WO2016041508A1 - 一种噁唑烷酮类化合物及其中间体的制备方法 - Google Patents

一种噁唑烷酮类化合物及其中间体的制备方法 Download PDF

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WO2016041508A1
WO2016041508A1 PCT/CN2015/089839 CN2015089839W WO2016041508A1 WO 2016041508 A1 WO2016041508 A1 WO 2016041508A1 CN 2015089839 W CN2015089839 W CN 2015089839W WO 2016041508 A1 WO2016041508 A1 WO 2016041508A1
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compound
formula
group
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iodine
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袁建栋
陈耀
杭文明
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博瑞生物医药技术(苏州)有限公司
信泰制药（苏州）有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C219/06—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having the hydroxy groups esterified by carboxylic acids having the esterifying carboxyl groups bound to hydrogen atoms or to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • 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
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of medicinal chemical synthesis, in particular to a preparation method of an oxazolidinone compound and an intermediate thereof.
  • Oxazolidinones are widely used as a class of chemical ingredients in the preparation of drugs for the treatment and prevention of medical diseases such as bacterial infections and atherosclerosis.
  • Various structures of the oxazolidinone derivatives are known, for example, in U.S. Patent No. 4,461,773, U.S. Patent 4,476,136, U.
  • Tedizolid is a new class of oxazolidinone antibiotics. Its tedizolid phosphate has been approved by the FDA for the treatment of Staphylococcus aureus (including methicillin-resistant strains, methicillin-sensitive strains). Acute bacterial skin and skin structure infections (ABSSSI) caused by Gram-positive bacteria such as Streptococcus and Enterococcus faecalis. The structural formula of ticlopamide is shown in the following formula TD.
  • the method first replaces the hydrogen atom on the phenyl group of the hydroxymethyl oxazolidinone derivative (II) with a halogen atom to form the derivative (III); then, a palladium catalyst is added to make the derivative (III) and hexamethylditin. Or substituted with tributyltin hydride to form derivative (IV), the yield of this step is about 61%; in the third step, the derivative (IV) is reacted with a pyridine derivative substituted by bromine or iodine under a palladium catalyst condition. An oxazolidinone derivative (V) having a pyridine ring is produced.
  • This method produces tertazole, requires two palladium catalysts, and the third step consists of (R)-3-(4-tributyltinyl-3-fluorophenyl)-2-oxo-5-
  • the reaction of oxazolidinemethanol with 2-(2-methyltetrazol-5-yl)-5-bromopyridine to form desadizolamide yields only 26%.
  • the whole route has high cost and low yield, and is not suitable for industrial production; on the other hand, the method involves a synthetic route of organotin coupling, which easily leads to residual tin in the final product, and is not suitable for preparation of a medicine.
  • Y is from ZnCl, BF 3 and BR 3 R 4 , wherein R 3 and R 4 are independently selected from OH and optionally substituted C 1 -C 6 mono and diol, wherein R 3 and R 4 together may be ring.
  • terthadiazole TD
  • the purity and yield of the intermediate 3 prepared in the first step reaction are both low (HPLC: 89.8%, yield: 66%); the last step of the coupling reaction, using a strong base (lithium hexamethyldisil) leads to the vice
  • the reaction is much, the introduction of impurities is more, the post-treatment is difficult, the operation is cumbersome; the final one-step reaction time is long, the prepared terthazolamide has low purity, requires multiple purifications, and the operation is cumbersome, and the Pd residue remains high after purification; An anhydrous solvent is required, which is not suitable for industrial production.
  • the object of the present invention is to provide a method for preparing an oxazolidinone compound which is low in production cost, simple in operation, high in yield and purity, short in reaction time, and suitable for industrial production, and particularly relates to a method for preparing medizolamide.
  • the present invention provides the following technical solutions:
  • R is hydrogen or a hydroxy protecting group
  • one of L and R 1 is a leaving group and the other is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from OH and optionally substituted C 1 A group consisting of -C 6 monohydric and diol, wherein R 2 and R 3 together may form a ring; optionally, the hydroxy protecting group R of the compound of TD-1 is removed to form a compound represented by TD.
  • R 1 is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from 1-6 and optionally substituted C 1 -C 6 mono- and diols A group consisting of wherein R 2 and R 3 together may form a ring.
  • priority L is BF 3 or BR 2 R 3 , wherein R 2 and R 3 are independently selected from the group consisting of OH and optionally substituted C 1 -C 6 mono- and diols, wherein R 2 Together with R 3 can form a ring and R 1 is a leaving group.
  • the leaving group includes a halogen such as chlorine, bromine, iodine, a sulfonyloxy group such as a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group, a benzenesulfonyloxy group, or one or more substituents.
  • a substituted benzenesulfonyloxy group, the substituent being selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 alkoxy; preferably the leaving group is chlorine, bromine, iodine; more preferably The deactivating group is bromine or iodine.
  • R is hydrogen or a hydroxy protecting group
  • the hydroxy protecting group comprises: an alkyl group, an acyl group, an alkyl silicon group, preferably the hydroxy protecting group is a benzyl group, substituted by one or more substituents. a benzyl group, a C 1-4 alkyl acyl group, or a trimethylsilyl group selected from the group consisting of a C 1-6 alkyl group, a C 1-6 alkoxy group, and a halogen.
  • R is hydrogen, benzyl, p-methylbenzyl, acetyl, propionyl, or butyryl.
  • BR 2 R 3 is preferably B(OH) 2 or
  • L is bromine or iodine
  • R 1 is BF 3 , B(OH) 2 or
  • the preparation method of the compound represented by the formula TD is as follows:
  • the compound of formula I is reacted with a compound of formula II, preferably under the catalytic conditions of a palladium catalyst, such as sodium carbonate, carbon
  • a palladium catalyst such as sodium carbonate, carbon
  • the reaction is carried out under the environment of potassium acid, sodium hydroxide or potassium hydroxide, and the solvent is preferably toluene, THF, DMF, DMSO, dioxane, isopropanol or ethanol, and the reaction temperature is about 60 to 80 ° C, and the coupling is carried out.
  • the compound TD-1 (R is a hydroxy protecting group) or TD (R is hydrogen) is obtained; optionally, the compound TD-1 is deprotected from the hydroxy protecting group R to give the compound TD.
  • R 1 is BF 3 , B(OH) 2 or It can be prepared as follows:
  • the boric acid compound IIa can also be obtained by a method disclosed in "Suzuki-coupled reaction of palladium-catalyzed pyrimidine chloroform with pyridine borate" (Xiao Wenjing, 2011-Zhengzhou University: Medicinal Chemistry, Master Thesis).
  • a diborate such as a dipinacol of diboric acid
  • a halogenated hydrocarbon ii
  • the resulting boronic ester IIb can be hydrolyzed in acid water to be boric acid IIa; trifluoroboric acid
  • the derivative IIc can be formed by reacting IIa with KF and/or KHF 2 ; or the trifluoroboric acid derivative IIc by formula ii with a boronic ester (such as triisopropyl borate) under basic conditions (such as n-butyllithium)
  • the solvent is preferably THF, which is formed by the formation of triisopropyl lithium borate and then reacted with KHF 2 .
  • the IIa can be obtained by the method shown in the following reaction formula:
  • the compound of the formula (1-4) can be obtained by the method disclosed in CN1894242B, the disclosure of which is incorporated herein by reference.
  • a compound of the formula IIa is prepared by reacting a compound of the formula (II) with a boronic acid ester compound under conditions of strong basicity (such as n-butyllithium), preferably a reaction solvent of THF, and a reaction temperature. It is about -70 ° C ⁇ -65 ° C.
  • priority R 1 is bromine or iodine
  • L is BF 3 , B(OH) 2
  • the preparation method of the compound represented by the formula TD is as follows:
  • the compound of the formula I is reacted with a compound of the formula II, preferably under the catalytic conditions of a palladium catalyst, the solvent is preferably DMF, and the reaction temperature is about 60 to 80 ° C to prepare the compound TD-1 (R is a hydroxy protecting group) or TD (R is hydrogen), optionally, the compound TD-1 is deprotected from the hydroxy protecting group R to give the compound TD.
  • the intermediate compound of formula I is preferably under the catalytic conditions of a palladium catalyst, the solvent is preferably DMF, and the reaction temperature is about 60 to 80 ° C to prepare the compound TD-1 (R is a hydroxy protecting group) or TD (R is hydrogen), optionally, the compound TD-1 is deprotected from the hydroxy protecting group R to give the compound TD.
  • L is BF 3 , B(OH) 2 or
  • the preparation method is similar to the preparation method of the compound of the above formula II when R 1 is a boric acid ester or BF 3 , and the specific reaction formula is as follows:
  • X is chlorine, bromine or iodine; and R is hydrogen, benzyl, p-methylbenzyl, acetyl, propionyl or butyryl. Still more preferably, X is bromine or iodine and R is hydrogen.
  • the L is bromine or iodine
  • the R is hydrogen
  • the reaction is preferably carried out under catalytic conditions of a palladium catalyst, preferably a solvent, DMF, a reaction temperature of about 60 to 80 ° C, preferably a reaction temperature of 70 ° C.
  • a palladium catalyst preferably a solvent, DMF
  • a reaction temperature of about 60 to 80 ° C, preferably a reaction temperature of 70 ° C.
  • the halogen of the present invention includes fluorine, chlorine, bromine, and iodine;
  • the alkyl group includes a linear or branched alkyl group (e.g., ethyl, isopropyl, etc.), and an aryl-substituted alkyl moiety (e.g., benzyl, etc.) ).
  • the compound of the formula I and the compound of the formula IIa are preferably subjected to a coupling reaction under the catalytic conditions of a palladium catalyst
  • the reaction solvent is dimethylformamide (DMF) ), 1-methyl-2-pyrrolidone, tetrahydrofuran (THF), toluene, dimethyl sulfoxide, toluene, isopropanol, ethanol, etc., at a temperature of about 60 ° C to 150 ° C.
  • R is a hydroxy protecting group
  • the protecting group R is removed according to the conventional method for dehydroxy protecting groups in the art to give a compound of the formula TD.
  • the reaction solvent is preferably THF, methanol, toluene or hexane; etc.
  • R is an alkyl silicon group (such as trimethylsilyl), it is preferred to remove the alkylsilyl protecting group in an organic solvent under acidic conditions (such as HCl-MeOH, HCl-dioxane system, or AcOH-THF system);
  • R is When the alkyl acyl group (acetyl group, propionyl group, butyryl group, etc.) is selected, it can be subjected to hydrolysis and removal under acid-washing or alkaline conditions, for example, under the condition of sodium meth
  • the invention provides a process for the preparation of a compound of formula I, preferably wherein L is chlorine, bromine or iodine, which is converted from a compound of formula III with carbonyldiimidazole,
  • the reaction solvent is preferably dichloromethane, DMF, isopropanol or THF, and the reaction temperature is about 25 to 40 °C.
  • a protecting group-free compound I and a hydroxy protecting group for example, benzyl chloride, p-methylbenzyl chloride, a C1-6 alkyl carboxylic acid, dimethyl tert-butyl silicon chloride, trimethylsilyl chloride or dimethyl t-butyl silicon chloride, etc., to obtain a compound I corresponding to R as a hydroxy protecting group;
  • R is hydrogen, benzyl, p-methylbenzyl, acetyl, propionyl, butyryl, dimethyl tert-butyl chloride, trimethylsilyl chloride or dimethyl t-butylsilyl chloride.
  • the compound of formula III is a compound of formula IV.
  • the method of the present invention further comprises the use of the method of the present invention to prepare a compound of the formula TD, with POCl 3 , POCl (OBn) 2 or P(N-iPr 2 ) (O-tBu). 2 )
  • the compound represented by TD-P is formed under the reaction conditions.
  • the method further comprises reacting a compound with TD-P under a reaction condition to form a compound represented by the following formula TD-PN.
  • M is a pharmaceutically acceptable salt of PO(OH) 2 .
  • pharmaceutically acceptable salt refers to a salt formed from a suitable biocompatible cation and/or anion.
  • the cations include metal element cations such as sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, and organic nitrogen-containing base quaternary ammonium cations including metal element cations such as N,N-dibenzylethylenediamine. Chlorprocaine, choline, diethylalcoholamine, ethylenediamine, procaine and N-methylglucamine.
  • the anion includes an anion of a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, Malay. Acid, tartaric acid, citric acid, palmitic acid, malonic acid, hydroxymalonic acid, phenylacetic acid, glutamic acid, benzoic acid salicylic acid, toluenesulfonic acid, malic acid and the like.
  • the base is a sodium-containing base, preferably the M is PO 3 Na 2 .
  • the present invention provides a compound of the formula
  • L is bromine or iodine.
  • Step 1) 4-bromo-3-fluoroaniline and benzyl chloroformate are reacted under basic conditions (such as sodium hydrogencarbonate) to prepare benzyl carbamate compound (1-7); step 2) benzyl group
  • the carbamate compound (1-7) is reacted with butyl glycidate under strong basic conditions (such as n-butyl lithium) to obtain a compound of the formula (1-9); finally, the reaction is selected according to the difference of X.
  • the compound of the formula (1-9) is converted to the compound of the formula i' under the conditions.
  • a compound of formula i' is reacted with a hydroxy protecting agent to provide a compound containing a hydroxy protecting group R.
  • the compound represented by the formula (1-9) is reacted with a halogenating agent (such as ICl/CF 3 COOAg, BrCl/CF 3 COOAg), preferably a solvent.
  • a halogenating agent such as ICl/CF 3 COOAg, BrCl/CF 3 COOAg
  • the compound of formula i' is prepared by reaction at room temperature for acetonitrile.
  • the halogen X in the compound I' can be converted into a methanesulfonic anhydride group by a conventional method in the art, and then a compound TD can be obtained by a coupling reaction with the compound IIa.
  • the "hydroxy protecting agent” means a reagent capable of reacting with a hydroxyl group to form an ester protecting group, a silyl ether protecting group, an alkyl ether protecting group, for example, a hydroxyl group capable of reacting with a hydroxyl group to form an ester protecting group.
  • Protecting agents including but not limited to, formic acid, acetic acid, butyric acid, propionic acid, etc.; the hydroxy protecting agent forming a silyl ether protecting group, including but not limited to, trifluoromethylsilyl, trimethylsilyl, Dimethylphenylsilyl, dimethyl-tert-butylsilyl, etc.; a hydroxy protecting agent capable of forming an alkyl ether with a hydroxyl group, including, but not limited to, a benzyl group, a p-methylbenzyl group, and the like.
  • TD- 1 is the same structure as TD, then TD-1 does not need to further remove the hydroxy protecting group to prepare TD; when R is benzyl or silicon protecting group, compound I reacts with compound II to obtain compound TD-1 first, then need to choose Further, the hydroxy protecting group R in TD-1 was removed to prepare TD.
  • the present invention provides a novel synthesis method of teridazole (TD), which has significant technical effects compared with the prior art.
  • the raw materials used in the present invention are readily available, and the method used in the present invention is used.
  • the compound represented by I can be obtained by various methods, and the yield is high; the compound of the formula II used in the invention is simple in preparation and easy to obtain;
  • the compound represented by the formula I and the formula II are The compound was coupled to prepare tertazole (compound TD), the yield was significantly improved (not less than 87%), and the reaction time was remarkably shortened.
  • the method provided by the invention has the advantages that the reagents used are easy to obtain, the cost is low, and the prepared intermediates are all solid, and the post-treatment is simple.
  • the inventors have found that, especially when L in the compound I is a halogen, especially bromine or iodine, and R 1 in the compound II is B(OH) 2 , or when L in the compound I is B(OH) 2 And when R 1 in the compound II is a halogen, particularly bromine or iodine, when the compound TD (tedizamide) is prepared by the Suzuki reaction of the compound I and the compound II, the charge ratio is more easily controlled, the reaction yield is higher, and the reaction The material is more stable and easy to store, and its synthesis method is simpler.
  • the compound TD-1 (the hydroxy protecting group R is a benzyl group) is prepared by reacting the compound (I-3) with the compound IIa.
  • the compound (I-2) is reacted with IIa in the same manner as in the preparation of the compound TD-1 (R is positive). Butyryl) method.
  • step (3) (R)-3-(4-iodo-3-fluorophenyl)-2-oxo-5-oxazole alkylmethanol, trifluorobenzene in acetonitrile Silver acetate and iodine monochloride are substituted at the 4-position iodine of the benzene ring to obtain a compound of the formula (1-9) in which the 4-position is substituted with iodine and the oxazolidinone hydroxy group is protected by a benzyl group, and then the procedure of Example 1 is followed.
  • the compound (70.0 g, 0.189 mol), THF (1.4 L, 20 vol) and triethylamine (58.2 g, 0.575 mol) were added to the flask.
  • the slurry was stirred and the jacket temperature was set to 0 °C.
  • To the additional funnel was added phosphorus oxychloride (87.0 g, 0.567 mol) dissolved in THF (70 mL, 1 volume). When the internal temperature reached 1 ° C, the POCl 3 solution was added dropwise over 44 min. The mixture was stirred at 1-2 ° C for 3 hours.
  • the tertidamine phosphate (30.0 g) prepared in Example 9 was added to a 1 L reactor, methanol (360 mL) was added, the slurry was stirred at room temperature, and 25% sodium methoxide in methanol (43.1 g) was added dropwise at 10 min. ) solution. The slurry was stirred at room temperature for 1 h and then filtered. The reactor and filter cake were rinsed with methanol (150 mL) and acetone (150 mL). The product was dried in a vacuum oven at 50-60 ° C to give 32.6 g of crude teridazolidinium phosphate disodium salt.
  • the crude product was dissolved in water (325 mL), activated carbon was added and stirred at room temperature for 30 min. 2N NaOH adjusted the pH of the slurry to 11. The slurry was filtered through celite and the filtrate was re-filtered on 0.45.

Abstract

提供一种噁唑烷酮类化合物及其中间体的制备方法。具体地，采用Suzuki反应，将两个片段进行偶联，制备噁唑烷酮类化合物。该方法工艺简单，反应时间短，收率高，适合工业化生产。并且，提供的噁唑烷酮类化合物中间体的制备方法具有操作简单，收率高，成本低的优点。

Description

一种噁唑烷酮类化合物及其中间体的制备方法 技术领域
本发明涉及药物化学合成领域，具体涉及一种噁唑烷酮类化合物及其中间体的制备方法。
背景技术
噁唑烷酮作为一类化学成分在制备治疗和预防比如细菌感染和动脉粥样硬化的医学疾病的药物中有广泛的应用。噁唑烷酮衍生物的各种结构已公知，例如US4461773，US4476136，US4250318等中公开了3-苯基-2-噁唑烷酮的单取代或二取代衍生物。
泰地唑胺(Tedizolid)是一种新型噁唑烷酮类抗菌素，其磷酸盐(tedizolid phosphate)已经获得FDA批准用于治疗金黄色葡萄球菌(包括耐甲氧西林菌株，甲氧西林敏感菌株)和各种链球菌属和粪肠球菌等革兰氏阳性细菌引起的急性细菌性皮肤和皮肤结构感染(ABSSSI)。泰地唑胺结构式如下式TD所示，
Figure PCTCN2015089839-appb-000001
化学名：(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)-3-氟苯基)-5-羟甲基噁唑烷-2-酮。
中国专利CN102516238A和CN102702184A公开了泰地唑胺及磷酸泰地唑胺通式化合物的制备方法，如反应式(1)：
Figure PCTCN2015089839-appb-000002
Figure PCTCN2015089839-appb-000003
该方法先用卤素原子取代羟甲基噁唑烷酮衍生物(II)的苯基上的氢原子，生成衍生物(III)；然后加入钯催化剂使衍生物(III)与六甲基二锡或三丁基氢化锡取代，生成衍生物(IV)，该步收率约61％；第三步，使衍生物(IV)在钯催化剂条件下与由溴或碘取代的吡啶衍生物反应，生成具有吡啶环的噁唑烷酮衍生物(V)。该方法制备泰地唑胺，需要两次用到钯催化剂，并且第三步反应由(R)-3-(4-三丁基锡基-3-氟苯基)-2-氧代-5-噁唑烷基甲醇与2-(2-甲基四唑-5-基)-5-溴吡啶反应生成泰地唑胺，收率仅能达到26％。整条路线成本高，收率低，不适合工业化生产；另一方面，本方法涉及有机锡偶联的合成途径，容易导致终产品中锡的残留，不适合制备成药。
US8604209B2公开了如下反应式(2)所示的泰地唑胺的制备方法：
Figure PCTCN2015089839-appb-000004
其中Y为自ZnCl、BF3和BR3R4，其中R3和R4独立地选自OH和任意取代的C1-C6一元和二元醇，其中R3和R4在一起可以成环。
该方法先将化合物1与化合物2进行偶联反应后，将得到化合物3在碱性条件下与缩水甘油丁酸酯反应，生成泰地唑胺(TD)。其中，第一步反应制备的中间体3纯度和收率均较低(HPLC：89.8％，收率：66％)；最后一步偶联反应，使用强碱(六甲基二硅化锂)导致副反应多，引入杂质较多，后处理困难，操作繁琐；最后一步反应时间长，制备得到的泰地唑胺纯度低，需要经过多次纯化，操作繁琐，纯化之后Pd残留量仍然较高；反应需要用到无水溶剂，不适合工业化生成。
目前关于泰地唑胺的制备方法文献报道的比较少，现有方法，操作复杂，反应时间长，生产成本高，总收率低，纯度较低，不适合工业化生成。
发明内容
本发明目的是提供一种生产成本低，操作简单，收率和纯度较高，反应时间短，适合工业化生产的制备噁唑烷酮类化合物的方法，具体涉及制备泰地唑胺的方法。
为实现上述目的，本发明提供以下技术方案：
一种下式TD所示化合物的制备方法
Figure PCTCN2015089839-appb-000005
包括将下式I所示化合物
Figure PCTCN2015089839-appb-000006
与式II所示化合物
Figure PCTCN2015089839-appb-000007
反应，生成下式TD-1所示化合物
Figure PCTCN2015089839-appb-000008
其中，R为氢或羟基保护基；L和R1中一个为离去基团，另一个为BF3或BR2R3，其中R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起 可以成环；任选的，脱去TD-1所示化合物的羟基保护基R，生成TD所示化合物。
在一实施方式中，优选L为离去基团，R1为BF3或BR2R3，其中R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环。
在另一实施方式中，优先L为BF3或BR2R3，其中R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环，R1为离去基团。
其中，所述离去基团包括卤素如氯、溴、碘，磺酰氧基如三氟甲磺酰氧基、甲磺酰氧基、苯磺酰氧基，或被一个或多个取代基取代的苯磺酰氧基，所述取代基选自：卤素，C1～6烷基和C1～6烷氧基组成的组；优选离去基团为氯、溴、碘；更优选离去基团为溴或碘。
其中，所述R为氢，或羟基保护基，所述羟基保护基包括：烷基，酰基，烷基硅基，优选所述的羟基保护基为苄基，被一个或多个取代基取代的苄基，C1～4烷基酰基，或三甲基硅基，所述取代基选自由C1～6烷基，C1～6烷氧基和卤素组成的组。进一步的优选，R为氢，苄基，对甲基苄基，乙酰基，丙酰基，或丁酰基。
其中，所述BR2R3，优选为B(OH)2或
Figure PCTCN2015089839-appb-000009
在另一实施方式中，优选L为溴或碘，R1为BF3、B(OH)2或
Figure PCTCN2015089839-appb-000010
所述式TD所示化合物的制备方法如下反应式所示：
Figure PCTCN2015089839-appb-000011
式I所示化合物与式II所示化合物反应，优选在钯催化剂催化条件下，碱性(如碳酸钠、碳 酸钾、氢氧化钠或氢氧化钾等)环境下反应，溶剂优选为甲苯，THF，DMF，DMSO，二氧六环，异丙醇或乙醇等，反应温度约为60～80℃，偶联得到化合物TD-1(R为羟基保护基)或TD(R为氢)；任选的将化合物TD-1脱去羟基保护基R，得到化合物TD。其中中间体式II所示化合物：
Figure PCTCN2015089839-appb-000012
其中R1为BF3、B(OH)2或
Figure PCTCN2015089839-appb-000013
可按照下述方法制备：
Figure PCTCN2015089839-appb-000014
中间体ii，其中X为氯、溴或碘，与2当量的强碱(如C1～6烷基锂如正丁基锂或叔丁基锂)反应，然后加入合适的亲电试剂如B(OR2)3，具体的，如C1～6三烷氧基硼酸酯(如硼酸三异丙酯)，优选溶剂为THF或甲苯，反应温度约为-75℃～-65℃。亲电试剂为三烷氧基硼酸酯时，所得反应混合物经后处理得到硼酸IIa。将中间体ii的二价阴离子与环硼酸酯反应，而后即可分离得到环硼酸酯IIb。硼酸化合物IIa还可以参考“钯催化的嘧啶氯代物与吡啶硼酸酯的Suzuki偶联反应”(肖文静，2011-郑州大学：药物化学，硕士学位论文)公开的方法 制备获得。或者将二硼酸酯(如二硼酸的二频哪醇)在钯催化剂作用下偶联到卤代烃(ii)上，生成的硼酸酯IIb可以在酸水中水解成为硼酸IIa；三氟硼酸衍生物IIc能够通过IIa与KF和/或KHF2反应生成；或者三氟硼酸衍生物IIc通过式ii与硼酸酯(如硼酸三异丙酯)在碱性条件下(如正丁基锂)反应，溶剂优选为THF，生成硼酸三异丙基锂盐，然后再与KHF2反应制备得到，具体方法可参见“钯催化下2-吡啶三氟硼酸钾与芳杂卤代物的Suzuki-Miyaura偶联反应”(任伟，2011-郑州大学：有机化学，硕士论文)，该文献通过引用结合到本专利中。
具体的，所述IIa可通过如下反应式所示方法制备获得：
Figure PCTCN2015089839-appb-000015
其中式(1-4)所示化合物可参考CN1894242B公开的方法制备获得，该专利公开的内容通过引用结合到本发明中。例如，包括但不限于(1-4)所示化合物在强碱性(如正丁基锂)条件下与硼酸酯类化合物反应，制备得到式IIa所示化合物，优选反应溶剂为THF，反应温度约为-70℃～-65℃。
在另一实施方式中，优先R1为溴或碘，L为BF3、B(OH)2或
Figure PCTCN2015089839-appb-000016
所述式TD所示化合物的制备方法如下反应式：
Figure PCTCN2015089839-appb-000017
Figure PCTCN2015089839-appb-000018
式I所示化合物与式II所示化合物反应，优选在钯催化剂催化条件下反应，溶剂优选为DMF，反应温度约为60～80℃，制备得到化合物TD-1(R为羟基保护基)或TD(R为氢)，任选的，将化合物TD-1脱去羟基保护基R，得到化合物TD。其中中间体式I所示化合物：
Figure PCTCN2015089839-appb-000019
其中，L为BF3、B(OH)2或
Figure PCTCN2015089839-appb-000020
的制备方法与前述式II所示化合物当R1为硼酸酯或BF3时的制备方法类似，具体反应式如下：
Figure PCTCN2015089839-appb-000021
其中式i中X为氯，溴或碘；所述R为氢，苄基，对甲基苄基，乙酰基，丙酰基，或丁酰基。更进一步的优选X为溴或碘，R为氢。
在另一实施方式中，优选所述L为溴或碘，且所述R为氢，具体的，所述式TD所示化合物的制备方法如下反应流程所示：
Figure PCTCN2015089839-appb-000022
所述反应优选在钯催化剂催化条件下反应，溶剂优选为DMF，反应温度约为60～80℃，优选反应温度为70℃。
本发明所述卤素是包括氟、氯、溴、碘；所述烷基包括直链或支链烷基(如乙基，异丙基等)，芳基取代的烷基部分(如苄基等)。
所述式I所示化合物与式IIa所示化合物优选在钯催化剂的催化条件下进行偶联反应，所述的钯催化剂可以包括二氯双(三苯基膦)钯(II)，四(三苯基膦)钯(0)，钯碳，Pd(OAc)2以及PCy3/Pd2(dba)3(dba＝苯亚甲基丙酮)等，优选该反应溶剂为二甲基甲酰胺(DMF)、1-甲基-2-吡咯烷酮、四氢呋喃(THF)、甲苯、二甲亚砜、甲苯、异丙醇、乙醇等，温度为约60℃～150℃。
当R为羟基保护基时，根据本领域常规的脱羟基保护基的方法，脱去保护基R，得到式TD所示化合物。例如，当R为苄基或取代苄基时可选择Pb-C/H2催化氢化的方法脱去保护基，反应溶剂优选为THF、甲醇、甲苯或己烷等；当R为烷基硅基(如三甲基硅基)时，优选在酸性条件下有机溶剂中(如HCl-MeOH，HCl-二氧六环体系，或AcOH-THF体系)脱去烷基硅基保护基；当R为烷基酰基(乙酰基，丙酰基、丁酰基等)时，可选择在酸洗或碱性条件下进行水解脱去，如在甲醇钠条件下，以甲醇为溶剂室温搅拌脱去相应的烷基酰基。
另一方面，本发明提供了式I所示化合物，优选L为氯，溴或碘时的制备方法，其由式III所示化合物与羰基二咪唑反应转化成，
Figure PCTCN2015089839-appb-000023
所述反应溶剂优选为二氯甲烷，DMF，异丙醇或THF等，反应温度为约25℃～40℃。反应结束后，任选的将不含保护基的化合物I与羟基保护基(例如氯化苄，对甲基氯化苄， C1～6烷基羧酸，二甲基叔丁基氯化硅，三甲基氯化硅或二甲基叔丁基氯化硅等)反应，得到对应R为羟基保护基的化合物I；其中优选R为氢，苄基，对甲基苄基，乙酰基，丙酰基，丁酰基，二甲基叔丁基氯化硅，三甲基氯化硅或二甲基叔丁基氯化硅。
进一步的，所述式III所示化合物由式IV所示化合物
Figure PCTCN2015089839-appb-000024
与缩水甘油丁酯反应，生成，其中，L为氯，溴或碘；所述反应优选在异丙醇中进行回流至反应结束。
在一些实施例中，本发明所述方法还包括，使用本发明所述方法制备得到的式TD所示化合物，与POCl3、POCl(OBn)2或P(N-iPr2)(O-tBu)2在反应条件下生成TD-P所示化合物
Figure PCTCN2015089839-appb-000025
进一步的，所述方法还包括使用TD-P所示化合物在反应条件下与碱反应生成下式TD-PN所示化合物
Figure PCTCN2015089839-appb-000026
其中，M为PO(OH)2的药学上可接受的盐。药物化学领域的技术人员会理解，术语“药学上可接受的盐”是指与合适的生物相容的阳离子和/或阴离子生成的盐。所述的阳离子包括金属元素阳离子，比如钠、锂、钾、镁、铝、钙、锌和有机含氮碱的季铵阳离子包括金属元素阳离子，比如N,N-二苄基乙二胺。氯普鲁卡因、胆碱、二乙基醇胺、乙二胺、普鲁卡因和N-甲基葡萄糖胺等。所述阴离子包括无机酸的阴离子，所述无机酸比如盐酸，氢溴酸、硫酸、磷酸、硝酸、高氯酸、延胡索酸、醋酸、丙酸、丁二酸、乙醇酸、甲酸、乳酸、马来 酸、酒石酸、柠檬酸、棕榈酸、丙二酸、羟基丙二酸、苯乙酸、谷氨酸、苯甲酸水杨酸、甲苯磺酸、苹果酸及类似酸。优选所述的碱为含钠的碱，优选所述M为PO3Na2。
第三方面，本发明提供了下式化合物
Figure PCTCN2015089839-appb-000027
其中，L为溴或碘。
另一方面，本发明所述式i’所示化合物(R＝H时)，还可以通过如下反应式(4)所示方法制备获得：
Figure PCTCN2015089839-appb-000028
步骤1)将4-溴-3-氟苯胺与氯甲酸苄酯在碱性(如碳酸氢钠)条件下反应，制备苄基氨基甲酸酯类化合物(1-7)；步骤2)将苄基氨基甲酸酯类化合物(1-7)在强碱性(如正丁基锂)条件下与缩水甘油丁酯反应，得到式(1-9)所示化合物；最后，根据X的不同选择在反应条件下将式(1-9)所示化合物转化成式i’所示化合物。任选的，将式i’所示化合物与羟基保护剂反应制备得到含羟基保护基R的化合物。
具体的，当X为卤素时(即，优选L为溴或碘时)，式(1-9)所示化合物与卤化试剂(如ICl/CF3COOAg、BrCl/CF3COOAg)反应，溶剂优选为乙腈，室温条件下反应制备式i’所示化合物。
化合物i’任选的与羟基保护剂(例如氯化苄，对甲基氯化苄，C1～6烷基羧酸等)反应，得到对应R为羟基保护基的化合物I，
Figure PCTCN2015089839-appb-000029
另一方面，化合物I’中卤素X可通过本领域常规方法转化成甲磺酸酐类基团，然后再与化合物IIa通过偶联反应得到化合物TD。
在本发明中，所述“羟基保护剂”是指能与羟基反应生成酯类保护基，硅醚保护基，烷基醚保护基的试剂，例如，能与羟基反应生成酯类保护基的羟基保护剂，包括但不限于，甲酸，乙酸，丁酸，丙酸等；所述形成硅醚类保护基的羟基保护剂，包括但不限于，三氟甲基硅基，三甲基硅基，二甲基苯基硅基，二甲基叔丁基硅基等；所述能与羟基形成烷基醚的羟基保护剂，包括但不限于，苄基，对甲基苄基等。
本发明中所述“任选的”，是指根据反应需要，可以选择是或不是，举例说明的，本发明中化合物I与化合物II反应制备化合物TD的过程，当R为H时，TD-1与TD的结构相同，则TD-1不需要进一步脱去羟基保护基制备TD；当R为苄基或硅基保护基时，化合物I与化合物II反应首先得到化合物TD-1，则需要选择进一步将TD-1中羟基保护基R脱去，制备得到TD。
本发明提供了一种泰地唑胺(TD)的新的合成方法，所述方法与现有技术相比具有显著的技术效果，首先，本发明所用到的原料易得，本发明所用到式I所示化合物，可通过多种方法制备获得，且收率均较高；本发明所用到的式II所示化合物，制备方法简单，容易获得；其次，由本式I所示化合物与式II所示化合物偶联制备泰地唑胺(化合物TD)，收率显著提高(不低于87％)，反应时间显著缩短。第三，本发明提供的的方法，所用试剂易得，成本低，制备的各中间体均为固体，后处理简单。
意外的，发明人发现，特别是当化合物I中L为卤素，特别是溴或碘，并且化合物II中R1为B(OH)2，时，或者当化合物I中L为B(OH)2，并且化合物II中R1为卤素，特别是溴或碘时，化合物I与化合物II通过Suzuki反应制备化合物TD(泰地唑胺)时，投料比更容易控制，反应收率更高，并且反应原料稳定性更好，易于储存，其合成方法更简便。
Figure PCTCN2015089839-appb-000030
具体实施例
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合具体实施例，对本发明作进一步的说明，所给出的具体实施例为本发明的优选实施例。
实施例1：式IIa所示化合物的制备
Figure PCTCN2015089839-appb-000031
(1)、2-氰基-5-溴吡啶的制备：
将100克2,5-二溴吡啶溶于1升二甲基甲酰胺中，在室温下将32克氰化铜和17.8克氰化钠加入溶液中，在温度为150℃下将溶液搅拌7小时进行反应。冷却至室温后，反应混合物中加入水，并用乙酸乙酯萃取。有机层用盐水洗涤并脱水、过滤和真空浓缩，得到54克标题化合物，收率70％。
1H-NMR(CDCl3)δ8.76(s，1H)，7.98(dd，1H)，7.58(dd，1H)。
(2)、2-(四唑-5-基)-5-溴吡啶的制备：
将10克2-氰基-5-溴吡啶溶于100毫升二甲基甲酰胺中，在室温下将5.33克叠氮化钠和4.4克氯化铵加入到溶液中，溶液在温度为110℃下搅拌3小时进行反应。反应混合物中加入水，然后用乙酸乙酯萃取，分离所得的有机层用盐水洗涤、脱水、过滤并真空浓缩，由此得到10.5克标题化合物，收率85％。
(3)、2-(1-甲基四唑-5-基)-5-溴吡啶和2-(2-甲基四唑-5-基)-5-溴吡啶的制备
将10.5克2-(四唑-5-基)-5-溴吡啶溶于100毫升二甲基甲酰胺中，然后将6.5克氢氧化钠加入到溶液中，并在0℃下将9.3克碘代甲烷慢慢加入到溶液中。溶液在室温下搅拌6小时，然后加入水，并用乙酸乙酯萃取。然后所得有机层用盐水洗涤、脱水、过滤、真空浓缩并通过柱色谱提纯，得到4克2-(1-甲基四唑-5-基)-5-溴吡啶和5克2-(2-甲基四唑-5-基)-5- 溴吡啶。
(4)、式IIa所示化合物的制备：
氮气保护下，将240克2-(2-甲基四唑-5-基)-5-溴吡啶溶于2.4升四氢呋喃中，加入207g硼酸三异丙酯，于液氮/乙醇浴中降温至-75℃，缓慢滴加840ml 2.5M的正丁基锂四氢呋喃溶液，控制温度在-65℃以下，于-75～-65℃反应2h，HPLC检测反应，直至完全。滴加1.3L20％氯化铵水溶液，控制温度在0℃以下，滴毕，搅拌0.5h，静置分层，有机层用无水硫酸钠干燥，拉干，加入600ml乙酸乙酯打浆2h，过滤，干燥，得到149.7g目标化合物，收率为73％。
实施例2：(R)-3-(4-碘代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇(即，化合物i’)的制备：
Figure PCTCN2015089839-appb-000032
(1)、N-苯甲氧甲酰基-3-氟苯胺(1-7)的制备：
将100克3-氟苯胺溶于1升四氢呋喃(THF)中，并将150克(1.8摩尔)碳酸氢钠(NaHCO3)加入到该溶液中，冷却到0℃后，将154毫升N-苯甲氧甲酰氯(CbzCl)缓慢加入溶液中进行反应。在搅拌条件下将反应混合物在0℃下持续反应2小时，之后用0.5升乙酸乙酯萃取反应体系，分离后，有机层用盐水洗涤，用无水硫酸镁(MgSO4)干燥并真空浓缩，残留物用正己烷洗涤两次，得到为白色晶体的132克标题化合物，收率85％。
(2)、(R)-3-(3-氟苯基)-2-氧代-5-噁唑烷基甲醇(1-9)的制备：
将132克N-苯甲氧甲酰基-3-氟苯胺溶于1.3升四氢呋喃中，并将溶液冷却至-78℃。将370毫升正丁基锂(1.6摩尔/升，正己烷)在氮气气氛下慢慢加入到溶液中，然后搅拌10分钟。将84毫升(R)-(-)-丁酸缩水甘油酯慢慢加入到反应混合物中，在相同的温度下搅拌2小时，然后在室温下反应24小时。反应完成后，往溶液中加入氯化铵溶液，并在室温下用0.5升乙酸乙酯萃取。用盐水洗涤分离所得的有机层，并用无水硫酸镁干燥、真空浓缩。将所得残留物溶于100毫升乙酸乙酯中并用正己烷洗涤，得到白色晶体，该白色晶体纯化为80克标题化合物，收率70％。
1H-NMR(DMSO-d6)δ7.85(t，1H)，7.58(dd，1H)，7.23(dd，1H)，4.69(m，1H)，4.02(t，1H)，3.80(dd，1H)，3.60(br dd，2H)。
(3)、(R)-3-(4-碘代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇(式i’所示化合物)的制备：
将30克(R)-3-(3-氟苯基)-2-氧代-5-噁唑烷基甲醇溶于300毫升乙腈中，并将46克三氟乙酸银盐(CF3COOAg)和43克碘化氯加入到溶液中，在室温下搅拌1天后，往溶液中加入水，并用乙酸乙酯萃取，分离所得的有机层用盐水洗涤并脱水。然后将残留物过滤、真空浓缩并干燥，由此得到44克标题化合物，收率94％。
1H-NMR(DMSO-d6)δ7.77(t，1H)，7.56(dd，1H)，7.20(dd，1H)，5.20(m，1H)，4.70(m，1H)，4.07(t，1H)，3.80(m，1H)，3.67(m，2H)，3.56(m，3H)。
(R)-3-(4-溴代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇(式I’所示化合物，当L为溴)的制备方法类似(R)-3-(4-碘代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇的制备方法，不同之处是用响应的溴化物代替步骤(3)中的碘化物(碘化氯)。
实施例3：泰地唑胺(TD所示化合物)的制备：
Figure PCTCN2015089839-appb-000033
在配置有回流冷凝管和温度计的500ml的三口瓶中，加入1.57g Pd(OAc)2，3.7g PPh3溶于150ml DMF，置换成氮气，然后加入33.75ml三乙胺，70℃下搅拌直至溶液变为红黑色，加入47.2g实施例2制备的(R)-3-(4-碘代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇(化合物i’)和34.4g实施例1制备的式IIa所示化合物，溶于100ml DMF溶液，氮气保护下，在90℃搅拌反应2h，TLC监测反应，趁热经硅藻土过滤。在70℃浓缩至50ml，加入500ml纯化水，搅拌1.0h，过滤，滤饼用50ml 50％甲醇水溶液(体积浓度)洗涤，50℃干燥8h。于所得固体中加入430ml 50％甲醇水溶液(体积浓度)，加热至70度打浆2h，冷却至室温，过滤，30ml甲醇润洗，于50度干燥得到TD所示化合物45g,收率为87％，纯度为98.6％。
1H-NMR(DMSO-d6)δ8.89(s,1H),8.16(m,2H),7.69(m,2H),7.49(dd,1H),5.25(t,1H),4.73(m,1H),4.45(s,3H),4.13(t,1H),3.86(dd,1H),3.67(m,1H),3.58(m,1H)。
实施例4：(2R)-(4-溴-3-氟苯基氨基)-2-羟基-丙醇丁酸酯(化合物III’)的制备
Figure PCTCN2015089839-appb-000034
将19.0g 4-溴-3-氟苯胺溶解于200ml异丙醇中，加入14.4g(R)-丁酸缩水甘油酯，加热回流，保温反应12h。减压蒸除溶剂，得到产品(2R)-(4-溴-3-氟苯基氨基)-2-羟基-丙醇丁酸酯，产品无需纯化，可直接用于下一步反应。
实施例5：(R)-3-(4-溴代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇(化合物I”)的制备
Figure PCTCN2015089839-appb-000035
将33.4g(2R)-(4-溴-3-氟苯基氨基)-2-羟基-丙醇丁酸酯溶解于150ml二氯甲烷中，加入17.8g羰基二咪唑，加热至30～35℃，保温反应16h。加入100ml水，搅拌0.5h，分出有机层，无水硫酸钠干燥，浓缩。加入100ml甲醇溶解残余物，溶解澄清后，加入5.94g甲醇钠，于室温下搅拌2h，减压蒸除溶剂，加入200ml二氯甲烷，分别用50ml 5％稀盐酸、50ml7％碳酸氢钠水溶液、50ml纯化水洗涤，有机层用无水硫酸钠干燥，过滤、浓缩得到标题化合物31.5g，收率为85％。
使用实施例5方法制备的(R)-3-(4-溴代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇与实施例1方法制备的式II所示化合物反应，制备泰地唑胺(TD所示化合物)的方法类似实施例3。
实施例6：下式(I-2)所示化合物的制备
Figure PCTCN2015089839-appb-000036
将33.4g实施例制备的(2R)-(4-溴-3-氟苯基氨基)-2-羟基-丙醇丁酸酯溶解于150ml二氯甲烷中，加入17.8g羰基二咪唑，加热至30～35℃，保温反应16h。加入100ml水，搅拌0.5h，分出有机层，无水硫酸钠干燥，浓缩，得到标题化合物31.5g，收率为85％。
实施例7：泰地唑胺的制备
Figure PCTCN2015089839-appb-000037
在配置有回流冷凝管和温度计的500ml的三口瓶中，加入1.57g Pd(OAc)2，3.7g PPh3溶于150ml DMF，置换成氮气，然后加入33.75ml三乙胺，70℃下搅拌直至溶液变为红黑色，加入47.2g实施例6制备的式(I-2)所示化合物和34.4g实施例1制备的式II所示化合物，溶于100ml DMF溶液，氮气保护下，在90℃搅拌反应2h，TLC监测反应，趁热经硅藻土过滤。在70℃浓缩至50ml，加入500ml纯化水，搅拌1.0h，过滤，滤饼用100ml甲醇溶解，加入5.94g甲醇钠，于室温下搅拌2h，减压蒸除溶剂，滤饼用50ml 50％甲醇水溶液(体积浓度)洗涤，50℃干燥8h。于所得固体中加入430ml 50％甲醇水溶液(体积浓度)，加热至70度打浆2h，冷却至室温，过滤，30ml甲醇润洗，于50℃干燥得到TD所示化合物45g,收率为87％，纯度为98.6％，Pd含量：＜2ppm。
实施例8 下式化合物TD-1的制备
1)化合物(I-3)的制备：
Figure PCTCN2015089839-appb-000038
将14.5g化合物Ⅰ”溶于70mL四氢呋喃(THF)中，并将6.33g(1.2eq.)氯化苄加入到该溶液中，冷却到0℃后，缓慢分批加入1.2g(1.0eq)氢化钠。在搅拌条件下将反应混合物升温至40℃下持续反应5小时，降压浓缩，加入300mL乙酸乙酯，有机层用盐水洗涤，用 无水硫酸钠干燥、过滤、浓缩，得到为白色晶体的15.6g标题化合物，收率82％。
2)、由化合物(I-3)制备化合TD-1
Figure PCTCN2015089839-appb-000039
于250ml的三口瓶中，加入11.41g化合物1-3、6.46g(1.05eq.)化合物Ⅱa、1.14g Pd/C,9.09g三乙胺、80ml DMF，氮气保护，加热至80℃，保温反应3h，通过硅藻土过滤，加入400ml7％碳酸氢钠水溶液，搅拌10min，用150ml*3乙酸乙酯萃取，依次用150ml蒸馏水、150ml饱和氯化钠水溶液洗涤、无水硫酸钠干燥、过滤、浓缩得到目标化合物TD-19.26g,收率为67％。
由化合物(I-3)与化合物IIa反应制备化合物TD-1(羟基保护基R为苄基)的方法类似实施例7中化合物(I-2)与IIa反应制备化合物TD-1(R为正丁酰基)的方法。
实施例9：泰地唑胺的制备(TD-1所示化合物中R＝苄基时)：
Figure PCTCN2015089839-appb-000040
将TD-1(R＝苄基时):将10g TD-1溶解于80ml甲醇中，加入0.5gPb-C/H2，氮气置换3次，氢气置换三次，氢气压力为0.5Mpa,加热回流，HPLC监测反应，反应完全，冷却至室温，经微孔滤膜过滤两次，浓缩，干燥，得到标题所述化合物。
实施例10：下式I’所示化合物的制备
Figure PCTCN2015089839-appb-000041
将化合物(1-9)(0.9eq)溶于1L四氢呋喃(THF)中，将钠氢(1.1eq)加入到该溶液中，冷却到约0℃后，将氯化苄(1.0eq)加入到反应液中，搅拌至反应结束，乙酸乙酯萃取，分离，浓缩后得到苄醚。随后类似实施例2步骤(3)(R)-3-(4-碘代-3-氟苯基)-2-氧代-5-噁唑烷基甲醇的制备方法，在乙腈中经三氟乙酸银和一氯化碘作用在苯环的4位碘取代，得到4位被碘取代，噁唑烷酮羟基被苄基保护的式(1-9)所示化合物，然后参照实施例1步骤(4)的合成方法制备相应的硼酸，最后在浓盐酸中脱除苄基得到目标化合物式I’所示化合物，收率80.4％，MS ESI[M]+：255。
实施例11：泰地唑胺(TD所示化合物)的制备
Figure PCTCN2015089839-appb-000042
在配置有回流冷凝管和温度计的500ml的三口瓶中，加入1.83g Pd2(dba)3，1.12g PCy3溶于400ml DMF，置换成氮气，室温下搅拌0.5h，然后加入60.6g三乙胺，加入51.0g式Ⅰ’所示化合物和57.6g式Ⅱ’所示化合物，氮气保护下，在70℃搅拌反应，HPLC监测反应，趁热经硅藻土过滤。在70℃浓缩至50ml，加入500ml纯化水，用二氯甲烷400ml*2萃取，无水硫酸钠干燥，过滤，浓缩得到固体，于所得固体中加入500ml 50％甲醇水溶液(体积浓度)，加热至70度打浆2h，冷却至室温，过滤，40ml甲醇润洗，于50℃干燥得到TD所示化合物65.9g,收率为89％，纯度为98.8％。
实施例12：磷酸泰地唑胺(TD-P)的制备
5L的包套的圆底烧瓶，装有顶部的机械搅拌机、外加的漏斗、热偶、氮气入口和循环冷却单元。烧瓶内加入TD所示化合物(70.0g，0.189mol)、THF(1.4L，20体积)和三乙胺(58.2g，0.575mol)。浆体搅拌，包套温度设定为0℃。外加的漏斗内加入溶于THF(70mL，1体积)的三氯氧磷(87.0g，0.567mol)。内部温度达到1℃时，POCl3溶液即在44min内逐滴加入。该混合物在1-2℃搅拌3小时。向三颈圆底烧瓶中，加入水(1.4L)，在冰、盐水浴中冷却至3.8℃。反应混合物在1小时内泵入淬灭水表面。淬灭期间的最高温度为11.9℃。黄色浆体搅拌过夜，过滤，滤饼用水(700mL)和甲醇(700mL)冲洗。产物于室温下在真空干燥至恒重。 得到目标产物，的收率为83.4g(98.1％)，纯度为96.5％。
实施例13：泰地唑胺磷酸二钠盐的制备
Figure PCTCN2015089839-appb-000043
实施例9制备的磷酸泰地唑胺(30.0g)加入到1L的反应器中，加入甲醇(360mL)，浆体在室温下搅拌，在10min逐滴加入25％的甲醇钠的甲醇(43.1g)溶液。浆体在室温下搅拌1h后过滤。反应器和滤饼用甲醇(150mL)和丙酮(150mL)冲洗。产物于50-60℃在真空箱内干燥，得到32.6g粗品泰地唑胺磷酸二钠盐。粗产物溶于水(325mL)，加入活性炭，室温下搅拌30分钟。2N NaOH调节浆体pH值至11。浆体通过硅藻土过滤，滤液以0.45μ的滤膜重新过滤。滤液逐滴加入丙酮(1.3L)中，所得浆体搅拌过夜，然后浆体过滤，以丙酮(320mL)冲洗，于50℃在真空箱中干燥，将其重新溶于水(230mL)，加入氢氧化钠溶液将pH值调至10，该溶液通过0.45μ的滤膜过滤除去颜色，滤液逐滴加入丙酮(950ml)中,过滤，然后用丙酮(230mL)冲洗。产物干燥后，重为25.8g(总收率为79％)，HPLC：99.6％。
实施例14：下式化合物Ib的制备
Figure PCTCN2015089839-appb-000044
在配置有回流冷凝管和温度计的500ml的三口瓶中，加入14.5g化合物i、13.97g(1.1eq.)频哪醇二硼酸酯、1.83g(0.05eq.)PdCl2(dppf)2、110ml DMF，氮气保护下，在70℃搅拌反应，HPLC监测反应，趁热经硅藻土过滤。在70℃浓缩至50ml，加入400ml纯化水，用二氯甲烷400ml*2萃取，无水硫酸钠干燥，过滤，浓缩得到化合物Ib 12.74g,收率为74％，纯度为99.3％；1H-NMR(DMSO-D6)：1.32(s,12H),4.45(s,3H),8.13(d,1H),8.18(d，1H),8.90(s，1H)。
实施例15 泰地唑胺(TD)的制备
Figure PCTCN2015089839-appb-000045
在配置有回流冷凝管和温度计的500ml的三口瓶中，加入1.83g Pd2(dba)3，1.12g PCy3溶于400ml DMF，置换成氮气，室温下搅拌0.5h，然后加入60.6g三乙胺，加入51.0g化合物i和85.2g化合物lb，氮气保护下，在70℃搅拌反应，HPLC监测反应，趁热经硅藻土过滤。在70℃浓缩至50ml，加入500ml纯化水，用二氯甲烷400ml*2萃取，无水硫酸钠干燥，过滤，浓缩得到固体，于所得固体中加入500ml 50％甲醇水溶液(体积浓度)，加热至70度打浆2h，冷却至室温，过滤，40ml甲醇润洗，于50℃干燥得到TD所示化合物61.2g,收率为82.7％，纯度为98.9％。
应当说明的是，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。

Claims (13)

  1. 一种下式TD所示化合物的制备方法
    Figure PCTCN2015089839-appb-100001
    包括：将下式I所示化合物
    Figure PCTCN2015089839-appb-100002
    与式II所示化合物
    Figure PCTCN2015089839-appb-100003
    反应，生成下式TD-1所示化合物
    Figure PCTCN2015089839-appb-100004
    其中，R为氢或羟基保护基；L和R1中一个为离去基团，另一个为BF3或BR2R3，其中R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环；
    任选的，脱去TD-1所示化合物的羟基保护基R，生成TD所示化合物。
  2. 根据权利要求1所述方法，其中L为离去基团，R1为BF3或BR2R3，其中R2和R3独立 的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环。
  3. 根据权利要求1所述方法，其中L为BF3或BR2R3，其中R2和R3独立的选自由OH和任意取代的C1～C6一元和二元醇组成的组，其中R2和R3在一起可以成环，R1为离去基团。
  4. 根据权利要求1～3任一项所述方法，其中所述离去基团选自卤素，三氟甲磺酰氧基，甲磺酰氧基，和取代或未取代的苯基磺酰氧基组成的组；所述R为氢，苄基，取代苄基，烷基酰基，或烷基硅基。
  5. 根据权利要求1～3任一项所述方法，其中所述离去基团选自氯，溴和碘；所述R为氢，苄基，对甲基苄基，乙酰基，丙酰基，丁酰基，二甲基叔丁基硅基，三甲基硅基，或二甲基苯基硅基。
  6. 根据权利要求1～3任一项所述方法，其中离去基团选自溴和碘，R为氢。
  7. 根据权利要求1所述方法，其中L为溴或碘，R为氢，R1为BF3、B(OH)2或
    Figure PCTCN2015089839-appb-100005
    或者，R1为溴或碘，R为氢，L为BF3、B(OH)2或
    Figure PCTCN2015089839-appb-100006
  8. 根据权利要求2所述方法，其中式I所示化合物由式III所示化合物与羰基二咪唑反应，任选的，再与羟基保护剂反应生成，
    Figure PCTCN2015089839-appb-100007
    其中，L为氯，溴或碘；R为氢，苄基，对甲基苄基，乙酰基，丙酰基，丁酰基，二甲基叔丁基硅基，三甲基硅基，或二甲基苯基硅基。
  9. 根据权利要求8所述方法，其中所述式III所示化合物由式IV所示化合物
    Figure PCTCN2015089839-appb-100008
    其中，L为氯，溴或碘，与缩水甘油丁酯反应，生成。
  10. 根据权利要求1～3任一项所述方法，其中式I所示化合物与式II所示化合物在钯试剂催化下反应。
  11. 一种制备下式TD-P所示化合物的方法，其特征在于，使用权利要求1～3任一所述方法制备得到的式TD所示化合物，与POCl3、POCl(OBn)2或P(N-iPr2)(O-tBu)2在反应条件下生成：
    Figure PCTCN2015089839-appb-100009
  12. 根据权利要求11所述方法，其特征在于，还包括使用TD-P所示化合物在反应条件下与碱反应生成下式TD-PN所示化合物
    Figure PCTCN2015089839-appb-100010
    其中，M为PO(OH)2的药学上可接受的盐。
  13. 一种下式化合物
    Figure PCTCN2015089839-appb-100011
    其中，L为溴或碘。
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