过0.6mm筛。这样得到358g微晶盐酸齐哌特罗(水＝0.4％，乙醇＝0.05％，颗粒的粒度：3％＜15μ，93％＜200μ，100％＜245μ)。
制备方法2
将200ml水加入反应器并加热至30℃。快速加入粘稠的无水盐酸齐哌特罗160g。几乎可以达到完全溶解。约10分钟后，自发地产生结晶。在光学显微镜下观察结晶证明它确实是三水合物的形式(粒状形式的结晶)。在30℃接触反应1.5小时后，在1小时内将混悬液稳恒地冷却至0℃，然后在0℃搅拌2小时。将产品分离后用40ml水洗涤置换母液。在制备方法1的条件下干燥产品。这样得到盐酸齐哌特罗微晶144g，将它置于三维振动器中的不锈钢筛上过筛。收集到137g在50μ过筛的过筛后产品(水＝0.65％，颗粒的粒度：1％＜15μ，92％＜200μ，99％＜250μ)。
制备方法3
在反应器中，将30g盐酸齐哌特罗溶于含50％水的300ml乙醇中。将溶液冷却至15℃，加入4g压碎的三水合物晶种(水＝11.8％，颗粒粒度：60％＜50μ)。将存在于300ml含50％水的乙醇中的210g盐酸齐哌特罗溶液保持在约85℃，然后用3小时在15℃边搅拌边加入其中。然后将该混悬液加热至27℃并在27℃搅拌20小时。然后在1.5小时内将此混悬液稳恒地冷却至0℃并在0℃搅拌2小时。然后将混悬液分离，用含50％水的80ml乙醇在0℃置换母液。被分离的结晶在制备方法1的条件下减压干燥。收集到215g盐酸齐哌特罗微晶(水＝1.3％，颗粒的粒度：4％＜15μ，90％＜200μ，99％＜250μ)。
物理化学特性
红外光谱
表1：每个多晶型物的特征带如下：
  形式     无水     一水合物     三水合物
  特征带的波长     3280318017051600785745     33803230318016901610795785750735     34703350310016701620785750
微分量热法分析
每个多晶型物也通过其在微分量热法分析(DCA)中的表现加以定性。
表2：每个多晶型物的DCA特征
  DCA特征
  无水形式     一水合物     三水合物
  在219℃吸热     在170℃219℃吸热     在64℃103℃232℃吸热
粉末的X-衍射图
在波长λ＝1.54A用铜的Kα辐射得到的X-衍射图。在以后的表中，D和I/I1分别表示中间网状空间和相对密度。
表3：每个多晶型物的X射线特征：
    无水     一水合物     三水合物
    D     I/I1     D     I/I1     D     I/I1
    10.998.597.796.095.935.825.294.304.203.983.903.723.593.452.882.71     0.920.200.510.550.480.340.240.370.280.330.380.841.000.470.310.18     42.4412.597.737.006.636.095.935.755.635.514.914.524.274.213.903.823.753.713.613.513.463.353.323.283.213.143.123.052.90     0.200.191.000.190.130.150.160.130.130.130.180.170.210.210.220.270.270.330.190.360.340.310.200.160.240.230.160.120.13     9.187.826.866.105.325.044.794.734.594.273.983.833.723.583.493.453.343.233.083.062.992.962.822.692.632.602.502.43     0.6690.140.200.290.130.180.170.230.180.160.221.000.300.140.740.260.660.950.140.140.130.130.130.100.150.170.120.12
    2.802.682.642.602.502.45     0.140.110.120.130.140.10
用X射线衍射测定的三水合物结构
因为在实验室大气压中三水合物自然失去其结合水慢慢变为无水形式，所以得到具有3分子水的稳定结晶是很困难的。用X射线证实只有制备三水合物形式的单晶才允许每摩尔盐酸齐哌特罗(ZC)存在3摩尔的水。于是可测定结晶体系、晶格参数、空间基团及原子排列。
结晶体系                                 三斜晶
a(A)                                     8.080
b(A)                                     10.268
c(A)                                     11.884
α(度)                                   113.51
β(度)                                   90.65
γ(度)                                   102.34
空间基团                                 P1 -
Z                                        2
R                                        6.6
原子排列
    原子   x/a   y/b   z/c     U(异)
    N(3)C(7)C(17)C(15)C(9)C(8)N(4)O(2)C(11)C(14)C(18)C(12)C(21)N(10)C(13)C(23)C(19)O(5)C(20)CL(1)O(6)O(16)O(22)   0.4065(4)0.2882(5)0.3973(5)0.3405(5)0.4474(5)0.2511(5)0.2008(5)0.4486(4)0.1122(6)0.4657(6)0.2821(6)0.3426(7)0.3124(6)0.1406(5)0.4260(6)0.1943(7)0.3766(7)0.0251(5)0.1591(7)0.2366(2)0.2083(4)-0.1916(5)0.0405(7)   0.2628(4)0.4401(5)0.5156(5)03057(5)0.4538(4)0.5136(5)0.2939(4)0.5546(3)0.2777(5)0.6642(5)0.1423(5)0.1890(5)0.6610(5)0.4126(4)0.7355(5)0.1669(5)0.0613(6)0.1608(4)0.2100(7)0.8016(1)0.7071(4)0.5875(4)0.5001(5)   -0.0120(3)0.3820(4)0.3268(4)0.1118(4)0.1967(4)0.5029(4)0.3449(3)0.1403(3)0.4390(4)0.3992(4)-0.1169(4)0.1599(4)0.5710(4)0.5330(4)0.5177(4)0.2302(5)-0.2193(5)0.4340(3)-0.1595(6)0.9663(1)1.1889(4)0.0697(4)0.7688(4)     0.01930.02010.02150.02110.02060.02310.02470.02350.02800.02680.02760.02730.02970.02890.03050.03190.03720.03750.04310.03760.03900.04970.0598
结论
得到了所需的颗粒。
由方法1制备的产品按照欧洲专利0197188的方法以3％(质量/质量)制备30kg预混物。
制得的预混物应满足Heubach试验，这是一个众所周知的试验，如D.Pickard在《饲料配料员》(Feed Compounder)1992，18页以后所述。
Heubach试验
用Heubach仪按照下列条件调整产生粉尘：
样品的大小：50g预混物
鼓的转速：30r/m
旋转的时间：5分钟
空气注入速率：4L/分钟
滤膜的孔隙度：0.45μm。
产品保留在滤膜上，然后通过声处理在甲醇中提取并通过HPLC分析。
试验的结果：每个滤膜的齐哌特罗＜0.1μg。
Heubach试验表明得到的结晶优选适用于按照欧洲专利申请197188描述的方法制备预混物，以对其加以应用。

Claims (2)

1.盐酸齐哌特罗的一水合物。
2.盐酸齐哌特罗的一水合物在制备结晶形式的无水盐酸齐哌特罗中的用途。
CNB021030898A 1995-06-13 1996-06-12 盐酸齐哌特罗单水合物 Expired - Lifetime CN1164591C (zh)

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FR9506966 1995-06-13
FR9506966A FR2735474B1 (fr) 1995-06-13 1995-06-13 Chlorhydrate de zilpaterol sous une forme cristallisee particuliere, son procede de preparation et les produits intermediaires mis en oeuvre

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MX9602307A (es) 1998-04-30
UA48941C2 (uk) 2002-09-16
ATE196471T1 (de) 2000-10-15
IN2014DE02233A (zh) 2015-06-19
PT753518E (pt) 2000-12-29
DE69610374T2 (de) 2001-01-25
HUP9601617A3 (en) 1999-07-28
HUP9601617A2 (en) 1997-06-30
FR2735474B1 (fr) 1997-08-08
US5847124A (en) 1998-12-08
CA2178783A1 (fr) 1996-12-14
DK0753518T3 (da) 2001-01-29
EA199600027A3 (ru) 1997-03-31
CN1083244C (zh) 2002-04-24
HU9601617D0 (en) 1996-08-28
ES2151999T3 (es) 2001-01-16
JPH093069A (ja) 1997-01-07
US5731028A (en) 1998-03-24
JP4249273B2 (ja) 2009-04-02
ZA964977B (en) 1997-06-12
CA2178783C (fr) 2005-04-12
KR970001215A (ko) 1997-01-21
EP0753518B1 (fr) 2000-09-20
BR9602788A (pt) 1998-09-08
AU701653B2 (en) 1999-02-04
EA000011B1 (ru) 1997-12-30
CN1396165A (zh) 2003-02-12
EP0753518A1 (fr) 1997-01-15
GR3034458T3 (en) 2000-12-29
EA199600027A2 (ru) 1996-12-30
CN1147902A (zh) 1997-04-23
DE69610374D1 (de) 2000-10-26
AU5592596A (en) 1997-01-02
KR100395204B1 (ko) 2003-11-17
HU220461B1 (hu) 2002-02-28
FR2735474A1 (fr) 1996-12-20

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