CN103172640A - Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives - Google Patents

Preparation method of (R)-N-bromine-methyl naltrexone and naltrexone derivatives Download PDF

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CN103172640A
CN103172640A CN2012105620726A CN201210562072A CN103172640A CN 103172640 A CN103172640 A CN 103172640A CN 2012105620726 A CN2012105620726 A CN 2012105620726A CN 201210562072 A CN201210562072 A CN 201210562072A CN 103172640 A CN103172640 A CN 103172640A
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naltrexone
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derivative
anion
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张晓军
邹美香
韩学文
孙歆慧
吴疆
郭振华
范巧云
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天津康鸿医药科技发展有限公司
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    • YGENERAL 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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Abstract

The invention provides a preparation method of (R)-N-bromine-methyl naltrexone. The preparation method adopting naltrexone as the raw material comprises the following steps of: protecting 3-phenolic hydroxyl by adopting an organic silicon group to obtain a first naltrexone derivative; reacting the first naltrexone derivative with a methylation reagent CH3X to obtain a second naltrexone derivative; and removing the phenolic hydroxyl protective group from the second naltrexone derivative, and carrying out bromine anion exchange while necessary to obtain a target product. The invention further provides the two naltrexone derivatives related in the preparation method. The preparation method provided by the invention is high in directional rate and purity, less in steps, simple to operate, gentle in reaction conditions, low in device requirements and convenient to realize industrial production.

Description

—种(R)-N-溴甲基纳曲酮的制备方法以及纳曲酮衍生物技术领域 - Species (R) -N- preparation bromo methylnaltrexone and naltrexone DERIVATIVES

[0001] 本发明涉及一种(R)-N-溴甲基纳曲酮的制备方法以及作为该制备方法的中间体的纳曲酮衍生物。 [0001] The present invention relates to (R) -N- preparation bromo methylnaltrexone and naltrexone derivative as an intermediate in the preparation process.

背景技术 Background technique

[0002] 甲基纳曲酮(MNTX)是纯阿片样物质拮抗剂纳曲酮的季胺盐衍生物,MNTX由于甲基基团的加入,使其具有比纳曲酮更大的极性和更小的脂溶性。 [0002] Methylnaltrexone (of MNTX) is a quaternary amine salt derivative pure opioid antagonist naltrexone, due to the addition of MNTX methyl groups, it has a greater than naltrexone polar and less fat soluble. 这个特征使得MNTX更难通过血脑屏障,其更多地作用于外周而不是中枢神经,具有不与阿片样物质对中枢神经体系的镇痛作用相对抗的优点。 This feature makes it more difficult MNTX blood-brain barrier, which acts on the outer circumference of more rather than the central nervous system, it does not have the advantage of opioid analgesic effect on the central nervous system against phase.

[0003] MNTX是手性分子,手性中心季胺氮有R和S两种构型。 [0003] MNTX is a chiral molecule, quaternary amine nitrogen chiral center has two configurations R and S. 美国专利4176186、4719215、4861781、5102887、5972954、6274591、6559158 和6608075,中国专利200480009190.8、2004800009191.2,200680008123.3、200680022957.X 等都有描述。 US Patents 6,608,075 and 4176186,4719215,4861781,5102887,5972954,6274591,6559158, Chinese patent 200480009190.8,2004800009191.2,200680008123.3,200680022957.X and others have described. R 型异构体(R)-N-溴甲 R isomer (R) -N- bromomethyl

基纳曲酮(代号为R-MNTX),其结构如式(I)所示: Naltrexone (code-named R-MNTX), as shown in the structure of formula (I):

[0004] [0004]

Figure CN103172640AD00051

[0005] R-MNTX具有降低阿片样物质的副作用而不降低阿片样物质的镇痛作用的特点,其中所述副作用包括恶心、呕吐、烦躁不安、尿潴留、肠蠕动减慢、便秘、胃蠕动减慢及胃排空的延迟等。 [0005] R-MNTX with reduced side effects of opioids without reducing the analgesic effect of the characteristics of the opioid, wherein said side effects include nausea, vomiting, restlessness, urinary retention, bowel movements slow down, constipation, gastric motility slow down and delay gastric emptying. 此外,R-MNTX不但可以降低源自阿片样物质镇痛治疗的副作用,而且能降低由单独内源性阿片样物质所介导的副作用,包括胃肠蠕动抑制、手术后胃肠功能紊乱、特发性便秘和其他病症。 In addition, R-MNTX not only can reduce the side effects from opioid analgesic treatment but also reduces the endogenous opioids alone mediated side effects, including inhibition of gastrointestinal motility, post-operative gastrointestinal dysfunction, especially idiopathic constipation and other symptoms.

[0006] W02004043964A2公开了以纳曲酮为原料,在不同的有机碱溶剂中,与溴甲烷反应。 [0006] W02004043964A2 discloses a naltrexone as a raw material, an organic base in different solvents, is reacted with methyl bromide. 纳曲酮的17-位季铵盐化,得到溴甲基纳曲酮,即MNTX。 Naltrexone 17-position of a quaternary ammonium salt, to give bromo-methylnaltrexone, i.e. MNTX. 但并未提及反应的手性定向问题。 But it did not mention the reaction of chiral orientation issues.

[0007]鉴于文献(Funke,de Graaf, J.Chem.Soc., Perkins Trans.1I , 1985.385),研究显示吗啡喃生物碱17-N甲基化立体选择性生成R构型与3-位的空间位阻有关。 [0007] In view of the literature (Funke, de Graaf, J.Chem.Soc., Perkins Trans.1I, 1985.385), studies have shown morphinan alkaloid 17-N-methyl-R stereo-configuration and the selectivity to the 3-position steric hindrance related. W02006127899A2使用异丁酰基保护3-位酚羟基,增加3-位的空间位阻,来定向合成R-MNTX。 W02006127899A2 using isobutyryl phenolic hydroxyl protected 3-position, the 3-position increases the steric hindrance to directed synthesis R-MNTX. 其反应过程如下: Reaction process is as follows:

[0008] [0008]

Figure CN103172640AD00061

[0009] 该方法使用异丁酰基增加3-位的空间位阻实现了17-位氮甲基化的定问反应。 [0009] The method used to increase the 3-position of isobutyryl steric hindrance to achieve 17-bit set of N-methyl-ask reaction. 但该路线中异丁酰氯与3-位酚羟基成酯收率不高,只有76.8%,后处理需要柱层析纯化。 However, the route with isobutyryl chloride in the 3-position to the phenolic hydroxyl ester yield is not high, only 76.8%, purified by column chromatography requires post-treatment. 碘甲烷甲基化时,需要加压、加热条件才能保证其定向率,对设备要求较高,其后处理也需要柱层析纯化。 When methyl iodide, it is necessary pressure, heating rate in order to ensure its orientation, high equipment requirements, subsequent processing also requires purification by column chromatography. 而其定向率也不是很高,最后产物de值低于95%。 And its orientation rate is not very high, the final product was less than 95% of the value de. 由于该路线多步均需要柱层析纯化,甲基化操作对反应设备要求高,难以实现大规模工业化生产。 Since this multi-step route require column chromatography, methylation reaction requires the operation of the apparatus high, it is difficult to achieve large-scale industrial production.

[0010] 中国专利CN200810069852.0公开了另一合成路线: [0010] Chinese Patent CN200810069852.0 discloses another synthesis route:

[0011] [0011]

Figure CN103172640AD00062

[0013] 该路线开始用乙二醇保护6-位羰基,再保护3-位酚羟基,之后将17-位氮甲基化。 [0013] The route begins with ethylene glycol protected 6-position carbonyl group, a phenolic hydroxyl group and then protection of the 3-position, 17-position nitrogen after methylation. 该路线反应收率较高,但未提及其手性定向率问题。 The route reaction yield is higher, but did not mention its chiral directing rates.

发明内容 SUMMARY

[0014] 因此,本发明的目的是提供一种(R)-N-溴甲基纳曲酮的制备方法以及纳曲酮衍生物。 [0014] Accordingly, an object of the present invention is to provide a (R) -N- preparation bromo methylnaltrexone and naltrexone derivatives. [0015] 本发明目的是通过以下技术方案实现的。 Objective [0015] The present invention is achieved by the following technical solutions.

[0016] 本发明提供了一种(R)-N-溴甲基纳曲酮的制备方法,该方法包括以下步骤: [0016] The present invention provides a (R) -N- preparation bromo methylnaltrexone, the method comprising the steps of:

[0017] (I)在有机碱存在下,使式(IV)所示的纳曲酮与式R - Hal所示的化合物进行反应,得到式(II)所示的第一纳曲酮衍生物; [0017] (I) in the presence of an organic base of formula (IV) shown naltrexone formula R - reacting a compound represented by Hal, to give a first naltrexone derivative of formula (II) shown in FIG. ;

[0018] [0018]

Figure CN103172640AD00071

(IV) (II) (IV) (II)

[0019] 式(II)中,R为有机娃基团,优选为叔丁基_二甲基娃基、叔丁基_二苯基娃基、二异丙基硅基或2-(三甲基硅基)乙氧基甲基,更优选为2-(三甲基硅基)乙氧基甲基; In [0019] formula (II), R is an organic baby group, preferably tert-butyl-dimethyl-_ baby, t-butyl group baby _ diphenyl, diisopropyl silicon or 2- (trimethylsilyl silicon-yl) ethoxymethyl, and more preferably is 2- (trimethylsilyl) ethoxymethyl;

[0020] 所述式R —Hal中,R的定义与式(II)中R的定义相同,Hal表示卤素; [0020] In the formula R -Hal, R has the same definition as R defined in formula (II), Hal represents a halogen;

[0021] (2)使所述第一纳曲酮衍生物与CH3X进行反应,得到式(III)所示的第二纳曲酮衍生物; [0021] (2) said first naltrexone derivative is reacted with CH3X, to give formula (III) shown in the second derivative of naltrexone;

[0022] [0022]

Figure CN103172640AD00072

(III) (III)

[0023] 式(III)中,X—为阴离子,优选为卤素阴离子或有机阴离子,更优选为卤素阴离子。 In the [0023] Formula (III), X- is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion. 合适的卤素阴离子选自Br' 1_、Cl—或F_,优选为Br_或1_。 Suitable halogen anion selected from Br '1_, Cl- or F_, or preferably Br_ 1_.

[0024] 所述CH3X为甲基化试剂,其中X的定义与式(III)中X的定义相同。 [0024] The methylating agent is CH3X, wherein X is as defined in the definition of X are of formula (III).

[0025] 优选地,所述CH3X为碘甲烷或溴甲烷。 [0025] Preferably, the CH3X methyl iodide or methyl bromide.

[0026] (3)在酸性条件下,使所述第二纳曲酮衍生物上的基团R脱除;其中, [0026] (3) under acidic conditions, the second group on the sodium derivative of curvature R removal; wherein,

[0027] 当步骤(2)中的X—为Br—时,第二纳曲酮衍生物上的基团R脱除后获得式(I)所示的目标产物(R)-N-溴甲基纳曲酮; The desired product [0027] When step when X- Br-, group R on the second derivative of naltrexone removal (2) in the rear of formula (I), in (R) -N- bromomethyl naltrexone;

[0028] [0028]

Figure CN103172640AD00081

[0029] 当步骤(2)中的X_是Br_以外的其他阴离子时,该方法还包括步骤(4):第二纳曲酮衍生物上的基团R脱除后进行溴阴离子交换得到式(I)所示的目标产物(R)-N-溴甲基纳曲酮。 [0029] When step (2) is an anion other than X_ Br_, the method further comprises the step of (4): The bromine anion-exchange group R is satisfied on the second derivative curve obtained Removal of formula (I) represented the desired product (R) -N- methylnaltrexone bromo.

[0030] 根据本发明提供的制备方法,步骤(I)中所述有机碱为有机胺试剂。 [0030] The present invention provides a production method, the step (I) said organic base is an organic amine reagent. 所述有机胺试剂优选为吡啶、二甲氨基吡啶、吡咯、三乙胺和二异丙基乙基胺中的一种或多种。 The agent is preferably an organic amine, pyridine, dimethylaminopyridine, pyrrole, triethylamine and diisopropylethylamine in one or more amine.

[0031] 根据本发明提供的制备方法,其中,所述步骤(I)中的反应可以在有机溶剂中进行,合适的有机溶剂包括二氯甲烷和/或苯。 [0031] The present invention provides a production method, wherein said step (I) the reaction can be carried out in an organic solvent, Suitable organic solvents include methylene chloride and / or benzene. 此外,还可以直接在过量的有机碱试剂中进行。 In addition, it is also directly in an excess of an organic base reagent.

[0032] 根据本发明提供的制备方法,其中,所述步骤(I)中由纳曲酮制备第一纳曲酮衍生物在广泛的温度条件下即可反应,合适的反应温度优选为(Tl50°C,更优选为2(T60°C。 [0032] The present invention provides a production method, wherein said step (I) a first naltrexone derivative can be prepared by the reaction of naltrexone at a wide range of temperature conditions, suitable reaction temperature is preferably (TL50 ° C, more preferably 2 (T60 ° C.

[0033] 根据本发明提供的制备方法,其中,所述步骤(2)中反应可以在溶剂中进行,合适的溶剂为非质子极性溶剂,例如丙酮或N,N- 二甲基甲酰胺;也可以直接在过量的甲基化试剂中进行。 [0033] The present invention provides a production method, wherein the step (2) the reaction can be carried out in a solvent, suitable solvents are aprotic polar solvents, such as acetone or N, N- dimethylformamide; It may be performed directly in an excess of the methylating agent. 例如,当甲基化试剂为碘甲烷时,向所述第一纳曲酮衍生物中加入过量的碘甲烷进行反应。 For example, when the reagent is methyl iodide, methyl iodide is added in excess to the first derivative of naltrexone in the reaction.

[0034] 根据本发明提供的制备方法,其中,所述步骤(2)的反应在加热条件下进行,反应温度优选为3(T90°C,更优选为4(T80°C。 [0034] The present invention provides a method of preparing the reaction wherein the step (2) is carried out under heating, the reaction temperature is preferably 3 (T90 ° C, more preferably from 4 (T80 ° C.

[0035] 根据本发明提供的制备方法,其中,所述步骤(3)中所述酸性条件为在稀氢溴酸与甲醇的混合液中进行。 [0035] The present invention provides a production method, wherein said step (3) is carried out in acidic conditions in a mixture of dilute hydrobromic acid and methanol.

[0036] 根据本发明提供的制备方法,其中,步骤(3)中反应温度为5(T80°C,更优选为60^70 0C o [0036] The present invention provides a production method, wherein, in step (3) the reaction temperature was 5 (T80 ° C, more preferably 60 ^ 70 0C o

[0037] 根据本发明提供的制备方法,其中,所述步骤(4)包括:在强碱性载溴阴离子交换树脂柱中进行溴阴离子交换。 [0037] The present invention provides a production method, wherein said step (4) comprises: carrier-bromo strongly basic anion exchange resin column for anion exchange bromine.

[0038] 作为优选方案,本发明提供了一种(R)-N-溴甲基纳曲酮的具体制备方法,包括以下步骤: [0038] As a preferred embodiment, the present invention provides a (R) -N- bromo-specific preparation of methylnaltrexone, comprising the steps of:

[0039] (I)在有机碱和二氯甲烷存在下,使式(IV)所示的纳曲酮与RCl进行反应,制得式 [0039] (I) in the presence of an organic base and methylene chloride, of formula (IV) shown naltrexone reacted with RCl, to produce a formula

(II)所示的第一纳曲酮衍生物; (II) a first derivative of naltrexone;

[0040] 所述有机碱为二甲氨基吡啶、三乙胺或其混合物; [0040] The organic base is dimethylaminopyridine, triethylamine, or mixtures thereof;

[0041] [0041]

Figure CN103172640AD00091

[0042] 式(II)和RCl中的R为2-(三甲基硅基)乙氧基甲基; [0042] Formula (II) and RCl in which R is 2- (trimethylsilyl) ethoxymethyl;

[0043] (2)使所述第一纳曲酮衍生物与过量的CH3X在4(T80°C下反应制备式(III)所示的第二纳曲酮衍生物; [0043] (2) said first naltrexone derivative with an excess of CH3X reaction (III second naltrexone derivative represented by the formula) at 4 (T80 ° C;

[0044] 所述CH3X为碘甲烷或溴甲烷; [0044] The CH3X methyl iodide or methyl bromide;

[0045] [0045]

Figure CN103172640AD00092

[0046] 式(III)中X—为相应的r或Br_ ; [0046] Formula (III), the corresponding r X- or Br_;

[0047] (3)在酸性条件下,在6(T70°C下,使所述第二钠曲酮衍生物上的基团R脱除;其中, [0047] (3) under acidic conditions, at 6 (T70 ° C, the second group on the sodium derivative of curvature R of removal; wherein,

[0048] 当步骤(2)中X_为Br_时,第二纳曲酮衍生物上的基团R脱除后直接获得式(I)所示的目标产物(R)-N-溴甲基纳曲酮; When the desired product is X_ Br_ (2) in [0048] When step, the R groups on the second derivative of naltrexone directly removing formula (I) represented by (R) -N- bromomethyl naltrexone;

[0049] [0049]

Figure CN103172640AD00093

[0050] 当步骤(2)中X_是r时,该方法还钮括步骤(4):第二纳曲酮衍生物上的基团R脱除后进行溴阴离子交换得到式(I)所示的目标产物(R) -N-溴甲基纳曲酮。 Bromine anion exchange for formula (I) the group R after the second removal of the sodium derivative curve: when [0050] When Step (2) of the X_ is r, the method further comprises the step button (4) the object product (R) -N- bromo illustrated methylnaltrexone.

[0051] 优选地,步骤(I)的反应温度为2(T60°C,更优选为室温。[0052] 优选地,步骤(2)的反应温度为4(T80°C,更优选为4(T45°C。 [0051] Preferably, the reaction temperature in step (I) is 2 (T60 ° C, more preferably room temperature. [0052] Preferably, step (2) a reaction temperature of 4 (T80 ° C, and more preferably 4 ( T45 ° C.

[0053] 优选地,步骤(3)的反应温度为6(T70°C。 [0053] Preferably, step (3) the reaction temperature was 6 (T70 ° C.

[0054] 本发明还提供了制备(R)-N-溴甲基纳曲酮过程中涉及的两种作为中间体化合物的钠曲酮衍生物。 [0054] The present invention also provides processes for preparing (R) -N- methylnaltrexone Two Bromine involved in the process as the sodium derivative intermediate compound curvature. 具体地, specifically,

[0055] 一种纳曲酮衍生物,其结构式如式(II)所示: [0055] A naltrexone derivative having the formula formula (II) below:

[0056] [0056]

Figure CN103172640AD00101

[0057] 式(II)中,R为有机娃基团,优选T基二甲基娃基、叔丁基二苯基娃基、三异丙基硅基或2-(三甲基硅基)乙氧基甲基,更优选为2-(三甲基硅基)乙氧基甲基。 In [0057] formula (II), R is an organic group baby, preferably T dimethyl baby group, tert-butyldiphenylsilyl group baby, triisopropylsilyl or 2- (trimethylsilyl) ethoxymethyl, and more preferably is 2- (trimethylsilyl) ethoxymethyl.

[0058] 具体地,当R为2-(三甲基硅基)乙氧基甲基时,所述纳曲酮衍生物为3- [ [2-(三甲基硅基)乙氧基甲基]氧基]-4,5 a -环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃。 [0058] Specifically, when R is 2- (trimethylsilyl) ethoxymethyl, said naltrexone derivative is 3- [[2- (trimethylsilyl) ethoxymethyl yl] oxy] -4,5 a --epoxy-14-hydroxy-17-cyclopropylmethyl-morphinan-6-one.

[0059] 一种甲基纳曲酮衍生物,其结构式如式(III)所示: [0059] A naltrexone derivative having the formula formula (III) below:

[0060] [0060]

Figure CN103172640AD00102

[0061 ] 式(III)中,R为有机娃基团,优选为叔丁基_■甲基娃基、叔丁基_■苯基娃基、二异丙基硅基或2-(三甲基硅基)乙氧基甲基,进一步优选为2-(三甲基硅基)乙氧基甲基。 In the [0061] Formula (III), R is an organic baby group, preferably tert-butyl methyl baby _ ■, t-butyl group baby _ ■ phenyl, diisopropyl silicon or 2- (trimethylsilyl silicon-yl) ethoxymethyl, more preferably is 2- (trimethylsilyl) ethoxymethyl.

[0062] X—为阴离子,优选为卤素阴离子或有机阴离子,更优选为卤素阴离子。 [0062] X- is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion. 合适的卤素阴离子选自,优选为 Suitable anion selected from halogen, preferably

[0063] 具体地,当R为2-(三甲基硅基)乙氧基甲基,X—为1_时,所述甲基纳曲酮衍生物为R-17,17-环丙基甲基,甲基_3-[[2-(三甲基硅基)乙氧基甲基]氧基]-4,5a-环氧-14-羟基-6-酮吗啡喃碘化物。 [0063] Specifically, when R is 2- (trimethylsilyl) ethoxymethyl, X- is 1_, the derivative is methylnaltrexone cyclopropyl R-17,17- , methyl _3 - [[2- (trimethylsilyl) ethoxymethyl] oxy] -4,5a-epoxy-14-hydroxy morphinan-6-one iodide.

[0064] 本发明提供的(R) -N-溴甲基纳曲酮的制备方法,在3-位酚羟基的保护上,选取了空间位阻较大的基团,例如2-(三甲基硅基)乙氧基甲基、叔丁基二甲基硅基、叔丁基二苯基硅基或三异丙基硅基,定向率高,可达99.5% ;反应特异性的增加,使得产品纯度和收率有了很大提高,以原料纳曲酮计,本发明制备方法的总收率由W02006127899A2方法的不到40%提高到60%以上,最终产物的de值高于99.8%,从而使该制备方法的后处理纯化过程大为简化,便于实现工业化生产。 [0064] The present invention provides (R) -N- methylnaltrexone preparing bromo ketone in the 3-position of the phenolic hydroxyl group protection, selected larger steric hindrance group, such as 2- (trimethylsilyl silicon-yl) ethoxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or triisopropylsilyl silicon, orientation rate, up 99.5%; specificity of the reaction increases, such products has been greatly improved purity and yield, based on the starting naltrexone count, total yield production method of the present invention is from less than 40% W02006127899A2 method to more than 60%, the final product is higher than 99.8% de so that the preparation of post-treatment purification process greatly simplified, easy to realize industrial production. 此外,本发明提供的制备方法免去了对6-位羰基的保护,以及脱保护的步骤,步骤少,操作简便,收率高,且反应条件温和,设备要求较低,更加便于实现工业化生产。 Further, the present invention provides a production method eliminates the protection of the 6-position of the carbonyl group, and deprotection steps, fewer steps, simple, high yield, and the reaction conditions are mild, low equipment requirements, is more easy to be industrialized .

附图说明 BRIEF DESCRIPTION

[0065] 以下,结合附图来详细说明本发明的实施方案,其中: [0065] Hereinafter, detailed description in conjunction with the accompanying drawings embodiments of the present invention, wherein:

[0066] 图1是本发明所制备的R-MNTX的核磁共振氢谱; [0066] FIG. 1 is a R-MNTX of the present invention is prepared HNMR;

[0067] 图2是本发明所制备的R-MNTX的核磁共振碳谱; [0067] FIG. 2 is a R-MNTX of the present invention is prepared by C NMR;

[0068] 图3是本发明所制备的R-MNTX的高效液相色谱图。 [0068] FIG. 3 is a R-MNTX HPLC prepared in the present invention of FIG.

具体实施方式 Detailed ways

[0069] 下面结合具体实施方式对本发明进行进一步的详细描述,给出的实施例仅为了阐明本发明,而不是为了限制本发明的范围。 [0069] DETAILED DESCRIPTION The following embodiments of the present invention will be described in further detail, examples are given merely to illustrate the present invention and are not intended to limit the scope of the invention.

[0070] 本发明产物R-MNTX的高效液相色谱条件参考W02006127899A2公开的检测R-MNTX与S-MNTX的方法,使用通梯度高效液相色谱条件。 [0070] HPLC conditions R-MNTX product of the present invention with reference to R-MNTX and S-MNTX W02006127899A2 disclosed a method for detecting, through use of a gradient high performance liquid chromatography conditions.

[0071] 本发明制备样品的de值(S卩,非对应异构体过量百分率)的计算方法为液相色谱图中(R构型峰面积-S构型峰面积)/ (R构型峰面积+S构型峰面积)。 Calculation Method [0071] Samples were prepared according to the present invention, the de value (S Jie, diastereoisomer excess percentage) of liquid chromatogram (R-configuration -S configuration peak area peak area) / (R-configuration peak + S configuration area peak area). 使用的高效液相色谱仪器检测器为Warters2487,工作站为Lablliance。 HPLC instrument using a detector to Warters2487, workstation Lablliance.

[0072] 实施例1:制备第一纳曲酮衍生物 [0072] Example 1: Preparation of a first derivative of naltrexone

[0073] 本实施例用于说明3-[[2_(三甲基硅基)乙氧基甲基]氧基]-4,5a-环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃及其制备方法。 [0073] Examples for describing the present embodiment 3 - [[2_ (trimethylsilyl) ethoxymethyl] oxy] -4,5a-epoxy-14-hydroxy -17- cyclopropylmethyl - 6-keto morphinan their preparation.

[0074] (I)取11克卿32mmol)纳曲酮卿17-(环丙基甲基)_4、5 a -环氧-3、14-二羟基-6-氧代吗啡喃)溶于70毫升二氯甲烷中,接着依次向溶液中加入5.6克(即34mmol)2-(三甲基硅基)乙氧基甲基氯(简称SEMCl )、100毫克二甲氨基吡啶(简称DMAP )和I毫升三乙胺,在室温下搅拌至反应完全; [0074] (I) Take 11 g of State 32mmol) naltrexone Qing 17- (cyclopropylmethyl) _4,5 a - 3,14-epoxy-6-oxo-morphinan) was dissolved in 70 ml of methylene chloride were added followed by 5.6 g (i.e., 34mmol) 2- (trimethylsilyl) ethoxymethyl chloride (abbreviated SEMCl), 100 mg of dimethylaminopyridine (referred to as DMAP), and to the solution I ml of triethylamine, stirred at room temperature until the reaction is complete;

[0075] (2)将步骤(I)中得到的反应液倾入100毫升饱和碳酸氢钠水溶液中,搅拌5分钟,静置分层,分出上层的水层,然后用50毫升二氯甲烷对水层进行提取; [0075] (2) The reaction mixture in step (I) obtained was poured into 100 ml of saturated aqueous sodium bicarbonate, stirred for 5 minutes, standing layer, the upper aqueous layer was separated, and then with 50 ml of methylene chloride The aqueous layer was extracted;

[0076] (3)合并步骤(2)中的二氯甲烷层,接着用100毫升饱和氯化钠水溶液洗,然后用无水硫酸镁干燥,最后减压蒸干溶剂,向残余物中加入无水乙醇进行重结晶,得14.5克白色固体,收率为95.4%。 [0076] (3) step were combined dichloromethane layer (2), followed by 100 ml saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and finally the solvent was evaporated under reduced pressure, to the residue was added no water, recrystallized from ethanol, 14.5 g of a white solid, a yield of 95.4%.

[0077] 本施例制得的白色固体的核磁共振氢谱(简称1H-NMR)数据如下:S 0.02 (s, 9H), [0077] Proton NMR of the present embodiment obtained as a white solid (referred to as 1H-NMR) data was as follows: S 0.02 (s, 9H),

0.30 (m, 4H),0.45 (m, 1H),0.79 (m, 2H),1.75 (m, 2H),1.91 (m, 2H),2.20-2.35 (m, 6H),2.80 (m, 1H),3.04 (m, 2H),3.40 (t, 2H),4.79 (s, 1H),6.02 (s, 2H),6.33-6.46 (q, 2H),9.04 (s,1H)。 0.30 (m, 4H), 0.45 (m, 1H), 0.79 (m, 2H), 1.75 (m, 2H), 1.91 (m, 2H), 2.20-2.35 (m, 6H), 2.80 (m, 1H) , 3.04 (m, 2H), 3.40 (t, 2H), 4.79 (s, 1H), 6.02 (s, 2H), 6.33-6.46 (q, 2H), 9.04 (s, 1H). 其中,上述1H-NMR数据是以氘代二甲基亚砜(简称DMS0-d6)为溶剂测得的。 Wherein the 1H-NMR data is in deuterated dimethyl sulfoxide (abbreviated DMS0-d6) as solvent measured.

[0078] 该白色固体的质谱数据中,分子离子峰的质荷比(M+H) /Z为472.24。 [0078] The mass spectral data of the white solids, molecular ion mass to charge ratio (M + H) / Z was 472.24.

[0079] 该白色固体的核磁共振碳谱(即13C-NMR)数据如下:0.3,2.1,7.5,16.9,21.0,27.5,28.1,29.0,46.2,48.5,61.2,61.4,66.4,80.3,89.2,98.5,111.4, 120.5,129.0,133.6,140.9,144.5,208.2。 [0079] C NMR of the white solid (i.e., 13C-NMR) data was as follows: 0.3,2.1,7.5,16.9,21.0,27.5,28.1,29.0,46.2,48.5,61.2,61.4,66.4,80.3,89.2, 98.5,111.4, 120.5,129.0,133.6,140.9,144.5,208.2.

[0080] 由以上数据可知,该白色固体为3-[[2_(三甲基硅基)乙氧基甲基]氧基]-4,5 a -环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃。 [0080] From the above data, the white solid of 3 - [[2_ (trimethylsilyl) ethoxymethyl] oxy] -4,5 a - cyclopropylmethyl-epoxy-14-hydroxy-17 morphinan-6-one.

[0081] 实施例2:制备第二纳曲酮衍生物 [0081] Example 2: Preparation of a second derivative of naltrexone

[0082] 本实施例用于说明R-17,17-环丙基甲基,甲基_3-[[2-(三甲基硅基)乙氧基甲基]氧基]-4,5 a -环氧-14-羟基-6-酮吗啡喃碘化物及其制备方法。 [0082] The examples serve to illustrate the present R-17,17- cyclopropylmethyl, methyl _3 - [[2- (trimethylsilyl) ethoxymethyl] oxy] -4,5 a - epoxy-14-hydroxy morphinan-6-one iodide their preparation.

[0083] 向10克(即21.2mmol) 3-[[2-( 二甲基娃基)乙氧基甲基]氧基]-4,5 a _环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃中加入20毫升碘甲烷,搅拌均匀,加热至42°C反应16小时。 [0083] To 10 g (i.e., 21.2mmol) 3 - [[2- (dimethylamino baby-yl) ethoxymethyl] oxy] -4,5 a _ cyclopropylmethyl-epoxy-14-hydroxy-17 was added methyl morphinan-6-one in 20 ml of methyl iodide, uniformly stirred and heated to 42 ° C for 16 hours. 最后,减压蒸馏除去过量的碘甲烷(其中,碘甲烷可回收重复利用),得13克黄色粉末状固体,收率为99.9%。 Finally, distilled under reduced pressure to remove excess iodomethane (wherein, iodomethane recycled reuse), to give 13 g yellow powder, yield 99.9%.

[0084] 本施例制得的黄色粉末状固体的核磁共振氢谱(简称1H-NMR)数据如下:8 0.02 (s, 9H) ,0.30 (m, 4H),0.79 (m, 2H) ,0.84 (m, 1H),1.91 (m, 2H),1.98 (m, 2H), [0084] proton nuclear magnetic resonance of the present embodiment obtained as a yellow powdered solid spectra (abbreviated 1H-NMR) data was as follows: 8 0.02 (s, 9H), 0.30 (m, 4H), 0.79 (m, 2H), 0.84 (m, 1H), 1.91 (m, 2H), 1.98 (m, 2H),

2.22 (m, 2H),3.20 (m, 2H),3.24 (t, 2H),3.30 (m, 3H),3.40 (t, 2H),3.75 (m, 1H),4.79 (s, 1H), 2.22 (m, 2H), 3.20 (m, 2H), 3.24 (t, 2H), 3.30 (m, 3H), 3.40 (t, 2H), 3.75 (m, 1H), 4.79 (s, 1H),

6.02 (s,2H),6.33〜6.46 (q, 2H),9.04 (s, 1H)。 6.02 (s, 2H), 6.33~6.46 (q, 2H), 9.04 (s, 1H). 其中,上述1H-NMR数据是以氘代二甲基亚砜(简称DMS0-d6)为溶剂测得的。 Wherein the 1H-NMR data is in deuterated dimethyl sulfoxide (abbreviated DMS0-d6) as solvent measured.

[0085] 该黄色粉末状固体的质谱数据中,分子离子峰的质荷比M+为486.3。 [0085] The mass spectral data of yellow powder, molecular ion mass to charge ratio of 486.3 M +.

[0086] 该黄色粉末状固体的核磁共振碳谱(即13C-NMR)数据如下:0.3,1.2,2.9,16.9,21.0,21.8,28.3,29.0,43.7,53.0,59.3,61.2,71.0,80.3,85.5,89.6,98.5,111.4,120.5,129.0,133.6,140.9,144.5,208.2。 [0086] The yellow powder is C NMR (i.e., 13C-NMR) data was as follows: 0.3,1.2,2.9,16.9,21.0,21.8,28.3,29.0,43.7,53.0,59.3,61.2,71.0,80.3, 85.5,89.6,98.5,111.4,120.5,129.0,133.6,140.9,144.5,208.2.

[0087] 由上述数据可知,该黄色粉末状固体为R-17,17-环丙基甲基,甲基_3-[[2-(三甲基硅基)乙氧基甲基]氧基]-4,5 a -环氧-14-羟基-6-酮吗啡喃碘化物。 [0087] From the above data, the yellow powder is R-17,17- cyclopropylmethyl, methyl _3 - [[2- (trimethylsilyl) ethoxymethyl] oxy ] -4,5 a - epoxy-14-hydroxy morphinan-6-one iodide.

[0088] 实施例3 [0088] Example 3

[0089] 本实施例用于说明R-17,17-环丙基甲基,甲基-3-羟基-4,5a-环氧-14-羟基-6-酮吗啡喃碘/溴化物及其制备方法。 [0089] The examples serve to illustrate the present R-17,17- cyclopropylmethyl, -4,5a- epoxy-3-hydroxy morphinan-6-one 14-hydroxy iodide / bromide and Preparation.

[0090] 向10克(即16.3mmol) R-17, 17~环丙基甲基,甲基_3_ [ [2~ ( 二甲基娃基)乙氧基甲基]氧基]-4,5 a-环氧-14-羟基-6-酮吗啡喃碘化物中加入70毫升甲醇,搅拌溶解,通氮气保护。 [0090] To 10 g (i.e., 16.3mmol) R-17, 17 ~ cyclopropylmethyl, methyl _3_ [[2 - (dimethylamino baby-yl) ethoxymethyl] oxy] -4, Add 5 a--epoxy-14-hydroxy morphinan-6-one iodide 70 ml of methanol, stirred to dissolve, nitrogen protection. 室温下,滴加50毫升的6%氢溴酸水溶液,加完后升温至6(T7(TC搅拌反应5小时。减压浓缩反应物,得6.8克浅黄色固体。 At room temperature, was added dropwise 50 ml of 6% aqueous hydrobromic acid, the addition is complete warm to 6 (T7 (TC was stirred for 5 hours. The reaction was concentrated under reduced pressure, 6.8 g of a light yellow solid.

[0091] 实施例4 [0091] Example 4

[0092] 本实施例用于说明R-17,17-环丙基甲基,甲基-3-羟基-4,5a-环氧-14-羟基-6-酮吗啡喃溴化物及其制备方法。 [0092] The examples serve to illustrate the present R-17,17- cyclopropylmethyl, -4,5a- epoxy-3-hydroxy 14-hydroxy morphinan-6-one bromide and preparation method .

[0093] 向6.8克实施例3中得到的R-17, 17-环丙基甲基,甲基-3-轻基-4,5 a -环氧-14-羟基-6-酮吗啡喃碘/溴化物的浅黄色固体中加入40毫升蒸馏水溶解。 [0093] R-17 obtained in Example 3 6.8 g of the embodiments, 17-cyclopropylmethyl, methyl-3-yl light -4,5 a - epoxy-14-hydroxy morphinan-6-one iodide / bromide as a pale yellow solid was dissolved in 40 ml of distilled water. 将得到的溶液加入过强碱性载溴阴离子交换树脂柱,用蒸馏水洗脱,收集约200毫升洗脱液。 The resulting solution was added over brominated strongly basic anion exchange resin column, eluted with distilled water, about 200 ml eluate was collected.

[0094] 将洗脱液减压浓缩,接着向残余物加入20毫升甲醇,冷却析晶,过滤,得白色结晶。 [0094] The eluate was concentrated under reduced pressure, followed by addition of 20 ml of methanol to the residue, cooling crystallization, and filtered to give white crystals. 向白色晶体中加入35晕升95%乙醇进行重结晶,5.2克白色粉末状固体,实施例3与实施例4两步合并的收率为73.1%。 Halo was added 35 liters of 95% ethanol was recrystallized to white crystals, 5.2 g white powder, Example 3 and Example 4 a two-step combined yield of 73.1%.

[0095] 将得到的白色粉末状固体通过核磁共振进行分析,其结果如图1和2所示。 [0095] The white powdery solid obtained was analyzed by NMR, and the results shown in Figures 1 and 2. 从图1和图2中可以看出,该白色粉末状固体为R-MNTX产品。 As can be seen in FIG. 2 and FIG. 1, the white powdery solid as R-MNTX product. 采用高效液相色谱法分析R-MNTX产品的纯度。 Analysis of R-MNTX product purity by HPLC. HPLC谱图如图3所示,数据详见表I。 FIG HPLC profile, the data shown in Table 3 I.

[0096] 从结果可以看出,HPLC纯度为99.91%,产品中几乎检测不到(R)-N-溴甲基纳曲酮的S构型异构体,而该HPLC条件下最小检出限为0.02%,则其S构型异构体的含量低于最小检出限0.02%,根据de值计算方法,样品de值应高于(99.91%-0.02%)/(99.91%+0.02%)=99.96%,即高于99.96%o [0096] From the results, HPLC purity of 99.91%, was hardly detected in the product (R) -N- methylnaltrexone bromo-S configuration isomers, and the lower limit of detection of the HPLC conditions 0.02%, the S configurational isomer content lower than the minimum detection limit of 0.02%, according to de value calculation method, the sample must be above de (99.91% -0.02%) / (99.91% + 0.02%) = 99.96%, i.e., greater than 99.96% O

[0097]表 IR-MNTX 的HPLC 数据 [0097] TABLE HPLC data of IR-MNTX

[0098] [0098]

Figure CN103172640AD00131

[0099] 实施例5:制备第一纳曲酮衍牛物 [0099] Example 5: Preparation of Naltrexone first derivatives thereof bovine

[0100] 本实施例用于说明3-[[叔丁基二苯基硅基]氧基]-4,5a-环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃及其制备方法。 [0100] Examples for describing the present embodiment 3 - [[tert-butyldiphenylsilyl silicon] oxy] -4,5a-hydroxy-17-epoxy-14-cyclopropylmethyl-morphinan-6-one its preparation method.

[0101] (I)取20 克(即58.6mmol)纳曲酮(SP 17-(环丙基甲基)_4、5 a -环氧-3、14-二羟基-6-氧代吗啡喃)溶于100毫升二氯甲烷中,接着依次向溶液中加入16.5克(SP60.0mmol)叔丁基二苯基硅基氯(简称TBDPSC1)、190毫克二甲氨基吡啶(简称DMAP)和13 [0101] (I) to take 20 grams (i.e., 58.6 mmol) naltrexone (SP 17- (cyclopropylmethyl) _4,5 a - 3,14-epoxy-6-oxo-morphinan) dissolved in 100 ml of methylene chloride, followed by successively added to a solution of 16.5 g (SP60.0mmol) tert-butyl-diphenyl-chloro-silicon (abbreviated TBDPSC1), 190 mg of dimethylaminopyridine (referred to as DMAP) and 13

毫升三乙胺,在室温下搅拌反应至完全; Ml of triethylamine, stirred at room temperature until complete;

[0102] (2)将步骤(I)中得到的反应液倾入200毫升饱和碳酸氢钠水溶液中,搅拌5分钟,静置分层,分出上层的水层,然后用100毫升二氯甲烷对水层进行提取; [0102] (2) The reaction mixture in step (I) obtained was poured into 200 ml of saturated aqueous sodium bicarbonate, stirred for 5 minutes, standing layer, the upper aqueous layer was separated, and then with 100 ml of methylene chloride The aqueous layer was extracted;

[0103] (3)合并步骤(2)中的二氯甲烷层,接着用200毫升饱和氯化钠水溶液洗,然后用无水硫酸镁干燥,最后减压蒸干溶剂,向残余物中加入无水乙醇进行重结晶,得30.8克白色固体,收率为90.7%。 [0103] (3) step were combined dichloromethane layer (2), and then washed with 200 ml of saturated sodium chloride solution, then dried over anhydrous magnesium sulfate, and finally the solvent was evaporated under reduced pressure, to the residue was added no recrystallized from aqueous ethanol to give 30.8 g of white solid, a yield of 90.7%.

[0104] 本施例制得的白色固体的核磁共振氢谱(简称1H-NMR)数据如下:8 0.0 8^0.3 0 (m, 4H) , 0.4 5 (m, 1H) , 0.98 (s, 9H) , 1.7 5 (m, 2H) , 1.91 (m, 2H), [0104] Proton NMR of the present embodiment obtained as a white solid (referred to as 1H-NMR) data was as follows: 8 0.0 8 ^ 0.3 0 (m, 4H), 0.4 5 (m, 1H), 0.98 (s, 9H ), 1.7 5 (m, 2H), 1.91 (m, 2H),

2.20〜2.35 (m, 6H),2.80 (m, 1H),3.04 (q, 2H),3.40 (t, 2H),4.79 (s, 1H),6.29〜6.31 (m, 2H),7.36 (m, 6H), 7.54 (m, 4H), 9.22 (s, 1H)。 2.20~2.35 (m, 6H), 2.80 (m, 1H), 3.04 (q, 2H), 3.40 (t, 2H), 4.79 (s, 1H), 6.29~6.31 (m, 2H), 7.36 (m, 6H), 7.54 (m, 4H), 9.22 (s, 1H). 其中,上述1H-NMR数据是以氘代二甲基亚砜(简称DMS0-d6)为溶剂测得的。 Wherein the 1H-NMR data is in deuterated dimethyl sulfoxide (abbreviated DMS0-d6) as solvent measured.

[0105] 该白色固体的质谱数据中,分子离子峰的质荷比(M+H)/Z为580.3。 [0105] Mass spectrometry data of the white solids, molecular ion mass to charge ratio (M + H) / Z was 580.3.

[0106] 该白色固体的核磁共振碳谱(即13C-NMR)数据如下:2.1,7.5,14.1,20.5,21.0,27.5,28.1,29.0,46.2,48.5,61.2,61.4,66.4,80.3,89.6,113.0,120.9,128.1,129.3,129.8,133.0,134.0,135.8,139.8,142.5,208.2。 [0106] C NMR of the white solid (i.e., 13C-NMR) data was as follows: 2.1,7.5,14.1,20.5,21.0,27.5,28.1,29.0,46.2,48.5,61.2,61.4,66.4,80.3,89.6, 113.0,120.9,128.1,129.3,129.8,133.0,134.0,135.8,139.8,142.5,208.2.

[0107] 由以上数据可知,该白色固体为3-[[叔丁基二苯基硅基]氧基]-4,5a_环氧-14-羟基-17-环丙基甲基-6-酮吗啡喃。 [0107] From the above data, the white solid of 3 - [[tert-butyldiphenylsilyl silicon] oxy] -4,5a_-epoxy-14-hydroxy-17-cyclopropylmethyl-6- ketomorphinans.

[0108] 实施例6:制备第二纳曲酮衍生物[0109] 本实施例用于说明R-17,17-环丙基甲基,甲基-3-[[叔丁基二苯基硅基]氧基]-4,5 a -环氧-14-羟基-6-酮吗啡喃碘化物及其制备方法。 [0108] Example 6: Preparation of naltrexone second derivatives [0109] R-17,17- cyclopropylmethyl, methyl-3 for explaining an embodiment of the present embodiment - [[tert-butyldiphenylsilyl silicon yl] oxy] -4,5 a - epoxy-14-hydroxy morphinan-6-one iodide their preparation.

[0110] 向25克(即43.1mmol) 3_[[叔丁基二苯基娃基]氧基]-4,5 a -环氧-14-轻基-17-环丙基甲基-6-酮吗啡喃中加入40毫升碘甲烷,搅拌均匀,加热至45°C反应18小时。 [0110] To 25 g (i.e., 43.1mmol) 3 _ [[tert-butyldiphenylsilyl baby yl] oxy] -4,5 a - light-17-epoxy-14-cyclopropylmethyl-6- morphine was added thiopyran-one in 40 ml of methyl iodide, stir and heated to 45 ° C for 18 hours. 最后,减压蒸馏除去过量的碘甲烷(碘甲烷可回收重复利用),得29.7克浅黄色粉末状固体,收率为95.4%。 Finally, distilled under reduced pressure to remove excess iodomethane (methyl iodide recycled reuse), 29.7 g of a light yellow powder, yield 95.4%.

[0111] 本施例制得的黄色粉末状固体的核磁共振氢谱(简称1H-NMR)数据如下:S 0.08〜0.30 (m, 4H),0.84 (m, 1H),0.98 (s, 9H),1.91 〜2.10 (m, 4H),2.22 (m, 2H), [0111] Proton NMR of the present embodiment obtained as a yellow powdery solid (referred to as 1H-NMR) data was as follows: S 0.08~0.30 (m, 4H), 0.84 (m, 1H), 0.98 (s, 9H) , 1.91 ~2.10 (m, 4H), 2.22 (m, 2H),

3.20 (m, 2H),3.25 (m, 2H),3.30 (m, 3H),3.75 (t, 1H),4.79 (s, 1H),6.29〜6.31 (m, 2H), 3.20 (m, 2H), 3.25 (m, 2H), 3.30 (m, 3H), 3.75 (t, 1H), 4.79 (s, 1H), 6.29~6.31 (m, 2H),

7.36 (m, 6H),7.54 (m, 4H),9.08 (s,1H)。 7.36 (m, 6H), 7.54 (m, 4H), 9.08 (s, 1H). 其中,上述1H-NMR数据是以氘代二甲基亚砜(简称DMS0-d6)为溶剂测得的。 Wherein the 1H-NMR data is in deuterated dimethyl sulfoxide (abbreviated DMS0-d6) as solvent measured.

[0112] 该黄色粉末状固体的质谱数据中,分子离子峰的质荷比M+为594.3。 [0112] The mass spectral data of yellow powder, molecular ion mass to charge ratio of 594.3 M +.

[0113] 该黄色粉末状固体的核磁共振碳谱(即13C-NMR)数据如下:1.2,2.9,14.1,20.5, [0113] The yellow powder is C NMR (i.e., 13C-NMR) data was as follows: 1.2,2.9,14.1,20.5,

21.0,21.8,28.3,29.0,43.7,53.0,59.3,71.0,80.3,85.5,89.6,113.0,120.9,128.1,129.3,129.8,133.0,134.0,135.8,139.8,142.5,208.2。 21.0,21.8,28.3,29.0,43.7,53.0,59.3,71.0,80.3,85.5,89.6,113.0,120.9,128.1,129.3,129.8,133.0,134.0,135.8,139.8,142.5,208.2.

[0114] 由上述数据可知,该黄色粉末状固体为R-17,17-环丙基甲基,甲基-3_[[叔丁基二苯基硅基]氧基]-4,5a-环氧-14-羟基-6-酮吗啡喃碘化物。 [0114] From the above data, the yellow powder is R-17,17- cyclopropylmethyl, methyl-3 _ [[tert-butyldiphenylsilyl silicon] oxy] -4,5a-ring oxygen 14-hydroxy morphinan-6-one iodide.

[0115] 实施例7 [0115] Example 7

[0116] 本实施例用于说明R-17,17-环丙基甲基,甲基-3-羟基-4,5a-环氧-14-羟基-6-酮吗啡喃碘/溴化物及其制备方法。 [0116] Examples of the present embodiment for explaining the R-17,17- cyclopropylmethyl, -4,5a- epoxy-3-hydroxy morphinan-6-one 14-hydroxy iodide / bromide and Preparation.

[0117] 向25克(即34.6mmol)R-17, 17-环丙基甲基,甲基_3_[[叔丁基二苯基娃基]氧基]-4,5 a -环氧-14-羟基-6-酮吗啡喃碘化物中加入150毫升甲醇,搅拌溶解,通氮气保护。 [0117] To 25 g (i.e., 34.6mmol) R-17, 17- cyclopropylmethyl, methyl _3 _ [[tert-butyldiphenylsilyl baby yl] oxy] -4,5 a - epoxy - 14-hydroxy morphinan-6-one iodide was added 150 ml of methanol, stirred to dissolve, nitrogen protection. 室温下,滴加100毫升的8%氢溴酸水溶液,加完后升温至60~70°C搅拌反应5小时。 At room temperature, 8% aqueous hydrobromic acid was added dropwise 100 ml, was added after stirring the reaction warmed to 60 ~ 70 ° C 5 hours. 减压浓缩反应物,得17.8克浅黄色固体。 The reaction was concentrated to give 17.8 g as a pale yellow solid under reduced pressure.

[0118] 实施例8 [0118] Example 8

[0119] 本实施例用于说明R-17,17-环丙基甲基,甲基-3-羟基-4,5a-环氧-14-羟基-6-酮吗啡喃溴化物及其制备方法。 [0119] Examples of the present embodiment for explaining the R-17,17- cyclopropylmethyl, -4,5a- epoxy-3-hydroxy 14-hydroxy morphinan-6-one bromide and preparation method .

[0120] 向17.8克实施例7得到的R-17,17-环丙基甲基,甲基_3_羟基_4,5 a -环氧-14-羟基-6-酮吗啡喃碘/溴化物的浅黄色固体中加入100毫升蒸馏水溶解。 [0120] R-17,17- cyclopropylmethyl obtained in Example 7 to 17.8 g, hydroxy methyl _3_ _4,5 a - epoxy-14-hydroxy morphinan-6-one iodine / bromine compound a pale yellow solid was dissolved in 100 ml of distilled water. 将得到的溶液加入过强碱性载溴阴离子交换树脂柱,用蒸馏水洗脱,收集约500毫升洗脱液。 The resulting solution was added over brominated strongly basic anion exchange resin column, eluted with distilled water, about 500 ml eluate was collected.

[0121] 将洗脱液减压浓缩,接着向残余物加入40毫升甲醇,冷却析晶,过滤,得白色结晶。 [0121] The eluate was concentrated under reduced pressure, then 40 ml of methanol was added to the residue, cooling crystallization, and filtered to give white crystals. 向白色晶体中加入70晕升95%乙醇进行重结晶,得10.4克白色粉末状固体,实施例7与实施例8两步合并收率为68.8%。 Was added to the white crystals in 70 liters of 95% ethanol halo recrystallized to yield 10.4 g white powder, Example 7 and Example 8 was a two-step combined yield of 68.8%.

Claims (9)

1.一种(R)-N-溴甲基纳曲酮的制备方法,该方法包括以下步骤: (1)在有机碱存在下,使式(IV)所示的纳曲酮与式R - Hal所示的化合物进行反应,得到式(II)所示的第一纳曲酮衍生物; An (R) -N- methylnaltrexone bromo naltrexone preparation, the method comprising the steps of: (1) in the presence of an organic base of formula (IV) shown naltrexone formula R - reacting a compound represented by Hal, to give the formula (II) a first derivative of naltrexone;
Figure CN103172640AC00021
式(II)中,R为有机娃基团,优选为叔丁基_■甲基娃基、叔丁基_■苯基娃基、二异丙基硅基或2-(三甲基硅基)乙氧基甲基,更优选为2-(三甲基硅基)乙氧基甲基; 所述式R — Hal中,R的定义与式(II)中R的定义相同,Hal表示卤素; (2)使所述第一纳曲酮衍生物与CH3X进行反应,得到式(III)所示的第二纳曲酮衍生物; In formula (II), R is an organic baby group, preferably tert-butyl methyl baby _ ■, t-butyl group baby _ ■ phenyl, diisopropyl silicon or 2- (trimethylsilyl ) ethoxymethyl, and more preferably is 2- (trimethylsilyl) ethoxymethyl; of the formula R - Hal are the same as R, R is as defined in formula (II) defined above, Hal represents halogen ; (2) contacting said first naltrexone derivative is reacted with CH3X, second naltrexone derivative of formula (III) as shown;
Figure CN103172640AC00022
式(III)中,X—为阴离子,优选为卤素阴离子或有机阴离子,更优选为卤素阴离子,进一步优选为Br_或1_ ; 所述CH3X中X的定义与式(III)中X的定义相同; (3)在酸性条件下,使所述第二纳曲酮衍生物上的基团R脱除;其中, 当步骤(2)中的X—为Br—时,第二纳曲酮衍生物上的基团R脱除后获得式(I)所示的目标产物(R)-N-溴甲基纳曲酮; Of formula (III),, X- is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion, or more preferably Br_ 1_; X is as defined in X of the CH3X defined in formula (III) ; (3) under acidic conditions, the second group on the sodium derivative of curvature R removal; wherein, when in step X- (2) is from Br-, the second derivative of naltrexone of formula (I), after removal of the group R on the object product (R) -N- methylnaltrexone bromo;
Figure CN103172640AC00031
当步骤(2)中的X_是Br_以外的其他阴离子时,该方法还包括步骤(4):第二纳曲酮衍生物上的基团R脱除后进行溴阴离子交换得到式(I)所示的目标产物(R)-N-溴甲基纳曲酮。 When Step (2) is an anion other than X_ Br_, the method further comprises the step of (4): The bromine anion-exchange group R is satisfied on the second derivative curve Removal formula (I ) of the target product (R) -N- bromo shown methylnaltrexone.
2.根据权利要求1所述的制备方法,其中,步骤(I)中所述有机碱为有机胺试剂,所述有机胺试剂优选为吡啶、二甲氨基吡啶、吡咯、三乙胺和二异丙基乙基胺中的一种或多种。 The production method according to claim 1, wherein the step (I) said organic base is an organic amine reagent, the reagent is preferably an organic amine is pyridine, dimethylaminopyridine, pyrrole, triethylamine and diisopropyl one or more amines cyclopropylethyl.
3.根据权利要求1或2所述的制备方法,其中,所述步骤(I)中的反应在有机溶剂中进行;优选地,所述有机溶剂包括二氯甲烷和/或苯。 The production method according to claim 1 or claim 2, wherein said step (I) the reaction is carried out in an organic solvent; preferably, the organic solvent comprises methylene chloride and / or benzene.
4.根据权利要求1至3中任一项所述的制备方法,其中,所述步骤(I)的反应温度为0〜150°C,优选为2(T60°C。 4. Preparation process according to any one of claims 1 to 3, wherein the reaction temperature of the step (I) of 0~150 ° C, preferably 2 (T60 ° C.
5.根据权利要求1至4中任一项所述的制备方法,其中,所述步骤(2)的反应温度为30〜90°C,优选为4(T80°C。 The production method according to any one of claims 1 to 4, wherein said step (2) reaction temperature is 30~90 ° C, preferably 4 (T80 ° C.
6.根据权利要求1至5中任一项所述的制备方法,其中,所述步骤(3)中所述酸性条件为在稀氢溴酸与甲醇的混合液中进行; 优选地,反应温度为5(T80°C,优选为6(T70°C。 The production method according to any one of claims 1 to 5, wherein said step (3) is carried out in acidic conditions in a mixture of dilute hydrobromic acid and methanol; preferably, the reaction temperature is 5 (T80 ° C, preferably of 6 (T70 ° C.
7.根据权利要求1至6中任一项所述的制备方法,其中,所述步骤(4)包括:在强碱性载溴阴离子交换树脂柱中进行溴阴离子交换。 7. Preparation process according to any one of claims 1 to 6, wherein said step (4) comprises: carrier-bromo strongly basic anion exchange resin column for anion exchange bromine.
8.一种纳曲酮衍生物,其结构式如式(II)所示: A naltrexone derivative having the formula formula (II) below:
Figure CN103172640AC00032
式(II)中,R为有机娃基团,优选为叔丁基_■甲基娃基、叔丁基_■苯基娃基、二异丙基硅基或2-(三甲基硅基)乙氧基甲基,更优选为2-(三甲基硅基)乙氧基甲基。 In formula (II), R is an organic baby group, preferably tert-butyl methyl baby _ ■, t-butyl group baby _ ■ phenyl, diisopropyl silicon or 2- (trimethylsilyl ) ethoxymethyl, and more preferably is 2- (trimethylsilyl) ethoxymethyl.
9.一种纳曲酮衍生物,其结构式如式(III)所示: A naltrexone derivative having the formula formula (III) below:
Figure CN103172640AC00041
式(III)中,R为有机娃基团,优选为叔丁基_■甲基娃基、叔丁基_■苯基娃基、二异丙基硅基或2-(三甲基硅基)乙氧基甲基,进一步优选为2-(三甲基硅基)乙氧基甲基; X—为阴离子,优选为卤素阴离子或有机阴离子,更优选为卤素阴离子,进一步优选为Br-或I'` Of formula (III), R is a baby organic group, preferably tert-butyl methyl baby _ ■, t-butyl group baby _ ■ phenyl, diisopropyl silicon or 2- (trimethylsilyl ) ethoxymethyl, more preferably is 2- (trimethylsilyl) ethoxymethyl; X-is an anion, preferably a halogen anion or an organic anion, more preferably a halogen anion, preferably Br- or more I'`
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