WO2015096786A1 - 制备2-(烷氧基亚烷基)-3-氧代羧酸酯、嘧啶化合物的方法及铁作为催化剂的用途 - Google Patents

制备2-(烷氧基亚烷基)-3-氧代羧酸酯、嘧啶化合物的方法及铁作为催化剂的用途 Download PDF

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WO2015096786A1
WO2015096786A1 PCT/CN2014/095008 CN2014095008W WO2015096786A1 WO 2015096786 A1 WO2015096786 A1 WO 2015096786A1 CN 2014095008 W CN2014095008 W CN 2014095008W WO 2015096786 A1 WO2015096786 A1 WO 2015096786A1
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group
structural formula
formula
oxocarboxylate
alkoxyalkylene
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PCT/CN2014/095008
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French (fr)
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陈文霆
杨光
高海军
胡凤霞
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北京乐威泰克医药技术有限公司
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J23/00—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00
    • B01J23/70—Catalysts comprising metals or metal oxides or hydroxides, not provided for in group B01J21/00 of the iron group metals or copper
    • B01J23/74—Iron group metals
    • B01J23/745—Iron
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a process for the preparation of 2-(alkoxyalkylene)-3-oxocarboxylates, in particular to the preparation of 2-(alkoxyalkylene)s from 3-oxocarboxylates using an iron catalyst.
  • 3-oxocarboxylate or 2-(alkoxyalkylidene)-3-oxocarboxylate, 2-(alkoxyalkyl)-3-oxocarboxylate
  • heterocyclic compounds such as pyrimidines as important intermediates in pharmaceutical, agricultural and other related industrial chemicals.
  • the U.S. Patent Application Serial No. 2005/0027140 A1 describes a process for carrying out such a reaction using at least one tertiary amine carboxylate as a catalyst.
  • EP 1 849 765 A1 describes a process for carrying out such reactions using acids such as sulfuric acid, methanesulfonic acid, benzenesulfonic acid and the like as catalysts.
  • the temperature of such reactions is generally high and must be carried out at the reflux temperature of the acid to increase the cost of industrial production.
  • One aspect of the invention provides a process for the preparation of 2-(alkoxyalkylene)-3-oxocarboxylates (or 2-(alkoxyalkylidene)-3-oxocarboxylates, 2-( A method for alkoxyalkylene)-3-oxocarboxylates, comprising:
  • the 3-oxocarboxylate of Structural Formula 2 is reacted with the orthoester of Structural Formula 3 to form a 2-(alkoxyalkylene)-3-oxocarboxylate of Structural Formula 1 in the presence of a catalyst iron.
  • R and R 2 are the same or different and each independently is a lower alkyl group
  • R 1 and R 3 are the same or different and are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
  • the wavy line indicates the E or Z isomer.
  • the invention also relates to a method for preparing a pyrimidine compound, comprising:
  • a pyrimidine compound is prepared by using the 2-(alkoxyalkylene)-3-oxocarboxylate obtained in the step (a) as a starting material.
  • step (b) comprises:
  • R 4 is a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group.
  • the present invention also relates to the use of iron as a catalyst in the preparation of a compound of Structural Formula 1 from a 3-oxocarboxylate of Structural Formula 2 and an orthoester of Structural Formula 3,
  • the method of the invention uses iron as a catalyst, has low cost, is easy to separate and recover, and has simple reaction.
  • Alkyl means a straight chain and a branched carbon chain, preferably having one to twenty carbon atoms (C1-C20 alkyl group), preferably one to six carbon atoms (C1-C6 alkyl group), more preferably C1-C3
  • the alkyl group further preferably has one and two carbon atoms (C1-C2 alkyl group).
  • the lower alkyl group means a linear and branched carbon chain of 1 to 4 carbon atoms (C1-C4 alkyl group), more preferably a C1-C3 alkyl group, further preferably having one and two carbon atoms (C1-C2 alkane) base). Specifically, it is a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, and a tert-butyl group.
  • the alkyl group may optionally bear one or more substituents which may be the same or different, and these substituents may be halogen, alkyl, aryl, cycloalkyl, alkoxy and fluorenyl.
  • substituents may be halogen, alkyl, aryl, cycloalkyl, alkoxy and fluorenyl.
  • These alkyl groups may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, But it is not limited to this.
  • the aryl group (containing an aralkyl group) means that the carbocyclic group is preferably 6 to 15 carbon atoms and contains at least one aromatic ring such as a phenyl group, a 1-naphthalene group, a 2-naphthyl group or the like.
  • the aromatic ring group may carry one or more substituents such as a halogen, an alkyl group, an alkoxy group, a phenoxy group, and a trifluoromethyl group. When the substituents are two or more, they may be the same or different.
  • alkyl, aryl and aralkyl groups described herein may be unsubstituted or may have one or more substituents at any position.
  • 2-(alkoxyalkylene)-3-oxocarboxylates can be prepared from 3-oxocarboxylates and orthoesters using iron as a catalyst.
  • the invention provides a process for the preparation of a 2-(alkoxyalkylene)-3-oxocarboxylate comprising:
  • the 3-oxocarboxylate of Structural Formula 2 is reacted with the orthoester of Structural Formula 3 to form a 2-(alkoxyalkylene)-3-oxocarboxylate of Structural Formula 1 in the presence of a catalyst iron.
  • R and R 2 are the same or different and each independently is a lower alkyl group
  • R 1 and R 3 are the same or different and are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl or heteroarylalkyl;
  • the wavy line indicates the E or Z isomer.
  • no additional solvent is used during the reaction except for the reactants and products.
  • R and R 2 are the same or different and are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, preferably methyl or base.
  • R 1 and R 3 are the same or different and are each independently: hydrogen; C 1-20 alkyl, preferably C 1-15 alkyl, more preferably C 1-10 alkyl, most preferably C 1-6 alkane a C 3-20 cycloalkyl group, preferably a C 3-15 cycloalkyl group, more preferably a C 3-10 cycloalkyl group, most preferably a C 3-7 cycloalkyl group; a C 3-20 heterocyclic group, preferably C 3 a -15 heterocyclic group, more preferably a C 3-10 heterocyclic group, most preferably a C 3-7 heterocyclic group; a C 6-20 aryl group, preferably a C 6-15 aryl group, more preferably a C 6-10 aryl group, Most preferred is a C 6-8 aryl group; a C 7-20 aralkyl group, preferably a C 7-15 aralkyl group, more preferably a C 7-10 aralkyl group, most preferred is
  • R 1 and R 3 are the same or different and are each independently hydrogen, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl; isopropyl, isobutyl , sec-butyl, tert-butyl, isopentyl, neopentyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, dimethylcyclopropyl, A Cyclobutyl, dimethylcyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl; phenyl, benzyl, tolyl, ethylphenyl, Naphthyl, anthracenyl, phenanthryl, or an
  • R 1 and R 3 are the same or different and are each independently hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the 3-oxocarboxylate of Structural Formula 2 is selected from the group consisting of methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, isopropyl acetoacetate; methyl propionyl acetate, ethyl propionate, and C. N-propyl acyl acetate or isopropyl propionate; methyl butyryl acetate, ethyl butyrate, n-propyl butyrate or isopropyl butyrate; preferably ethyl acetoacetate.
  • the orthoester of Structural Formula 3 is selected from the group consisting of trimethyl orthoformate, triethyl formate, tri-n-propyl formate, and triisopropyl formate; trimethyl acetate, ethyl acetate Ethyl ester, tri-n-propyl ethanoate, triisopropyl acetate; trimethyl butyl methacrylate, triethyl butyl methacrylate, tri-n-propyl butyrate or triisopropyl butyl methacrylate; Trimethyl ester.
  • the orthoester of Structural Formula 3 is selected from a methyl ester or an ethyl ester.
  • reaction products are removed from the reaction system by distillation during the reaction.
  • the 3-oxocarboxylic acid ester of the structural formula 2 is ethyl acetoacetate of the structural formula 2a; the orthoester of the structural formula 3 is triethyl orthoformate of the structural formula 3a; and the resulting 2-(1) of the structural formula 1 Alkoxyalkylene)-3-oxocarboxylate is a compound of formula 1a:
  • the molar ratio of the orthoester of Structural Formula 3 to the 3-oxocarboxylic acid ester of Structural Formula 2 is between 1:1 and 2:1, preferably between 1:1 and 1.3:1.
  • the weight ratio of the catalyst iron to the 3-oxocarboxylate of Structural Formula 2 is between 1:200 and 1:500, preferably between 1:250 and 1:300.
  • the catalyst iron is iron powder.
  • the invention also relates to a method for preparing a pyrimidine compound, comprising:
  • a pyrimidine compound is prepared by using the 2-(alkoxyalkylene)-3-oxocarboxylate obtained in the step (a) as a starting material.
  • step (b) comprises:
  • R 4 is a hydrogen atom, a hydroxyl group, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an aralkyl group, a heteroaryl group or a heteroaralkyl group.
  • R 4 is a hydrogen atom; a hydroxyl group; a C 1-20 alkyl group, preferably a C 1-15 alkyl group, more preferably a C 1-10 alkyl group, most preferably a C 1-6 alkyl group; a C 3-20 naphthenic ring; a group, preferably a C 3-15 cycloalkyl group, more preferably a C 3-10 cycloalkyl group, most preferably a C 3-7 cycloalkyl group; a C 3-20 heterocyclic group, preferably a C 3-15 heterocyclic group, more preferably C 3-10 heterocyclic group, most preferably C 3-7 heterocyclic group; C 6-20 aryl group, preferably C 6-15 aryl group, more preferably C 6-10 aryl group, most preferably C 6-8 aryl group C 7-20 aralkyl, preferably C 7-15 aralkyl, more preferably C 7-10 aralkyl, most preferably C 7-8 aral
  • R 4 is a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, a n-propyl group, a n-butyl group, a n-pentyl group, a n-hexyl group, a n-heptyl group; an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group Base, isoamyl, neopentyl; cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopropyl, dimethylcyclopropyl, methylcyclobutyl, dimethyl Cyclobutyl, methylcyclopentyl, dimethylcyclopentyl, methylcyclohexyl, dimethylcyclohexyl; phenyl, benzyl, tolyl,
  • R 4 may be a group defined for R 1 and R 3 .
  • step (b) further comprises:
  • M is H or a metal ion.
  • the metal ion is selected from alkali metal ions or alkaline earth metal ions, preferably lithium (Li), sodium (Na), potassium (K), calcium (Ca) ions.
  • step (b) further comprises:
  • M' is a metal ion, preferably selected from an alkali metal ion or an alkaline earth metal ion, preferably lithium (Li), sodium (Na), potassium (K).
  • the invention relates to the preparation of a compound of formula 1 using a novel catalyst:
  • R and R 2 are lower alkyl groups, and R 1 and R 3 are one of an alkyl group, an aryl group or an aralkyl group, and may be the same or different groups.
  • the synthesis process does not use any other solvent under the action of the catalyst.
  • the compounds of Structural Formula 1 are important intermediates in the preparation of a wide variety of heterocyclic compounds which are useful components of pharmaceutical, agricultural and other related industrial chemicals.
  • the invention discloses iron powder as a novel, inexpensive and easy-to-operate catalyst for preparing 2-(alkoxyalkylene)-3-oxocarboxylate (Structure 1).
  • R and R 2 are lower alkane
  • R 1 and R 3 are one of an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group or a heteroarylalkyl group, which may be the same or different Group.
  • the method is:
  • the compound of Structural Formula 1 is formed by the action of a catalyst (iron powder) without using a solvent.
  • the inventors have unexpectedly found that the reaction is more efficient and economical under the action of the catalyst.
  • the method can be simply used for the mass production of the compound of the structural formula 1, and the reaction product can be separated and purified by simple distillation, and can be directly used in the reaction for preparing a heterocyclic compound.
  • the pyrimidine compound formed can be isolated and purified by distillation, and the method is easily realized in industrial production.
  • the present invention discloses a novel catalyst (iron powder) for preparing 2-(alkoxyalkylene)-3-oxocarboxylate (Structure 1), which is a carboxy group.
  • the acid esters can be used to prepare a wide variety of heterocyclic compounds, especially pyrimidine derivatives, particularly pyrimidine carboxylic acids.
  • the method of the present invention is as shown in Scheme 1:
  • R and R 2 are lower alkane, preferably methyl and ethyl; and R 1 and R 3 are one of a hydrogen atom, an alkyl group, an aryl group or an aralkyl group, which may be the same or different groups, R 1 and R 3 are preferably a hydrogen atom and an alkyl group, and the alkyl group is preferably a methyl group, an ethyl group and a propyl group; and R 4 may be a hydrogen atom, a hydroxyl group, an alkyl group and an aryl group, preferably a hydrogen atom, a methyl group and a hydroxyl group.
  • a 3-oxocarboxylate such as ethyl acetoacetate, methyl acetoacetate
  • a carboxylic acid ester itself as a solvent eg Trimethyl orthoacetate
  • a catalyst such as iron powder
  • the reaction is carried out by distillation to remove by-products such as methanol or ethanol (for example, azeotrope of methanol or ethanol with trimethyl orthoacetate) to smoothly convert the product to complete the reaction.
  • the product can be directly used in the next step of generating a heterocyclic reaction after filtering off the catalyst, especially the synthesis of a pyrimidine compound.
  • the different reaction stages described in Scheme 2 comprise a suitable solvent or a mixture of two or more solvents and a base, usually in the reflux step with ethanol as the solvent and sodium ethoxide as the base.
  • a suitable solvent or a mixture of two or more solvents and a base usually in the reflux step with ethanol as the solvent and sodium ethoxide as the base.
  • ethanol as the solvent
  • sodium ethoxide as the base.
  • tetrahydrofuran is used as a solvent
  • an aqueous sodium hydroxide solution is used as a base to react.
  • the reaction is preferably carried out in a closed tube with a Vigrelet jacket (heating temperature up to 200 ° C).
  • the alcohol and the carboxylic acid ester are distilled off from the system at a suitable temperature; it is common that methanol and ethyl acetoacetate are azeotroped (80 ° C), and the reaction temperature can be raised to 140 ° C until no other fraction is distilled off from the system.
  • the reaction can be monitored by suitable conditions (e.g., gas chromatography) until the product does not increase in the reaction system. The reaction is continued for 3 to 72 hours depending on the circumstances.
  • the molar ratio of the trialkyl ester to the 3-oxocarboxylic acid ester is between 1:1 and 2:1, preferably between 1:1 and 1.3:1, and the weight ratio of the catalyst to the 3-oxocarboxylate is 1. : between 200 and 1:500, preferably 1:250 to 1:300.
  • More suitable ester groups are lower alkanols, especially methyl esters and ethyl esters, and the by-products thus obtained are methanol or ethanol which can be more easily removed from the system.
  • the product of Structural Formula 1 can be separated by distillation after a simple operation of filtering off the catalyst, and the heterocyclic ester can be isolated and purified by vacuum distillation or recrystallization. All products are characterized by nuclear magnetic resonance spectroscopy or mass spectrometry.
  • the invention relates to a process for the reaction of a compound of formula 2a as a starting material.
  • Iron powder was used as a catalyst for the preparation of the starting material of Structural Formula 1a in Scheme 3.
  • the compounds of Structural Formula 1a can be further useful in the preparation of heterocyclic rings such as the pyrimidine derivatives mentioned in Scheme 4, which are useful components of pharmaceutical, agricultural and other related industrial chemicals.
  • the raw materials selected in this case are ready-made, more economical materials, ethyl acetoacetate and triethyl orthoformate, and iron powder as a catalyst, which is more suitable for large-scale mass production.
  • the invention discloses iron powder as a novel, inexpensive and easy to operate catalyst for preparing 2-(alkoxyalkylene)-3-oxocarboxylate from 3-oxocarboxylic acid ester, the carboxylic acid Esters can be used to prepare a wide variety of heterocyclic compounds, such as pyrimidines, which are important intermediates in pharmaceutical, agricultural and other related industrial chemicals.
  • the method of the present invention uses an inexpensive and readily available catalyst, iron powder, and a more efficient separation and purification method, distillation; no other solvent is used in the reaction, and the carboxylate is used as the carboxylate. Solvents can be easily recycled and reused. This method is more efficient and economical, and is suitable for industrial production.
  • the product of the present invention represented by the compound of Structural Formula 1, is an important intermediate for the preparation of various heterocyclic compounds having a substituent.
  • Such a heterocyclic compound includes, but is not limited to, a 5-carboxyester pyrimidine, a pyridone whose substituent is a carboxylate, a pyrazole whose substituent is a carboxylate, a substituent which is a carboxylate oxazole, and a substituent. Pyrazolopyridone. These substituted heterocyclic compounds are useful components of pharmaceutical, agricultural and other related industrial chemicals.
  • pyrimidine derivatives with substituents are some useful pharmaceutical intermediates.
  • HMGCoA reductase inhibitors EP0022478
  • calcium channel antagonists WO02/022588
  • CCR5 antagonists are reported in several patents: US6391865B1; US2002/0147192A1; US2005/0261310A1; US2008/0249087A1; US2009/0270336A1 And other compounds involved in the series of patents.
  • Ethyl acetoacetate (105g), trimethyl orthoacetate (330g), iron powder (3.0g) were added to a 1000ml glass vial.
  • the internal temperature of the reaction solution reached 120 ° C.
  • the temperature of the distillation port was 60 ° C.
  • the mixture was distilled while heating.
  • the fraction was analyzed by HPLC, and the reaction was stopped after the reaction of the starting material ethyl acetoacetate.
  • the reaction was cooled to 40 ° C, and the fraction was distilled under reduced pressure to give 232.7 g, and the iron powder was filtered to obtain a product of 125.8 g, yield 83.7%.
  • Example 1b (industrial production scale):
  • the aqueous phase was further cooled to between 0 and 5 ° C, acidified to pH 1.5 by dropwise addition of concentrated hydrochloric acid, stirred at 0-5 ° C for 1 hour, centrifuged, and the filter cake was washed twice with ice water.
  • the filtrate was concentrated and the product was dried under vacuum at 40-45 °C. TLC detected impurities as well, washed with 29 kg and 22 kg of toluene, respectively, and dried under vacuum.
  • the product was added to a mixed solvent of 57.6 kg of absolute ethanol and 110 kg of acetonitrile, and the mixture was heated to 60 ° C - 75 ° C to dissolve. A solid precipitated after cooling.
  • Table 5 uses an iron catalyst, and the other reactions completed in accordance with the first step of Example 1 are as follows:

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Abstract

本发明涉及制备2-(烷氧基亚烷基)-3-氧代羧酸酯、嘧啶化合物的方法及铁作为催化剂的用途。本发明提供一种制备2-(烷氧基亚烷基)-3-氧代羧酸酯的方法，包括：结构式2的3-氧代羧酸酯与结构式3的原酸酯在催化剂铁的存在下反应，生成结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯，其中，R和R2各自是C1-C4低级烷基；R1和R3各自是氢、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基；波浪线表示E或Z异构体。本发明还提供一种制备嘧啶化合物方法，包括：（a）通过上述方法制备2-(烷氧基亚烷基)-3-氧代羧酸酯；以及（b）以步骤（a）获得的2-(烷氧基亚烷基)-3-氧代羧酸酯为原料，制备嘧啶化合物。该方法用铁作为催化剂，成本低，反应简单。

Description

制备2-(烷氧基亚烷基)-3-氧代羧酸酯、嘧啶化合物的方法及铁作为催化剂的用途 技术领域
本发明涉及制备2-(烷氧基亚烷基)-3-氧代羧酸酯的方法，尤其涉及用铁催化剂由3-氧代羧酸酯制备2-(烷氧基亚烷基)-3-氧代羧酸酯(或2-(烷氧基烷叉基)-3-氧代羧酸酯，2-(烷氧基次烷基)-3-氧代羧酸酯)，还涉及合成杂环化合物，例如作为药物，农业和其他相关工业化学制品的重要中间体的嘧啶。
背景技术
用一个含有活泼亚甲基的羧酸酯类化合物，例如：1,3-二酮、乙酰乙酸酯、丙二酸酯、丙二腈或氰基乙酸酯等，来制备2-(烷氧基亚烷基)化合物的方法已有报道，参见Robert H.DeWolfe Carboxylic Ortho Acid Derivatives,pp231-235,Academic Press,New York,1970。
使用羧酸酯与含有活泼亚甲基的化合物在催化剂的作用下反应生成2-(烷氧基亚烷基)化合物的方法在多处均有报道。
在Claisen,Ber.26,2729,1893和Post et al,J.Org.Chem.2,260,1937中，乙酸酐作为催化剂被使用在原甲酸三乙酯与不同的含有活泼亚甲基化合物的反应中。同时发现氯化锌在丙二酸二乙酯进行此类反应时是必要的催化剂(美国专利US 2824121)。但是使用这两种催化剂会导致反应中酸酯的分解导致产率降低。
在Johns，J.Am.Chem.Soc.,74,4889-4891,1952文章中则认为羧酸酯与含有活泼亚甲基化合物的反应中是不需要使用乙酸酐的。这种合成方法的缺点是反应温度高，收率低。
美国专利US 2824121中提到使用醋酸作催化剂进行同样的反应。
在Emeline et al,Zh.Obshsch.Khim.,133-134,64,1994的文章中介绍使用三氟化硼作为催化剂来进行原乙酸三甲酯和乙酰乙酸乙酯与原乙酸三乙酯的反应。
美国专利US4808747介绍金属羧酸盐能在醛和酮与某些含有活泼亚甲基的化合物进行反应时起催化作用。该类催化剂适用范围和选择性较单一。
美国申请号为2005/0027140A1的专利介绍了使用至少一种叔胺羧酸盐作为催化剂进行此类反应的方法。
申请号为EP1849765A1的欧洲专利介绍了使用酸(如硫酸、甲磺酸、苯磺酸及类似物)作为催化剂进行此类反应的方法。该类反应的温度一般较高，须在酸的回流温度下进行，增加工业化生产的成本。
因此，需要一种低成本的催化剂以及简单的合成方法。
发明内容
本发明目的在于提供制备2-(烷氧基亚烷基)化合物的简单方法，以及用于该反应的低成本催化剂。
本发明一方面提供一种制备2-(烷氧基亚烷基)-3-氧代羧酸酯(或2-(烷氧基烷叉基)-3-氧代羧酸酯，2-(烷氧基次烷基)-3-氧代羧酸酯)的方法，包括：
结构式2的3-氧代羧酸酯与结构式3的原酸酯反应，在催化剂铁的存在下反应生成结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯，
Figure PCTCN2014095008-appb-000001
其中，
R和R2相同或不同，各自独立地是低级烷基；
R1和R3相同或不同，各自独立地是氢、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基；
波浪线表示E或Z异构体。
本发明还涉及一种制备嘧啶化合物方法，包括：
(a)通过根据本发明的方法制备2-(烷氧基亚烷基)-3-氧代羧酸酯；以及
(b)以步骤(a)获得的2-(烷氧基亚烷基)-3-氧代羧酸酯为原料，制备嘧啶化合物。
其中，步骤(b)包括：
(b1)在碱存在下，结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯与结构式4的化合物反应，生成结构式5的嘧啶化合物，
Figure PCTCN2014095008-appb-000002
其中，
R4为氢原子、羟基、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基。
本发明还涉及铁在用于由结构式2的3-氧代羧酸酯和结构式3的原酸酯制备结构式1的化合物中作为催化剂的用途，
Figure PCTCN2014095008-appb-000003
其中，结构式2的3-氧代羧酸酯、结构式3的原酸酯和结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯和/或反应条件如本发明方法所限定。
本发明的方法采用铁作为催化剂，成本低，易于分离和回收，反应简单。
具体实施方式
在本发明中，在不矛盾或冲突的情况下，本发明的所有实施例、实施方式以及特征可以相互组合。
在本发明中，常规的设备、装置、部件等，既可以商购，也可以根据本发明公开的内容自制。
在本发明中，为了突出本发明的重点，对一些常规的操作和设备、装置、部件进行的省略，或仅作简单描述。
文中所用的条件除非有特殊说明均为以下含义。
烷基是指直链和支链的碳链，优选具有一个到二十个碳原子(C1-C20烷基)，优选一个到六个碳原子(C1-C6烷基)，更优选C1-C3烷基，进一步优选具有一个和二个碳原子(C1-C2烷基)。
低级烷基是指1至4个碳原子的直链和支链的碳链(C1-C4烷基)，更优选C1-C3烷基，进一步优选具有一个和二个碳原子(C1-C2烷基)。具体为甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
烷基基团可选带有一个或多个相同或不同的取代基，这些取代基可以是卤素、烷基、芳基、环烷基、烷氧基和巯基。这些烷基可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、正庚基，但不限于此。
芳基(包含芳烷基)是指碳环基团优选是6-15个碳原子，而且至少含有一个芳香环，例如苯基类，1-萘类，2-萘类等。芳环基团可以带有一个或多个卤素、烷基、烷氧基、苯氧基和三氟甲基等取代基。当取代基为两个或更多时，它们可以相同，也可以不同。
除非特指，这里所介绍的烷基、芳基和芳烷基基团可以是无取代基的，也可以是任意位置上有一个或多个取代基的。
用波浪线表示的键表示的是E和Z异构体。
本发明人出乎意料地发现，采用铁作为催化剂，可以由3-氧代羧酸酯和原酸酯制备2-(烷氧基亚烷基)-3-氧代羧酸酯。
本发明一方面提供一种制备2-(烷氧基亚烷基)-3-氧代羧酸酯的方法，包括：
结构式2的3-氧代羧酸酯与结构式3的原酸酯反应，在催化剂铁的存在下反应生成结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯，
Figure PCTCN2014095008-appb-000004
其中，
R和R2相同或不同，各自独立地是低级烷基；
R1和R3相同或不同，各自独立地是氢、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基；
波浪线表示E或Z异构体。
优选地，在反应期间，除反应物和产物外，不使用另外的溶剂。
优选地，R和R2相同或不同，各自独立地是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。
优选地，R1和R3相同或不同，各自独立地是：氢；C1-20烷基，优选C1-15烷基，更优选C1-10烷基，最优选C1-6烷基；C3-20环烷基，优选C3-15环烷基，更优选C3-10环烷基，最优选C3-7环烷基；C3-20杂环基，优选C3-15杂环基，更优选C3-10杂环基，最优选C3-7杂环基；C6-20芳基，优选C6-15芳基，更优选C6-10芳基，最优选C6-8芳基；C7-20芳烷基，优选C7-15芳烷基，更优选C7-10芳烷基，最优选C7-8芳烷基；C5-20杂芳基，优选C5-15杂芳基，更优选C5-10杂芳基，最优选C5-8杂芳基；或C5-20杂芳烷基，优选C5-15杂芳烷基，更优选C5-10杂芳烷基，最优选C5-8杂芳烷基。
优选地，R1和R3相同或不同，各自独立地是氢、甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基；异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基；环丙基、环丁基、环戊基、环己基、环庚基、甲基环丙基、二甲基环丙基、甲基环丁基、二甲基环丁基、甲基环戊基、二甲基环戊基、甲基环己基、二甲基环己基；苯基、苄基、甲苯基、乙基苯基、萘基、蒽基、菲基、或芘基。
优选地，R1和R3相同或不同，各自独立地是氢、甲基、乙基、正丙基或异丙基。
优选地，结构式2的3-氧代羧酸酯选自乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸正丙酯、乙酰乙酸异丙酯；丙酰乙酸甲酯、丙酰乙酸乙酯、丙酰乙酸正丙酯或丙酰乙酸异丙酯；丁酰乙酸甲酯、丁酰乙酸乙酯、丁酰乙酸正丙酯或丁酰乙酸异丙酯；优选乙酰乙酸乙酯。
优选地，结构式3的原酸酯选自甲原酸三甲酯、甲原酸三乙酯、甲原酸三正丙酯、甲原酸三异丙酯；乙原酸三甲酯、乙原酸三乙酯、乙原酸三正丙酯、乙原酸三异丙酯；丁原酸三甲酯、丁原酸三乙酯、丁原酸三正丙酯或丁原酸三异丙酯；优选乙原酸三甲酯。
优选地，结构式3的原酸酯选自甲基酯或乙基酯。
优选地，在反应期间，通过蒸馏将一种或多种反应产物从反应体系中去除。
优选地，所述结构式2的3-氧代羧酸酯为结构式2a的乙酰乙酸乙酯；所述结构式3的原酸酯为结构式3a的原甲酸三乙酯；生成的结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯为结构式1a的化合物：
Figure PCTCN2014095008-appb-000005
优选地，结构式3的原酸酯与结构式2的3-氧代羧酸酯的摩尔比为1:1到2:1之间，优选是1:1到1.3:1。
优选地，所述催化剂铁与结构式2的3-氧代羧酸酯的重量比是1:200到1:500之间，优选1:250到1:300。
优选地，所述催化剂铁是铁粉。
本发明还涉及一种制备嘧啶化合物方法，包括：
(a)通过本发明所述的方法制备2-(烷氧基亚烷基)-3-氧代羧酸酯；以及
(b)以步骤(a)获得的2-(烷氧基亚烷基)-3-氧代羧酸酯为原料，制备嘧啶化合物。
其中，步骤(b)包括：
(b1)在碱存在下，结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯与结构式4的化合物反应，生成结构式5的嘧啶化合物，
Figure PCTCN2014095008-appb-000006
其中，
R4为氢原子、羟基、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基。
优选地，R4为氢原子；羟基；C1-20烷基，优选C1-15烷基，更优选C1-10烷基，最优选C1-6烷基；C3-20环烷基，优选C3-15环烷基，更优选C3-10环烷基，最优选C3-7环烷基；C3-20杂环基，优选C3-15杂环基，更优选C3-10杂环基，最优选C3-7杂环基；C6-20芳基，优选C6-15芳基，更优选C6-10芳基，最优选C6-8芳基；C7-20芳烷基，优选C7-15芳烷基，更优选C7-10芳烷基，最优选C7-8芳烷基；C5-20杂芳基，优选C5-15杂芳基，更优选C5-10杂芳基，最优选C5-8杂芳基；或C5-20杂芳烷基，优选C5-15杂芳烷基，更优选C5-10杂芳烷基，最优选C5-8杂芳烷基。
优选地，R4为氢原子、羟基、甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基；异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基；环丙基、环丁基、环戊基、环己基、环庚基、甲基环丙基、二甲基环丙基、甲基环丁基、二甲基环丁基、甲基环戊基、二甲基环戊基、甲基环己基、二甲基环己基；苯基、苄基、甲苯基、乙基苯基、萘基、蒽基、菲基、或芘基；优选氢原子、羟基或甲基。
例如R4可以是用于R1和R3中定义的基团。
其中，步骤(b)进一步包括：
(b2)结构式5的化合物水解，生成结构式6的嘧啶化合物，
Figure PCTCN2014095008-appb-000007
其中，M为H或金属离子。
优选地，所述金属离子选自碱金属离子或碱土金属离子，优选锂(Li)、钠(Na)、钾(K)、钙(Ca)离子。
优选地，步骤(b)进一步包括：
(b2’)结构式5的化合物在碱性条件下水解，生成结构式6′的嘧啶羧酸盐，然后在酸的条件下生成结构式7的嘧啶羧酸，
Figure PCTCN2014095008-appb-000008
优选地，M′为金属离子，优先选自碱金属离子或碱土金属离子，优选锂(Li)、钠(Na)、钾(K)。
在一种优选的实施方式中，本发明涉及使用一种新颖的催化剂制备如结构式1的化合物：
结构式1：
Figure PCTCN2014095008-appb-000009
R和R2是低级烷基，R1和R3是烷基、芳基或芳烷基中的一种，可以是相同或不同的基团。优选地，合成过程在催化剂作用下不使用任何其他溶剂。
结构式1的化合物是制备各种各样杂环化合物的重要中间体，这些杂环化合物是药物，农业和其他相关工业化学制品的有用组分。
本发明公开了铁粉作为一种新颖、便宜且易操作的催化剂用于制备2-(烷氧基亚烷基)-3-氧代羧酸酯(结构式1)，
其中R和R2是低级烷烃，R1和R3是烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基的一种，可以是相同或不同的基团。该方法为：
结构式2的3-氧代羧酸酯
结构式2：
Figure PCTCN2014095008-appb-000010
与结构式3的原酸酯反应
结构式3：
Figure PCTCN2014095008-appb-000011
不使用溶剂，在催化剂(铁粉)的作用下反应生成结构式1的化合物。发明人出乎意料地发现在该催化剂的作用下使反应更加高效和经济实用。该方法可以简单的用于结构式1化合物的放量生产，且反应产物能够通过简单蒸馏达到分离纯化的效果，而且能够直接用于制备杂环化合物的反应中。
形成的嘧啶类化合物可以通过蒸馏的方法来分离纯化，该方法在工业化生产中很容易实现。
在一种优选的实施方式中，本发明公开了一种新颖的催化剂(铁粉)用于制备2-(烷氧基亚烷基)-3-氧代羧酸酯(结构式1)，该羧酸酯能够用于制备各种各样的杂环化合物，尤其是嘧啶衍生物，特指嘧啶羧酸。本发明的方法如方案1所示：
方案1：
Figure PCTCN2014095008-appb-000012
由2-(烷氧基亚烷基)-3-氧代羧酸酯(结构式1)制备嘧啶的方法是已知的(例如US2005002714)。
例如，制备嘧啶的工艺如方案2所示。
方案2：
Figure PCTCN2014095008-appb-000013
其中R和R2是低级烷烃，优选是甲基和乙基；同时R1和R3是氢原子、烷基、芳基或芳烷基的一种，可以是相同或不同的基团，R1和R3优选为氢原子和烷基，烷基优选为甲基、乙基和丙基；R4可以是氢原子、羟基、烷基和芳基，优选是氢原子、甲基和羟基。
方案1中所述的反应用以下方法能得到更好的结果：一种3-氧代羧酸酯(如乙酰乙酸乙酯，乙酰乙酸甲酯)与一种自身作为溶剂的羧酸酯(例如原乙酸三甲酯)在催化剂(如铁粉)存在的情况下，回流反应，同时持续地蒸馏出与羧酸酯共沸的副产物相应的醇，以推动反应平衡向产物方向移动。更具体地说，反应通过蒸馏的方法带走生成的相应甲醇或乙醇(如甲醇或乙醇与原乙酸三甲酯共沸)等副产物使产物顺利转化完成反应。该产品可在过滤掉催化剂后直接用于下一步生成杂环的反应，特别是嘧啶类化合物的合成。
方案2中所描述的不同反应阶段，包含一种适宜的溶剂或两种或多于两种溶剂的混合物以及一种碱，常见的有在回流步骤中以乙醇为溶剂，乙醇钠作为碱进行反应；在水解步骤中四氢呋喃为溶剂，氢氧化钠水溶液作为碱来反应。
反应优选是在带有维格勒列夹套的封管中进行(加热温度可达200℃)。醇和羧酸酯在适当的温度下会从体系中蒸馏除去；常见的情况是甲醇和乙酰乙酸乙酯共沸(80℃)，反应温度可升至140℃至无其他馏分从体系中蒸出，或者由合适的条件(例如气相色谱)来对反应进行监控，至反应体系中产物不再增加。反应一般条件下根据情况要持续3-72小时。
三烷基酯与3-氧代羧酸酯的摩尔比是1:1到2:1之间，优选是1:1到1.3:1，催化剂与3-氧代羧酸酯的重量比是1:200到1:500之间，优选是1:250到1:300。
在理论上，使用相同取代基(即R2与R相同)的酯进行反应，避免了酯基团之间的交换，能得到更好的结果，但是最终的水解反应能消除由于3-氧代羧酸酯和羧酸酯的不同酯基带来的影响。优选的起始原料是便宜易得的物质。
更适宜的酯基是低级烷醇，尤其是甲基酯和乙基酯类，这样得到的副产物是甲醇或乙醇，能够更简单地从体系中除去。
结构式1的产品能够通过过滤掉催化剂的简单操作后，蒸馏得到分离，杂环酯可通过真空蒸馏或重结晶得到分离纯化。所有的产品经过核磁共振谱或质谱得以表征。
在一个优选的实施方案中，本发明涉及结构式2a化合物作为初始原料进行反应的方法。
Figure PCTCN2014095008-appb-000014
结构式2a
如结构式3a所示的初始原料：
Figure PCTCN2014095008-appb-000015
结构式3a
铁粉作为催化剂用于方案3中结构式1a的原料的制备。
Figure PCTCN2014095008-appb-000016
结构式1(a)
结构式1a的化合物能够进一步用于制备方案4中所提及的嘧啶衍生物等杂环，它们是药物，农业和其他相关工业化学制品的有用组分。
方案4：
Figure PCTCN2014095008-appb-000017
在这种情况下选择的原料是现成的，更经济实用的物质，乙酰乙酸乙酯和原甲酸三乙酯，铁粉作为催化剂，更适合于大规模放量生产。
尽管使用相同取代基的酯进行反应，避免了酯基团之间的交换，能得到更好的结果，但是最终的水解反应能消除由于3-氧代羧酸酯和羧酸酯的不同酯基带来的影响。优选的起始原料是便宜易得的物质(乙酰乙酸乙酯和原甲酸三乙酯)。
本发明公开了铁粉作为一种新颖、便宜且易操作的催化剂用于由3-氧代羧酸酯制备2-(烷氧基亚烷基)-3-氧代羧酸酯，该羧酸酯能够用于制备各种各样的杂环化合物，例如嘧啶，它是药物，农业和其他相关工业化学制品的重要中间体。
与现有技术相比，本发明的方法使用了一种便宜且易得到的催化剂——铁粉；同时采用了更高效的分离纯化方法——蒸馏；反应中未使用其他溶剂，羧酸酯作为溶剂，能容易地回收和再利用。该方法更加高效和经济实用，并且适用于工业化生产。
本发明的产品，以结构式1化合物为代表，是制备各种带有取代基的杂环化合物的重要中间体。
这样杂环化合物包括但不限于，5-羧酸酯嘧啶、取代基为羧酸酯的吡啶酮、取代基为羧酸酯的吡唑类、取代基为羧酸酯噁唑和带有取代基的吡唑并吡啶酮。这些带有取代基的杂环化合物是药物，农业和其他相关工业化学制品的有用组分。
特别指出的是，带有取代基的嘧啶衍生物是一些有用的药剂中间体。例如，HMGCoA还原酶抑制剂(EP0022478)；钙通道拮抗剂(WO02/022588)；CCR5拮抗剂在多篇专利中均有报道：US6391865B1；US2002/0147192A1；US2005/0261310A1；US2008/0249087A1；US2009/0270336A1，以及该系列的专利涉及到的其他化合物。
实施例
以下非限制性的例子是为了展示本专利，而不应解释为对本发明的限制。
实施例1
实施例1a(小试数据)
Figure PCTCN2014095008-appb-000018
在1000ml玻璃瓶中加入乙酰乙酸乙酯(105g)、原乙酸三甲酯(330g)、铁粉(3.0g)，反应液内温达到120℃，蒸馏口温度在60℃，一边加热一边蒸馏出馏分,HPLC监测反应进程，无反应原料乙酰乙酸乙酯后停止反应，降温至40℃，减压蒸出馏分得232.7g，过滤铁粉，得到产品125.8g，收率83.7％。1H NMR(CDCl3)：δ1.27,1.33(3H，m,CH3),δ2.33,2.36,2.43(6H,3s,CH3),δ3.77(3H,s,CH3),δ4.21,4.31(2H,m,CH2)。LC-MS:化学式C9H14O4,M+1:187.09(理论值)，187.1(实测值)。
Figure PCTCN2014095008-appb-000019
在反应瓶中加入无水乙醇40mL，开动搅拌，在60℃以下氮气保护下分批加入金属钠0.69g，待钠完全溶解后，分批加入醋酸乙脒1.98g，然后控制温度在50-60℃，滴加2-(甲氧基亚烷基)-3-氧代乙酸乙酯3.6g。滴加完毕，反应至TLC检测无反应原料。将反应液降温至25-30℃，蒸除乙醇。浓缩的残留物加入乙酸乙酯，分别以水和饱和食盐水洗涤，干燥，除去乙酸乙酯后，残液经减压蒸馏得到产品。
Figure PCTCN2014095008-appb-000020
在反应瓶中加入2,4,6-三甲基-5-嘧啶甲酸乙酯(19.4g)，氢氧化钠(3.45g)和水(100mL)，50℃下搅拌至TLC监测反应完成。用乙酸乙酯萃取水相两次，水相用浓盐酸调节pH值为1.5，过滤出沉淀的固体，滤液浓缩后用少量乙酸乙酯重结晶得到固体，合并得到产品。
实施例1b(工业化生产规模)：
Figure PCTCN2014095008-appb-000021
在100L搪瓷釜中，加入乙酰乙酸乙酯(17.5kg)，原乙酸三甲酯(55kg)和铁粉(56g)。开动搅拌导热油升温。当搪瓷釜内温达到120℃左右时控制蒸馏口温度，一边加热一边蒸馏出馏分，TLC监测反应进程，无反应原料乙酰乙酸乙酯后停止反应。降温，减压蒸出过量的原乙酸三甲酯和其它副产物(搪瓷釜内温控制在100℃以下)。继续降温，反应釜下口放料，过滤铁粉。进一步蒸馏滤液得到2-(甲氧基亚烷基)-3-氧代乙酸乙酯，收率为60％，或将滤液直接用于下一步制备嘧啶类化合物的反应。1HNMR(CDCl3):δ1.27,1.33(3H，m,CH3),δ2.33,2.36,2.43(6H,3s,CH3),δ3.77(3H,s,CH3),δ4.21,4.31(2H,m,CH2)。LC-MS:化学式C9H14O4,M+1:187.09(理论值)，187.1(实测值)。
Figure PCTCN2014095008-appb-000022
在300L搪瓷釜中，加入处理过的无水乙醇144kg，开动搅拌，60℃以下在氮气保护下分批加入金属钠3.3kg，2小时待钠完全溶解后，分批加入真空干燥过的醋酸甲脒10.2kg，然后控制温度在50℃-60℃之间，滴加2-(甲氧基亚烷基)-3-氧代乙酸乙酯18kg。滴加完毕，在此温度保持5小时。TLC检测无原料乙酰乙酸乙酯后，降温至25-30℃，将物料放入离心机，滤液抽到蒸馏釜中减压蒸干乙醇，然后降温至20-25℃左右，加入乙酸乙酯70L，搅拌溶解有机物，然后加入30L水，分出水相，有机相用 饱和食盐水30L洗涤两次，合并以上三次的水相，用乙酸乙酯40L(×2)萃取；合并有机相，无水硫酸镁10kg干燥。最后，蒸除乙酸乙酯。减压蒸馏收集粗品，称重。产物表征：1H NMR(CDCl3)：δ1.42(3H，m,CH3),δ2.54(6H,s,CH3),δ4.5(2H,m,CH3),δ8.96(1H,s,ArH)。
Figure PCTCN2014095008-appb-000023
在200L搪瓷釜中，加入水，开动搅拌加入氢氧化钠。待氢氧化钠完全溶解后加入4,6-二甲基-5-嘧啶甲酸乙酯，升温至50℃保持三小时，TLC检测无原料4,6-二甲基-5-嘧啶甲酸乙酯后降温，乙酸乙酯萃取水相两次，直到无紫外吸收。再将水相降温至0-5℃之间，滴加浓盐酸酸化到pH值为1.5，0-5℃搅拌1小时，离心，滤饼用冰水洗涤两次。滤液浓缩，产品在40-45℃真空干燥。TLC检测还有杂质，分别用29kg和22kg甲苯洗涤过滤，再真空干燥。将产品加到57.6kg无水乙醇和110kg乙腈的混合溶剂中，升温至60℃-75℃使之溶解。降温后析出固体。过滤干燥后得到12.5kg，Mp：199-201℃。收率74.4％。产物表征：1H NMR(D2O):δ2.59(6H，s,CH3),δ9.01(1H,s,ArH),δ4.5(2H,m,CH3),δ8.96(1H,s,CH)。
表5采用铁催化剂，按照实施例1的第一步完成的其他反应如下：
Figure PCTCN2014095008-appb-000024
Figure PCTCN2014095008-appb-000025
当然，本发明还可有其他具体实施方式，以上仅为本发明的优选实施方式，并非用来限定本发明的保护范围；在不背离本发明精神的情况下，本领域普通技术人员凡是依本发明内容所做出各种相应的变化与修改，都属于本发明的权利要求的保护范围。

Claims (22)

  1. 一种制备2-(烷氧基亚烷基)-3-氧代羧酸酯的方法，包括：
    结构式2的3-氧代羧酸酯与结构式3的原酸酯反应，在催化剂铁的存在下反应生成结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯，
    Figure PCTCN2014095008-appb-100001
    其中，
    R和R2相同或不同，各自独立地是C1-C4低级烷基；
    R1和R3相同或不同，各自独立地是氢、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基；
    波浪线表示E或Z异构体。
  2. 根据权利要求1所述的方法，其中，在反应期间，除反应物和产物外，不使用另外的溶剂。
  3. 根据权利要求1或2所述的方法，其中，R和R2相同或不同，各自独立地是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，优选甲基或乙基。
  4. 根据权利要求1至3任一项所述的方法，其中，R1和R3相同或不同，各自独立地是：氢；C1-20烷基，优选C1-15烷基，更优选C1-10烷基，最优选C1-6烷基；C3-20环烷基，优选C3-15环烷基，更优选C3-10环烷基，最优选C3-7环烷基；C3-20杂环基，优选C3-15杂环基，更优选C3-10杂环基，最优选C3-7杂环基；C6-20芳基，优选C6-15芳基，更优选C6-10芳基，最优选C6-8芳基；C7-20芳烷基，优选C7-15芳烷基，更优选C7-10芳烷基，最优选C7-8芳烷基；C5-20杂芳基，优选C5-15杂芳基，更优选C5-10杂芳基，最优选C5-8杂芳基；或C5-20杂芳烷基，优选C5-15杂芳烷基，更优选C5-10杂芳烷基，最优选C5-8杂芳烷基。
  5. 根据权利要求1至4任一项所述的方法，其中，R1和R3相同或不同，各自独立地是氢、甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基；异丙基、 异丁基、仲丁基、叔丁基、异戊基、新戊基；环丙基、环丁基、环戊基、环己基、环庚基、甲基环丙基、二甲基环丙基、甲基环丁基、二甲基环丁基、甲基环戊基、二甲基环戊基、甲基环己基、二甲基环己基；苯基、苄基、甲苯基、乙基苯基、萘基、蒽基、菲基、或芘基。
  6. 根据权利要求1至5任一项所述的方法，其中，R1和R3相同或不同，各自独立地是氢、甲基、乙基、正丙基或异丙基。
  7. 根据权利要求1至6任一项所述的方法，其中，结构式2的3-氧代羧酸酯选自乙酰乙酸甲酯、乙酰乙酸乙酯、乙酰乙酸正丙酯、乙酰乙酸异丙酯；丙酰乙酸甲酯、丙酰乙酸乙酯、丙酰乙酸正丙酯或丙酰乙酸异丙酯；丁酰乙酸甲酯、丁酰乙酸乙酯、丁酰乙酸正丙酯或丁酰乙酸异丙酯；优选乙酰乙酸乙酯。
  8. 根据权利要求1至7任一项所述的方法，其中，结构式3的原酸酯选自甲原酸三甲酯、甲原酸三乙酯、甲原酸三正丙酯、甲原酸三异丙酯；乙原酸三甲酯、乙原酸三乙酯、乙原酸三正丙酯、乙原酸三异丙酯；丁原酸三甲酯、丁原酸三乙酯、丁原酸三正丙酯或丁原酸三异丙酯；优选乙原酸三甲酯。
  9. 根据权利要求1至9任一项所述的方法，其中，结构式3的原酸酯选自甲基酯或乙基酯。
  10. 根据权利要求1至9任一项所述的方法，其中，在反应期间，通过蒸馏将一种或多种反应产物从反应体系中去除。
  11. 根据权利要求1至10任一项所述的方法，其中，所述结构式2的3-氧代羧酸酯为结构式2a的乙酰乙酸乙酯；所述结构式3的原酸酯为结构式3a的原甲酸三乙酯；生成的结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯为结构式1a的化合物：
    Figure PCTCN2014095008-appb-100002
  12. 根据权利要求1至11任一项所述的方法，其中，结构式3的原酸酯与结构式2的3-氧代羧酸酯的摩尔比为1:1到2:1之间，优选是1:1到1.3:1。
  13. 根据权利要求1至12任一项所述的方法，其中，所述催化剂铁与结构式2的3-氧代羧酸酯的重量比是1:200到1:500之间，优选1:250到1:300。
  14. 根据权利要求1至13任一项所述的方法，其中，所述催化剂铁是铁粉。
  15. 一种制备嘧啶化合物方法，包括：
    (a)通过根据权利要求1至14任一项所述的方法制备2-(烷氧基亚烷基)-3-氧代羧酸酯；以及
    (b)以步骤(a)获得的2-(烷氧基亚烷基)-3-氧代羧酸酯为原料，制备嘧啶化合物。
  16. 根据权利要求15所述的方法，其中，步骤(b)包括：
    (b1)在碱存在下，结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯与结构式4的化合物反应，生成结构式5的嘧啶化合物，
    Figure PCTCN2014095008-appb-100003
    其中，
    R4为氢原子、羟基、烷基、环烷基、杂环基、芳基、芳烷基、杂芳基或杂芳烷基。
  17. 根据权利要求16所述的方法，其中，R4为氢原子；羟基；C1-20烷基，优选C1-15烷基，更优选C1-10烷基，最优选C1-6烷基；C3-20环烷基，优选C3-15环烷基，更优选C3-10环烷基，最优选C3-7环烷基；C3-20杂环基，优选C3-15杂环基，更优选C3-10杂环基，最优选C3-7杂环基；C6-20芳基，优选C6-15芳基，更优选C6-10芳基，最优选C6-8芳基；C7-20芳烷基，优选C7-15芳烷基，更优选C7-10芳烷基，最优选C7-8芳烷基；C5-20杂芳基，优选C5-15杂芳基，更优选C5-10杂芳基，最优选C5-8杂芳基；或C5-20杂芳烷基，优选C5-15杂芳烷基，更优选C5-10杂芳烷基，最优选C5-8杂芳烷基。
  18. 根据权利要求16所述的方法，其中，R4为氢原子、羟基、甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基；异丙基、异丁基、仲丁基、叔丁基、异戊基、新戊基；环丙基、环丁基、环戊基、环己基、环庚基、甲基环丙基、 二甲基环丙基、甲基环丁基、二甲基环丁基、甲基环戊基、二甲基环戊基、甲基环己基、二甲基环己基；苯基、苄基、甲苯基、乙基苯基、萘基、蒽基、菲基、或芘基；优选氢原子、羟基或甲基。
  19. 根据权利要求16至18任一项所述的方法，其中，步骤(b)进一步包括：
    (b2)结构式5的化合物水解，生成结构式6的嘧啶化合物，
    Figure PCTCN2014095008-appb-100004
    其中，M为H或金属离子。
  20. 根据权利要求19所述的方法，其中，所述金属离子选自碱金属离子或碱土金属离子，优选锂Li、钠Na、钾K、钙Ca离子。
  21. 根据权利要求19所述的方法，其中，步骤(b)进一步包括：
    (b2’)结构式5的化合物在碱性条件下水解，生成结构式6′的嘧啶羧酸盐，然后在酸的条件下生成结构式7的嘧啶羧酸，
    Figure PCTCN2014095008-appb-100005
    其中，M′为金属离子，优先选自碱金属离子或碱土金属离子，更优选锂Li、钠Na、钾K或钙Ca离子。
  22. 铁在用于由结构式2的3-氧代羧酸酯和结构式3的原酸酯制备结构式1的化合物中作为催化剂的用途，
    Figure PCTCN2014095008-appb-100006
    其中，结构式2的3-氧代羧酸酯、结构式3的原酸酯和结构式1的2-(烷氧基亚烷基)-3-氧代羧酸酯和/或反应条件如权利要求1至14所限定。
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