WO2012010106A1 - Preparation method for morphinan bromide quaternary ammonium salt - Google Patents

Abstract

Disclosed is a preparation method for a morphinan bromide quaternary ammonium salt as represented by Formula (I). The method comprises: transforming a compound as represented by Formula (II) in a compound as represented by Formula (I) by an ion-exchange using a brominated strongly basic anion-exchange resin. The definitions of A, R₁, R₁ and X^- found in Formula (I) and Formula (II) are as presented in the description.

Description

 The present invention claims to be submitted to the Chinese Patent Office on July 23, 2010, and the application number is 201010234541. 2. The Chinese patent entitled "Preparation Method of Bromomorphine Ammonium Salt" Priority of the application, the entire contents of which are incorporated herein by reference. Technical field

 The invention belongs to the field of chemical or medicinal chemistry, and particularly relates to a preparation method of a quaternary ammonium bromide bromo ammonium salt, which comprises ion exchange into a bromine guanidine ketone by a mixture of guanidinolone bromine and iodide. Purification operation to improve the purity of the product. Background technique

 臭 4匕? South season according to salt: 3⁄4 mouth;; skunk 曲 S S with (methylna l trexone bromide, which is called the 阳 纳 naltrexone, MNTX), the structural formula is as follows:

溴曱纳曲酮与主要位于胃肠道外周的 μ受体结合，起拮抗剂作用， 能有效 的緩解某些鸦片剂治疗不期望的副作用， 如便秘、 恶心等； 同时， 它由于是强 极性的季铵盐， 不能穿过血脑屏障进入中枢神经系统， 因此不影响鸦片剂的中 枢镇痛作用。

Bromoquinone ketone binds to the μ receptor mainly located in the periphery of the gastrointestinal tract and acts as an antagonist, which can effectively alleviate the undesirable side effects of certain opiates, such as constipation, nausea, etc. At the same time, it is strong Sexual quaternary ammonium salts cannot cross the blood-brain barrier and enter the central nervous system, thus not affecting the central analgesic effect of opiates.

 The preparation of bromoquinone ketone has been reported in the literature. There are two main types of synthesis methods, one is the direct quaternization of naltrexone with bromodecane, or the naltrexone and iodonium season. Ammonium reaction, and then ion exchange to obtain bromoquinone ketone; the other is to first protect the phenolic hydroxyl group in naltrexone, then quaternized with iodonium, and then deprotected, ion exchanged to obtain bromocana ketone. Both methods use ion exchange resins for ion exchange, such as:

The preparation process of bromo-nonazone as disclosed in US Pat. No. 4,176,186 is as follows:

 Bromomethylnaltrexone

 The process uses naltrexone as a raw material, acetone as a reaction solvent, and quaternization reaction with iodonium in a closed vessel at 70 ° C for 4 days to form iodine naltrexone, and then ion exchange with strong basic anion exchange resin. The bromoquinone bromine is obtained. The strong basic anion exchange resin employed in the ion exchange process has no specific parameters and does not disclose a specific preparation method.

 The technical process of W02006127899 is as follows:

The process of naltrexone bromide is also based on naltrexone, wherein the phenolic hydroxyl group is protected by isobutyryl chloride, then quaternized by iodonium, hydrolyzed and deprotected, and ion exchanged to obtain bromoquinone ketone. The process overcomes the disadvantages of direct alkylation which tends to produce phenol alkylation by-products; however, in the ion exchange process, only "AG1-X8 resin treated with 1N hydrobromic acid aqueous solution is used, The exchange of iodine ions in the mixture of keto bromo and iodide into bromide ions gives cerium bromide. However, some necessary process parameters in the ion exchange process, such as the treatment method, residues of other ions in the resin after treatment, etc., are not disclosed. And what is used The AG1-X8 resin is not easily available and expensive, so the process is difficult to apply industrially. In order to solve the above-mentioned deficiencies in the prior art, it is necessary to develop an ion exchange preparation process of brominated morphinan quaternary ammonium salt which is easy to obtain raw materials, controllable in operation cylinder, low in cost, and suitable for industrial production. Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to provide an ion exchange preparation method of a high quality brominated morphinan quaternary ammonium salt (compound of formula I) which is readily available in raw materials, controllable in operation, low in cost, and suitable for industrial production.

 In order to achieve the object, the present invention provides a process for the preparation of a compound of the formula I, which comprises subjecting a chlorine type strongly basic anion exchange resin to ion exchange with a strong alkali solution, a bromide solution or ion exchange with a bromide solution. Repeating the operation at least once to form a bromine-type strongly basic anion exchange resin; and then converting the compound of the formula II into the compound of the formula I by ion exchange with the bromine-type strongly basic anion exchange resin.

III, wherein A and R _{1 3⁄4} R ₂ in formula I and formula II have the same definition,

 ^ is a hydrocarbon group, including a mercapto group, an ethyl group, an allyl group, a cyclopropenyl group or the like, preferably a cyclopropenyl group;

R ₂ is a hydroxy protecting group or hydrogen, and when R ₂ is a hydroxy protecting group, it includes: an alkyl group such as a benzyl group, a decylbenzyl group or the like; an acyl group such as a decanoyl group, an acetyl group or an alkoxycarbonyl group (e.g., isobutyryl group) a silyl group such as a trimethylsilyl group, a tert-butyldimercaptosilyl group, a tert-butyldiphenylsilyl group, a triisopropylsilyl group, or the like;

X- is a single anion or mixed anion, including fluoride ion, chloride ion, iodide ion, nitrate, monodecyl sulfate, sulfonate, trifluorosulfonate, benzoate, p-toluenesulfonate, etc. or Mixed ions, and their mixed ions with bromide ions; \ _ \ _ \ _ C ^R 3

A is cadaver ⁰ , / ^C=S , / ^C=C3⁄4 , ^oR ₄ , wherein R ₃ and R ₄ are each independently a lower hydrocarbon group and an aromatic hydrocarbon group, of which a thiol group, an ethyl group, or R ₃ and R _{4 are} preferred. A support group (-CH ₂ CH ₂ -) is formed. Preferably, the method for preparing a compound of the above formula I of the present invention comprises the steps of: exchanging a chlorine type strongly basic anion exchange resin with a strong alkali solution, washing with water until neutral, bromide solution exchange, washing with water to neutral, or The bromide solution is exchanged, if necessary, washed with water to neutrality, and the foregoing operation is repeated at least once to prepare a bromine-type strongly basic anion exchange resin; and the compound of the formula II is ion-exchanged by the bromine-type strongly basic anion exchange resin into a compound of formula I.

 The "chlorine type strong basic anion exchange resin" mentioned in the above method includes: a strongly alkaline quaternary ammonium type I anion exchange resin, such as 201 X 7 (formerly known as 717), 201 X 2 , 201 X 4, etc. . Macroporous strong alkali quaternary ammonium type I anion exchange resin, such as D201; large pore strong alkaline quaternary ammonium type 11 anion exchange resin, such as D202; among them, 201 X 7 is preferred.

 The "strong alkali solution" referred to in the above method includes an aqueous alkali metal hydroxide solution, an alkaline earth metal hydroxide aqueous solution, and a quaternary ammonium alkali aqueous solution. Wherein the aqueous alkali metal hydroxide solution comprises an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like; the alkaline earth metal hydroxide aqueous solution comprises an aqueous solution of calcium hydroxide, barium hydroxide or the like; and the aqueous solution of the quaternary ammonium alkali comprises tetrahydroanhydride An aqueous solution of ammonium, tridecylethylammonium hydroxide, tetrabutylammonium hydroxide, benzyltriethylammonium hydroxide or the like. Alternatively, an appropriate amount of an organic solvent miscible with water such as decyl alcohol, ethanol, propanol, acetone or the like may be added to these aqueous solutions. In these "strong alkali solution", an aqueous solution of sodium hydroxide or potassium hydroxide is preferred, and the mass percentage thereof is generally 0.5 to 30%, preferably 1 to 10%.

The "bromide solution" as referred to in the above method means an aqueous solution of a water-soluble bromide, which includes an aqueous solution of hydrobromic acid, an aqueous solution of an alkali metal bromide, an aqueous solution of an alkaline earth metal bromide, and an aqueous solution of a quaternary ammonium bromide. The alkali metal bromide aqueous solution comprises an aqueous solution of lithium bromide, sodium bromide, potassium bromide or the like; the alkaline earth metal bromide aqueous solution comprises an aqueous solution of magnesium bromide, calcium bromide or the like; and the aqueous solution of the quaternary ammonium bromide comprises tetraammonium bromide An aqueous solution of tridecylethylammonium bromide, tetrabutylammonium bromide, benzyltriethylammonium bromide or the like. Alternatively, an appropriate amount of an organic solvent miscible with water such as decyl alcohol, ethanol, propanol, acetone or the like may be added to these aqueous solutions. Among these "bromide solutions", hydrobromic acid, sodium bromide, and bromination are preferred. 5〜40%优选优选3至15%。 The potassium aqueous solution, their mass percentage concentration is generally 0. 5 ~ 40%, preferably 3 ~ 15%. In the above method, "alternating ion exchange with a strong alkali solution or a bromide solution" means exchange of chloride ions in a chlorine-type strongly basic anion exchange resin with a strong alkali solution to hydroxide ions (that is, exchange for hydrogen) An oxygen-based strongly basic anion exchange resin), and then a bromide solution is used to exchange hydroxide ions in the resin to bromide ions. The exchange process generally involves sequential exchange with a strong base solution, water washing to neutral, bromide solution exchange, and water washing to neutral (if the bromide solution has been neutralized, the water washing operation can be omitted). The process may further comprise pretreating the chlorine-type strongly basic anion exchange resin into a strong basic anion exchange resin of other ion types (such as an acetate type, a citrate type, a trace type strong base anion exchange resin, etc.). The above process of "alternating ion exchange with a strong alkali solution or a bromide solution" is carried out.

 The "ion exchange with a bromide solution" as referred to in the above method means that a chloride ion in a chlorine-type strongly basic anion exchange resin is directly exchanged with a bromide ion by a bromide solution. The exchange process generally involves sequential exchange with bromide solution, water washing to neutral (if the bromide solution has been neutralized, the water washing operation can be omitted). The process may further comprise pretreating the chlorine-type strongly basic anion exchange resin into a strong basic anion exchange resin of other ion types (eg, hydroxide type, acetate type, citrate type, sulfonate type strong base anion). Exchange resin, etc.), and then go through the above process of "ion exchange with a bromide solution".

 The above method "repeating the operation at least once," means repeatedly alternately ion-exchange the resin with a strong alkali solution or a bromide solution for more than one time. The general operation is repeated sequential strong alkali solution exchange, water washing to neutral, The bromide solution is exchanged, washed with water to neutral for 1 to 6 times, preferably 1 to 4 times; or the resin is ion-exchanged for 1 to 6 times with a bromide solution. The general operation is repeated bromide solution exchange, water washing to neutral 1 ~ 6 times, preferably 1 ~ 4 times.

The "exchange" operation referred to in the above method, the manner of exchange includes washing, soaking, etc.; the exchange operation is carried out in accordance with conventional operations in the art. The amount of the "strong alkali solution" used for the exchange is generally 0.5 to 10,000 times, preferably 1 to 50 times the volume of the resin; the amount of the "bromide solution" used for the exchange is generally 0. 5 to 100 times, preferably 1 to 50 times. "Neutral" means the pH of an aqueous solution after washing or soaking the resin is 6-8. The process of "Ion exchange of the compound of the formula II with the bromine-type strongly basic anion exchange resin into the compound of the formula I" generally includes: after dissolving the compound of the formula II in a solvent, the bromine-type strong basic anion exchange The resin was washed with water until the effluent was monitored by TLC with almost no fluorescent coloration. The solvent for dissolving the compound of the formula II in the process generally comprises water or a mixed solvent of water and an organic solvent (for example, decyl alcohol, ethanol, propanol, acetone, etc.) which is miscible with water, preferably water; the compound of the formula II and the strong base of chlorine The weight ratio of the anion exchange resin is generally from 1:2 to 50, preferably from 1:5 to 20. The operations in this process are carried out in accordance with conventional operations in the art.

 05%。 The brominated morphine quaternary ammonium salt, wherein the chloride content of less than 0.1%, other anions (ie, anions other than bromine and chlorine) is less than 0.05%.

 The above method may further comprise: evaporating a part of the solvent containing the formula I after ion exchange through the bromine-type strongly basic anion exchange resin, and then adding an anti-solvent to crystallize. Wherein "distilling part of the solvent" can increase the concentration of the solution and increase the yield of the product; wherein "anti-solvent" means a solvent which is less soluble and soluble in water, such as decyl alcohol, ethanol, propanol, acetone, DMF or the like is preferably decyl alcohol or ethanol.

 Embodiment 1

 5至30%浓度水溶液的水溶液的水溶液之间的水溶液之间的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的优选的的的的的(When the amount of the resin is 0.5 to 100 times), washing with water, to a neutral, 0.5 to 40% aqueous solution of hydrobromic acid (0.5 to 100 times the volume of the resin), water washing To neutral, repeat the operation 1 to 6 times or more, preferably 1 to 4 times, optional, and then soak with 0.5 to 40% sodium bromide or potassium bromide solution (the amount of resin is 0 5 ~ 100 times), washed. Implementation plan two

5至40%的氢氢氢和钠钠和。 In the preparation of the above-mentioned bromine-type strongly basic anion exchange resin, in another embodiment, the method comprises: using a chlorine-type strongly basic anion exchange resin with a concentration of 0.5 to 40% hydrogen bromide, sodium bromide Or washing with potassium bromide solution, washing with water until neutral (if it is neutral, the washing operation can be omitted), repeat the operation 1 ~ 6 times or more, preferably repeat 1 ~ 4 times, optional, 0~40% 溴 Soak in sodium or potassium bromide solution (0.5 to 100 times the volume of the resin) and wash with water. Implementation plan three

 For the preparation of the above bromine-type strongly basic anion exchange resin, in a preferred embodiment, the method comprises: sequentially using a chlorine-type strongly basic anion exchange resin 201X7 with a 1 to 10% aqueous sodium hydroxide solution (amount of resin volume) 1 ~ 50 times) washing, washing with water to neutral, 3 ~ 15% aqueous solution of hydrobromic acid (1 to 50 times the volume of the resin), washing with water to neutral, repeating the operation 2 to 4 times, Optionally, soak it with 3 ~ 15% sodium bromide solution (1~50 times the volume of the resin) and wash it with water. Implementation 4

In a specific embodiment, the above process for the preparation of a compound of formula I according to the invention, wherein the compound of formula II is converted to a compound of formula I by ion exchange, wherein the compound of formula I is a cyclopropenyl group and R ₂ is hydrogen. A is > C = 0, that is, the compound of formula I is bromoquinone ketone (including the quaternary N chiral center configuration is R, S or a mixed configuration thereof); the compound of formula II is cyclopropenyl, R ₂ Is hydrogen, A is > C = 0, X - is iodide, mono-sulphate, sulfonate, benzenesulfonate, p-toluate or their mixed ions with bromide, ie, compound II,

 III

Y in formula III is iodide ion, succinic acid monodecanoate, sulfonate, benzenesulfonate, p-toluene or their mixed ions with bromide ions, and its quaternary N chiral center configuration includes R, S or a mixed configuration thereof, the process comprising: after dissolving the compound of formula III (or formula II) with water, an upper bromine type strong basic anion exchange resin column (prepared according to the above preparation method of the invention, used for preparing the The weight of the chlorine-type strongly basic anion exchange resin of the bromine type strong basic anion exchange resin is 5-20 times that of the compound of the formula III), and the effluent is collected; the resin column is washed with water, and the effluent is collected until the effluent Almost no fluorescence (254 nm) color development by TLC monitoring; this scheme may further include, combined collection The effluent containing bromoquinone ketone is partially evaporated under reduced pressure, cooled and crystallized by adding methanol, filtered, and dried to obtain bromoquinone ketone. 05%。 The content of the anion (ie, an anion other than bromine and chlorine) is less than 0. 05%. Embodiment 5

In a specific embodiment, the above process for the preparation of a compound of formula I according to the invention, wherein the compound of formula II is converted to a compound of formula I by ion exchange, wherein the compound of formula I and the compound of formula II are cyclopropenyl, R ₂ is a hydroxy protecting group, A is > C = 0; in the compound of formula II, X - is iodide ion, monodecyl sulfate, sulfonate, benzenesulfonate, p-toluenesulfonate or a mixed ion thereof with bromide At this time, the formula I,

 IV V

In the formula IV and formula V, ₁₅ is a hydroxy protecting group, including an alkyl group such as a benzyl group, a decylbenzyl group or the like; an acyl group such as a decanoyl group, an acetyl group, an alkoxycarbonyl group or the like; a silane group such as a trimethyl silane Base, tert-butyldimercaptosilyl, tert-butyldiphenylsilyl, triisopropylsilyl, etc.; in formula V, Y- is iodide, monodecyl sulfate, sulfonate, benzenesulfonate , p-toluenesulfonate or a mixed ion thereof with bromide; the quaternary N chiral center configuration of formula IV and formula V includes R, S or a mixed configuration thereof, the process comprising: formula V (or formula II) After the compound is dissolved in water, the upper bromine type strong basic anion exchange resin column (the weight of the chlorine type strong basic anion exchange resin used for preparing the bromine type strong basic anion exchange resin prepared by the above preparation method of the present invention) Ion exchange for 5 to 20 times of the compound of formula V (or formula II); wash the resin column with water, collect the effluent, until the effluent is almost free of fluorescence (254 nm) by TLC, and the chloride content of the obtained product Less than 0.1%, other anions (ie, yin other than bromine and chlorine) The content of the sub-) is less than 0.05%; the solution may further comprise: collecting the effluent containing the compound of the formula IV, distilling off part of the water under reduced pressure, and cooling the crystal by adding decyl alcohol or ethanol to obtain the formula IV (or I) a compound; The compound of formula IV (or formula I) can be deprotected by hydrobromic acid hydrolysis or hydrogenolysis to obtain bromoquinone ketone.

Implementation plan six

 In a specific embodiment, the above process for the preparation of a compound of formula I according to the invention, wherein the compound of formula II is converted by ion exchange to a compound of formula I, a compound of formula I and a compound of formula II wherein c, 3

Is a cyclopropenyl group, R ₂ is a hydroxy protecting group, A is z o- ^R ₄ , wherein R ₃ and R _{4 together} form a phenyl group (-CH ₂ CH −); in the compound of formula II, X—is an iodide ion, a monoterpene sulphate, an oxime sulfonate, a benzoate, a p-benzoate or a mixed ion thereof with a bromide ion, wherein the compound of the formula I and the compound of the formula II are the compounds represented by the formula VI and the formula VI, respectively.

 VI VII

R ₅ and Y— in formula VI and formula VII are as defined above; the quaternary N chiral center configuration in formula VI and formula VII includes R, S or a mixed configuration thereof, the process comprising: formula VII (or formula II) After the compound is dissolved in water, the upper bromine type strong basic anion exchange resin column (the weight of the chlorine type strong basic anion exchange resin used for preparing the bromine type strong basic anion exchange resin prepared by the above preparation method of the present invention) Ion exchange for 5 to 20 times of the compound of formula VII (or formula II), collect the effluent; wash the resin column with water, collect the effluent, until the effluent is almost free of fluorescence (254 nm) by TLC monitoring, the resulting product The content of chloride in the medium is less than 0.1%, and the content of other anions (ie anions other than bromine and chlorine) is less than 0.05%; the solution may further comprise, in combination, collecting the effluent containing the compound of formula VI (or formula I), minus Pressing part of the water under pressure, cooling and crystallization by adding methanol or ethanol to obtain a compound of formula VI (or formula I); the compound of formula VI (or formula I) can be deprotected by hydrobromic acid hydrolysis or hydrogenolysis to obtain bromine Naltrexone. The compound of the formula III, the compound of the formula V and the compound of the formula VI I in the present invention can be produced by referring to the method described in U.S. Patent No. 4,176,186, WO200627899, and CN101607963.

 The type and classification of the ion exchange resin referred to in this specification can be found in the definition given in GB1631-79 of the National Standard of the People's Republic of China, Classification, Nomenclature and Model of Ion Exchange Resin.

 The "chlorine type" in the chlorine type strong basic anion exchange resin of the present invention means that the anion in the resin is substantially chloride ion, and the "bromine type" in the bromine type strong basic anion exchange resin means that the anion in the resin is basically Bromide ion, hydroxide type means that the anion in the resin is a hydroxide ion.

 In the present invention, the determination of the chloride content and other anion contents is generally carried out in a limited manner, and their determination methods are generally carried out in accordance with the Chinese Pharmacopoeia method after the interference of bromine is excluded.

 The brominated morphine quaternary ammonium salt of the present invention, such as bromoquinone sulphate, as a clinically applied drug, the limit of the other ions should be strictly limited, for example, the chloride content of the drug is generally limited to 0.1. 5%以下以下。 The iodine ion limit is generally limited to 0. 05% or less. The raw materials provided by the prior art are not easy to obtain, and the handleability is poor, and it is not easy to produce bromo-halopentone which meets the medicinal standard. The present invention provides a brominated morphine such as bromine naltrexone by ion exchange of a morphine quaternary ammonium salt including a quinone naltrexone mixed anion compound using an inexpensive commercial product chlorine type strong basic anion exchange resin. A method of quaternary ammonium salt, which can effectively remove other anions in the quaternary ammonium salt of morphinan, and can effectively control the introduction of the original chloride ion in the resin, thereby ensuring the quality of the prepared product.

 Therefore, the preparation method of the bromomorphinium quaternary ammonium salt including the bromoquinone ketone provided by the invention not only effectively solves the deficiencies in the prior art, but also has easy availability of raw materials, operation cylinder, and controllability. Strong, suitable for industrial production, is an improved preparation method of brominated morphinan quaternary ammonium salt. Detailed ways

 The following examples are intended to provide a fuller understanding of the invention, but are not intended to limit the invention in any way.

 Example 1

 Preparation of bromine-type strong basic anion exchange resin

The THF of the 201 X 7 type resin was washed with water until the effluent was neutral; washed with about 3. L of a 3.8% aqueous sodium hydroxide solution, and then washed with water until the effluent was neutral; 7.6% aqueous hydrobromic acid solution was used. About 3L Wash and wash with water until the effluent is neutral. 5的洗洗进行进行进行进行。 After the above sodium hydroxide washing, washing to neutral, hydrobromic acid washing, water washing to neutral process 3 times; followed by adding 10% sodium bromide aqueous solution about 3.5 L washing and soaking for more than 12h, and then purified After washing with water, a strong basic anion exchange resin of bromine type is obtained. Example 2

 Preparation of bromine naltrexone

 The guanidinolone iodine/bromide 14.6 g was dissolved in 146 ml of purified water, and added to the column of the bromine-type strong basic anion exchange resin of Example 1, and eluted with purified water, and the effluent was monitored by TLC. The collection was stopped after no fluorescence (254 nm) color development. The collected effluent was concentrated under reduced pressure until a solid precipitated. The decyl alcohol was added while hot, stirred, and then cooled to crystallize at room temperature, filtered, and dried to give bromoquinone. 01%。 I. Iodide: less than 0. 02%. Example 3

 Preparation of bromine-type strong basic anion exchange resin

 200 g of 201 X 7 resin was washed with water until the effluent was neutral; washed with about 2 L of 2% aqueous sodium hydroxide solution, and washed with water until the effluent was neutral; washed with about 4 L of 4% hydrobromic acid aqueous solution, Wash again with water until the effluent is neutral. The above sodium hydroxide washing, washing with water to neutral, hydrobromic acid washing, and washing to neutral were repeated 3 times. After the treatment, it is washed with about 5% aqueous solution of 5% sodium hydroxide, and then washed with purified water until the effluent is neutral; washed with about 4 L of 4% aqueous hydrobromic acid solution, and then washed with purified water until the effluent is in the middle. The bromine-type strong basic anion exchange resin is obtained by adding 5% sodium bromide aqueous solution to about 0.5 L and washing for 6 hours or more, followed by washing with purified water. Example 4

 Preparation of bromine naltrexone

40 g of guanidinolone iodide was dissolved in 450 ml of purified water, and added to the column of the bromine-type strong basic anion exchange resin of Example 3, and eluted with purified water. When the effluent was monitored by TLC, there was almost no fluorescence (254 nm). ) Stop collecting after color development. The collected effluent is concentrated under reduced pressure, and decyl alcohol is added while hot, and the crystal is cooled and crystallized. Filtered and dried to obtain bromoquinone ketone. The content of the iodide: less than 0. 05%. Example 5

 Preparation of bromine-type strong basic anion exchange resin

 40 g of 201 X 7 type resin was washed with about 10 ml of 10% aqueous sodium hydroxide solution, and washed with water until the effluent was neutral; washed with about 15 ml of 15% aqueous hydrobromic acid solution, and washed with water until the effluent was neutral. . The above-mentioned sodium hydroxide washing, water washing to neutral, hydrobromic acid washing, and water washing to neutral were repeated once to obtain a bromine-type strongly basic anion exchange resin. Example 6

 Preparation of S-bromoindanac

 2 g of S-quinone naltrexone iodide was dissolved in 40 ml of purified water, and added to the column of the bromine-type strong basic anion exchange resin of Example 5, eluted with purified water, and the effluent was almost non-fluorescent by TLC monitoring. The collection was stopped after (254 nm) color development. The collected effluent was concentrated to dryness under reduced pressure, and cooled to give S-bromo- naltrexone. Content: 99. 7%, chloride: less than 0.1%, iodide: less than 0. 05%. Example 7

 4 g of guanidinolone iodide was dissolved in 40 ml of purified water, and then added to the column of the bromine-type strong basic anion exchange resin of Example 5, and eluted with purified water. When the effluent was monitored by TLC, almost no fluorescence was observed. The collection was stopped after (254 nm) color development. The collected effluent was concentrated under reduced pressure, and decyl alcohol was added while hot, cooled and decrystallized, filtered, and dried to obtain bromo-halothrone. 5%。 I. Iodide: less than 0. 05%.

 Comparative example

40 g of 201 X 7 type resin was washed with about 10 ml of 10% aqueous sodium hydroxide solution, and washed with water until the effluent was neutral; washed with about 15 ml of 15% aqueous hydrobromic acid solution, and washed with water until the effluent was neutral. , a bromine-type strong basic anion exchange resin. 0克的曱素纳纳纳曲酮 Iodide 4. 0g purified 40 ml of water was dissolved, and the column was added to the bromine-type strongly basic anion exchange resin column, and eluted with purified water. The effluent was stopped after TLC monitoring with almost no fluorescence (254 nm). The effluent is more than 0.1%. The chloride is found to be greater than 0.1%. Example 7

 Preparation of bromine-type strong basic anion exchange resin

 20 g of a 201 X 7 type resin was washed with water until the effluent was neutral, washed with 1 L of a 35% aqueous sodium bromide solution, and washed with water. The above procedure was repeated 4 times to obtain a bromine-type strongly basic anion exchange resin. Example 8

 Preparation of (isobutyryl)-17-(cyclopropenyl) _4, 5a-epoxy _14_hydroxy-6_N_mercaptomorphinan bromide

 2 g (isobutyryloxy) -17-(cyclopropenyl) _4, 5a-epoxy_14_hydroxy-6_N_decylmorphinan iodide 2 g was dissolved in 20 ml of purified water, and applied to the examples. The column of the bromide ion exchange resin of 7 was eluted with purified water, and the collection was stopped when the effluent was almost fluorescent-free (254 nm) developed by TLC. The effluent of the collected effluent is concentrated to a solid, and the ethanol is added to the mixture, and the mixture is stirred at room temperature to obtain a target product, wherein the chloride is less than 0.1%. Example 9

 Preparation of bromine naltrexone

 The compound prepared in Example 8 was added with 1 ml of water, 5 ml of ethanol and 1 ml of 48% hydrobromic acid, and the mixture was heated under reflux for 4 hours. After completion of the reaction, the mixture was cooled in an ice water bath to obtain crystals of bromoquinone. Example 10

3-[(tert-Butyldimercaptosilyl)oxy]-17-(cyclopropenyl)-4,5a-epoxy-14-hydroxy_6_ (1,3-dioxolane-2 - Preparation of -N-mercapto-morphinan bromide 3_[(tert-Butyldimercaptosilyl)oxy]-17-(cyclopropenyl)_4,5a-epoxy-14-hydroxy-6-(1,3-dioxolan-2- -N-decylmorphinan iodide was applied to the bromine-type strong basic anion exchange resin column prepared in Example 7, and eluted with purified water. When the effluent was monitored by TLC, almost no fluorescence (254 nm) was observed. Stop collecting after coloring. The collected effluent was concentrated under reduced pressure until a solid precipitated, and decyl alcohol was added while hot, and the mixture was stirred and cooled at room temperature to obtain a target. Example 11

 Preparation of bromine naltrexone

 The compound prepared in Example 10 was added with 2 ml of water, 8 ml of decyl alcohol and 2 ml of 48% hydrobromic acid, and the reaction was heated at 50 to 60 ° C for 3 hours. After the completion of the reaction, the mixture was cooled in an ice water bath to obtain bromoquinone ketone. . Example 12

 20 g of the D201 type resin was washed with water until the effluent was neutral, washed with 1 L of a 35% aqueous sodium bromide solution, and washed with water. The above procedure was repeated 4 times to obtain a bromine-type strongly basic anion exchange resin. 4. Og of guanidinolone iodide was dissolved in 40 ml of purified water, and then added to the column of the bromine-type strong basic anion exchange resin, and eluted with purified water. When the effluent was monitored by TLC, almost no fluorescence (254 nm) was observed. Stop collecting after coloring. The effluent of the collected effluent is concentrated under reduced pressure, and the hydrazine is added to the decyl alcohol, and the crystallization is carried out by cooling, crystallization, filtration, and drying to obtain bromoquinone naltrexone, wherein the chloride: less than 0.1%.

 The above is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims

Rights request A method for preparing a compound of the formula I, which comprises subjecting a chlorine-type strongly basic anion exchange resin to ion exchange with a strong alkali solution or a bromide solution or ion exchange with a bromide solution, and repeating the operation at least 1 a bromine-type strongly basic anion exchange resin; and a compound of the formula II is subjected to the bromine-type strong basic I compound,

 I I I Wherein, A and R _{1 3⁄4} R ₂ in formula I and formula II have the same definition.  ^ is a hydrocarbon group, including a mercapto group, an ethyl group, an allyl group or a cyclopropenyl group; R ₂ is a hydroxy protecting group or hydrogen, wherein the hydroxy protecting group includes an alkyl group, an acyl group, a silane group; X- is a single anion or a mixed anion, including a fluoride ion, a chloride ion, an iodide ion, a nitrate, a sulfuric acid single Tert-ester, sulfonate, trifluorosulfonate, benzoate, p-toluenesulfonate, etc. or mixed ions thereof, and their mixed ions with bromide ions;  \ 0 A is / ^C - ^Q , / ^C - ^S , / ^C - ^C3⁄4 , ^oR ₄ , wherein R ₃ and R 4 are each independently a lower hydrocarbon group and an aromatic hydrocarbon group. 2. The method of claim 1 wherein is a cyclopropenyl group; R ₂ is hydrogen; and A is > C = 0. 3. The method of claim 1, wherein is a cyclopropenyl group; R ₂ is a hydroxy protecting group; and A is > C = 0. 4. The method of claim 1 wherein is a cyclopropenyl group; R ₂ is a hydroxy protecting group; A \ ,0 C, ^R 3 Is z, o- R ₄ , wherein R ₃ and R 4 together form an ethylene group. The method according to any one of claims 1 to 4, wherein said chlorine type strong basic anion exchange resin It is a strong alkaline quaternary ammonium type I anion exchange resin, a macroporous strong alkaline quaternary ammonium type I anion exchange resin, a macroporous strong alkaline quaternary ammonium type II anion exchange resin; a strong alkali solution is sodium hydroxide or hydrogen An aqueous solution of potassium oxide; the bromide solution is an aqueous solution of hydrobromic acid, sodium bromide or potassium bromide.  6. The method according to claim 5, wherein said chlorine type strong basic anion exchange resin is a strongly basic quaternary ammonium type I anion exchange resin; said sodium hydroxide or potassium hydroxide aqueous solution has a mass percent concentration 5〜40%。 The mass concentration of the aqueous solution of the hydroquinic acid, sodium bromide or potassium bromide is 0. 5 ~ 40%.  7. The method according to claim 6, wherein the chlorine type strong base anion exchange resin is 201 7 type; the sodium hydroxide or potassium hydroxide aqueous solution has a mass percentage of 1 to 10%; hydrogen The aqueous solution of bromic acid, sodium bromide or potassium bromide has a mass concentration of 3 to 15%.  8. The method according to any one of claims 1 to 4, wherein the process of alternately performing ion exchange with the strong alkali solution or the bromide solution further comprises sequentially exchanging with a strong alkali solution, washing with water until neutral, bromide solution exchange, washing with water. To neutral, repeat the operation 1 to 6 times.  The method according to any one of claims 1 to 4, wherein the ion exchange using the bromide solution further comprises exchanging the bromide solution sequentially, washing with water to neutrality, and repeating the operation for 1 to 6 times.  The method according to any one of claims 1 to 4, wherein the weight ratio of the compound of the formula II to the chlorine-type strongly basic anion exchange resin is from 1:2 to 50.  11. The method of claim 1 further comprising the formula I obtained after ion exchange