CN1223250A - Preparation method of acetal, semi-acetal and glyoxal hydrate - Google Patents

Abstract

The invention discloses a preparation method of acetal, hemiacetal and glyoxal hydrate, and the steps included are described in detail in the description.

Description

Preparation method of acetal, semi-acetal and glyoxal hydrate

This application is a divisional application of CN 91108911.X. The filing date of the original application was September 10, 1991; the title of the invention of the original application was "the preparation method of salbutamol and its intermediate".

The present invention relates to the preparation of acetals, hemiacetals and arylglyoxal hydrates, which can be used as intermediates for the preparation of said arylethanolamines, especially salbutamol.

British Patent Specification No. 1,200,886 discloses certain arylethanolamines, which are pharmaceutically active compounds useful as antihypertensive agents and bronchodilators, and two processes for their preparation.

The preparation of salbutamol by condensation of haloacetophenones with benzyl-protected tert-butylamines has been reported in: British Patent Specification 1,200,886; "Pharmazeutische Wirkstoffe (Synthesen, Patente, Anwendungen)", Vol.5, Kleeman and Engel (2nd ed. New York and Stuttgart) P.813, 1982; and "Pharmaceutical Manufacturing Encyclopedia", 2nd Edition, Vol.1, by Marshall Sittig, Noyes Publication, Park Ridge, New Jersey, USA, 1988, pp. 31-33. The disadvantage of these methods is that the yield of salbutamol is low, while also producing large amounts of unwanted by-products. The inefficiency is due in part to hydrogenation that must use multiple reducing agents (eg, lithium aluminum hydride, sodium borohydride) and palladium/carbon catalysts, plus multiple purification steps. Another source of inefficiency is the necessity to use a benzyl protecting group on the amine to avoid dialkylation of the amine, which would require further deprotection and purification steps.

British Patent Specification 1,247,370 teaches the preparation of salbutamol by condensation of t-butylamine with arylglyoxal followed by multiple reductions with lithium aluminum hydride and sodium borohydride. This patent also pointed out a kind of preparation method of aryl glyoxal, and this method is multi-step, adopts low temperature (for example: room temperature) and longer reaction time (for example: up to a week), makes unstable aryl The undesirable phenomenon of polymerization of glyoxal is minimized. The disadvantage of this method is the low yield of salbutamol and the large amount of unwanted by-products.

Arylglyoxals are common intermediates in the preparation of pharmaceutical compounds. Conventional methods for the preparation of arylglyoxal compounds are well known in the art. N.Kornblum, J.W.Powers, G.J.Anderson, W.J.Jones, H.O.Larson, O.Levand and W.M.Weaver [JACS, Vol.79(1957) p.6562]; J.March [Advanced Organic Chemistry, Reactions, Mechanisms and Structure, 3rded .John Wiley &Sons; New York, New York, (1985) pp.1081-1083] and British Patent Specification 1247370 pointed out the method of oxidizing the ester of primary halide and primary alcohol with dimethyl sulfoxide to generate aldehyde. M.B.Floyd; M.T.Du, P.F.Fabio, L.A.Jacob and Berrard D.Johnson [J.Org.Chem.Vol.50(1985)pp.5022-5027] and R.Desmond, S.Mills, R.P.Volante and I.Shinkai [Synthetic Comm. Vol. 19 (3 and 4) (1989) pp. 379-385] discloses a method of producing glyoxal by reacting acetophenone and hydrobromic acid aqueous solution in dimethyl sulfoxide. G.Cardillo, M.Orena and S.Sandi [J.C.S.Chem.Comm.(1976)pp.190] disclose the preparation of Aldehyde method. K.R. Henery Logan and T.L. Fridinger [Chemical Communications (1968) pp. 130-131] disclose the conversion of α,α-dichloroacetophenone to phenylglyoxal by treatment with sodium methoxide in methanol. V.E.Gunn and J.P.Anselme [J.Org.Chem.Vol.42, No.4, (1977) pp.754-75] disclosed the use of N,N-diethyl and N,N-dibenzylhydroxylamine to convert benzene Formyl bromide is converted to phenylglyoxal. H.A.Rilley and A.R.Gray [OrganicSynth.Coll.Vol.2, pp.509-511] disclose the method of converting acetophenone into phenylglyoxal by using selenium dioxide as an oxidizing agent. The methods described above have serious limitations. For example, much of the literature teaches the direct preparation of arylglyoxals, which are labile or unstable. Moreover, these methods are not suitable for the preparation of arylglyoxals from a wide range of substrates or precursors. In addition, most of the above methods use toxic oxidizing agents such as selenium oxide, chromate, etc., which are not suitable for the preparation of pharmaceutical compounds.

In addition, we have found that the use of aqueous hydrogen bromide as a brominating agent is inappropriate for certain aryl substrates because the use of aqueous reagents can lead to undesired ring bromination.

In view of the problems with the processes taught in the prior art, it is clear that there is a need to provide a process for the preparation of arylethanolamines such as salbutamol which produces higher yields with less waste or by-products. It is also necessary to provide a new intermediate or derivative for the preparation of salbutamol, so that the preparation method of the compound can be simplified. We have surprisingly found that the above objects can be achieved by using specific precursors for the preparation of arylglyoxal hydrates, namely: acetals and hemiacetals. These acetals and hemiacetals are much more stable than arylglyoxal hydrates, and the protecting groups can be removed under mild conditions to produce the desired arylglyoxal hydrates. Furthermore, we have discovered a single reducing agent which can be used in the preparation of salbutamol instead of the composite reducing agents described in British Patents 1,247,370 and 1,200,886. There is also a need to provide a process which requires fewer reaction steps and purification steps than the prior art. Furthermore, it is necessary to provide an efficient method for the preparation of acetal and hemiacetal derivatives, which can be used as substrates or precursors for the preparation of the desired arylglyoxal hydrates . The use of such intermediates and methods is believed to overcome the limitations and problems in the methods for preparing salbutamol in the above-mentioned references.

    和     式中Y是OR¹⁷或OH，其中，R¹⁷是C-1至C-6烷基；R³和R⁵各自代表氢、烷基、芳基或取代芳基。最好Y是-OCH₃,R³代表H,R⁵代表叔丁基。硼芳基乙醇胺络合物(ⅩⅢ)可用作制备芳基乙醇胺(如柳丁醇胺)的有价值的中间体。In a first embodiment, the present invention is aimed at novel boron arylethanolamine complexes, the monomeric forms of which are shown in A and B of formula (XIII):

and In the formula, Y is OR ¹⁷ or OH, wherein, R ¹⁷ is C-1 to C-6 alkyl; R ³ and R ⁵ each represent hydrogen, alkyl, aryl or substituted aryl. Preferably Y is -OCH ₃ , R ³ represents H, and R ⁵ represents tert-butyl. The boron arylethanolamine complex (XIII) is useful as a valuable intermediate for the preparation of arylethanolamines such as salbutanolamine.

式中R³和R⁵各自代表氢、烷基、芳基或取代芳基。该方法包括将第一实施例中硼芳基乙醇胺络合物(ⅩⅢ)-A和-B裂解’，给出期望的芳基乙醇胺(ⅪⅤ)。最好通过向反应混合物中加入酸和醇来裂解芳基乙醇胺络合物(ⅩⅢ)-A和-B。将反应混合物蒸馏以除去用过的硼也是优选的。式中R³是H,R⁵是叔丁基的芳乙醇胺(ⅪⅤ)称为沙丁胺醇。In the second embodiment, the object of the present invention lies in the preparation method of following formula arylethanolamine:

In the formula, ^R3 and ^R5 each represent hydrogen, alkyl, aryl or substituted aryl. This method involves cleaving the boronarylethanolamine complex (XIII)-A and -B' of the first example to give the desired arylethanolamine (XIV). The arylethanolamine complexes (XIII)-A and -B are preferably cleaved by adding acid and alcohol to the reaction mixture. It is also preferred to distill the reaction mixture to remove used boron. In the formula, R ³ is H, and R ⁵ is tert-butyl aryl ethanolamine (ⅪⅤ) called albuterol.

式中R³和R⁵与第二实施例的定义相同；Ar’是   或   

式中R⁹代表氢或酰基；R¹¹代表氢或烷基。硼-硫醚试剂最好具有如下结构：

其中R¹³和R¹⁵可以相同或不同，代表C-1至C-6烷基，或与硫原子一起代表含有3～6个碳原子和1或2个碳或氧原子的环；或者与硫原子一起代表聚合硫烃。In a third embodiment, the present invention is directed to a process for the preparation of arylethanolamines of formula (XIV) comprising reduction of a Schiff base of formula below with a borane-thioether reagent to give (XIV).

In the formula, R ³ and R ⁵ are as defined in the second embodiment; Ar' is or

In the formula, R ⁹ represents hydrogen or an acyl group; R ¹¹ represents hydrogen or an alkyl group. The boron-thioether reagent preferably has the following structure:

Wherein R ¹³ and R ¹⁵ can be the same or different, represent C-1 to C-6 alkyl, or together with sulfur atom represent a ring containing 3-6 carbon atoms and 1 or 2 carbon or oxygen atoms; The atoms together represent a polymeric thiohydrocarbon.

式中Ar’和R³的定义同第三实施例，R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基。In the fourth embodiment of the present invention, the Schiff base (XI) of the third embodiment is obtained by combining glyoxal hydrate (IX) or hemiacetal (V) with amine H ₂ NR ⁵ (X) (wherein R ⁵ is as defined above) prepared by contacting. Formula (IX) and formula (V) are as follows:

In the formula, the definition of Ar' and R is the same as that of the ^third embodiment, and R represents alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted Aralkyl, heterocyclyl or heterocycloalkyl.

    和    

式中Ar’和R³的定义同第二和第三实施例，R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基。In the fifth embodiment of the present invention, the glyoxal hydrate (IX) of the fourth embodiment is prepared by hydrolyzing acetal (VII) or hemiacetal (V):

and

In the formula, the definition of Ar' and R is the same as that of the ^second and third embodiments, and R represents alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl group, substituted aralkyl group, heterocyclyl group or heterocycloalkyl group.

In the sixth embodiment of the present invention, the glyoxal hydrate (VII) or hemiacetal (V) of the fifth embodiment is obtained by combining the compound of formula (II) with sulfoxide and alcohol ROH (R) The fourth embodiment) made by contacting, the formula (II) is as follows: In the formula, the definitions of Ar' and R are the same as those in the second or ^third embodiment, and L is a leaving group, such as bromine, chlorine, iodine, methanesulfonyl, trifluoromethanesulfonyl, brosylate , Tosylate group. Alternatively, the compound of formula (I) is contacted with a halogenating agent, sulfoxide and alcohol ROH to obtain acetal or hemiacetal (VII) or (V), and the formula (I) is as follows: The definitions of Ar' and ^R3 are the same as those in the second or third embodiment.

    和     的制备方法。上式中Ar代表芳基或取代芳基，R代表烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、取代芳基、芳烷基、取代芳烷基、杂环基或杂环烷基，且，R³代表氢、烷基、芳基或取代芳基。该方法包括将式(Ⅱ)化合物与亚砜和醇ROH(R如上文定义)接触，式(Ⅱ)如下：

其中Ar和R³如上文定义，L是离去基，例如：溴、碳、氯、甲磺酰基、三氟甲磺酰基、对溴苯磺酸酯基或甲苯磺酸酯基。或者，将式(Ⅰ)化合物与卤化剂、亚砜和醇ROH接触制得乙缩醛或半乙缩醛(Ⅶ)或(Ⅴ)，式(Ⅰ)如下：

其中Ar和R³的定义同前。In a seventh embodiment, the invention targets acetals and hemiacetals.

and method of preparation. In the above formula, Ar represents aryl or substituted aryl, R represents alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl , heterocyclyl or heterocycloalkyl, and R ³ represents hydrogen, alkyl, aryl or substituted aryl. The process comprises contacting a compound of formula (II) as follows with sulfoxide and alcohol ROH (R is as defined above):

wherein Ar and ^R3 are as defined above and L is a leaving group such as bromine, carbon, chlorine, methanesulfonyl, trifluoromethanesulfonyl, brosylate or tosylate. Alternatively, the compound of formula (I) is contacted with a halogenating agent, sulfoxide and alcohol ROH to obtain acetal or hemiacetal (VII) or (V), and the formula (I) is as follows:

Wherein Ar and R ³ are as defined above.

其中Ar和R³的定义同第七实施例。该方法包括将第七实施例制得的乙缩醛(Ⅶ)或半乙缩醛(Ⅴ)水解得到水合物(Ⅸ)。In the eighth embodiment, the object of the present invention is the preparation method of glyoxal hydrate of formula (IX). Formula (Ⅸ) is as follows:

Wherein the definition of Ar and ^R3 is the same as that of the seventh embodiment. The method comprises hydrolyzing the acetal (VII) or hemi-acetal (V) prepared in the seventh embodiment to obtain the hydrate (IX).

其中Z是-NH₂,-OH或OR⁶,R⁶代表氢或1～10个碳原子的烷基；R⁷和R⁸各自代表氢，烷基、取代烷基、环烷基、环烷基烷基、羟烷基、芳基、芳烷基、取代芳烷基、杂环基或杂环烷基，其前提是R⁷和R⁸不都是氢，或R⁷和R⁸与氧原子一道形成五元或六元环。最好R⁷和R⁸代表氢或1～10个碳原子的烷基，但必须R⁷或R⁸只有一个是烷基，最好是1-4个碳原子的烷基。最佳的是Z是-OCH₃,R⁷和R⁸各自代表甲基、异丙基或正丁基。In the ninth embodiment, the object of the present invention lies in the preparation method of the compound of the following formula:

Where Z is -NH ₂ , -OH or OR ⁶ , R ⁶ represents hydrogen or an alkyl group of 1 to 10 carbon atoms; R ⁷ and R ⁸ each represent hydrogen, alkyl, substituted alkyl, cycloalkyl, cycloalkane ylalkyl, hydroxyalkyl, aryl, aralkyl, substituted aralkyl, heterocyclyl, or heterocycloalkyl, provided that ^R7 and ^R8 are not both hydrogen, or ^R7 and ^R8 are combined with oxygen Together the atoms form a five- or six-membered ring. Preferably R ⁷ and R ⁸ represent hydrogen or an alkyl group of 1-10 carbon atoms, but only one of R ⁷ or R ⁸ must be an alkyl group, preferably an alkyl group of 1-4 carbon atoms. Most preferably Z is -OCH ₃ , and R ⁷ and R ⁸ each represent methyl, isopropyl or n-butyl.

Compared with other known methods, the advantage of the present invention is that it can more efficiently and economically produce certain arylethanolamines, such as salbutamol, through acetal, hemiacetal and arylglyoxal hydrate intermediates , that is, high yield, high purity, short time and less by-products. The advantage of the present invention is that it can provide new intermediates, such as boronarylethanolamine complexes (XIII), acetals and hemiacetals (XX), which can be used to simplify the preparation of salbutamol. In one embodiment, it is an advantage of the present invention to provide a method for the reduction of three different groups in the same molecule using a single reducing agent. In another embodiment, the method for preparing arylglyoxal hydrate of the present invention has the advantage of being applicable to a wide range of substrates. A further advantage of the present invention is the ability to prepare arylglyoxal compounds, acetals and hemiacetals at temperatures above room temperature with little or no by-products resulting from the polymerization of unstable arylglyoxals . An advantage of the present invention when using a brominating agent is that anhydrous hydrogen bromide or bromine can be utilized to reduce or eliminate ring bromination. A further advantage is that it requires far fewer reaction steps or purification steps than other existing methods.

等，以免参与反应。当然也可以使用本领域公知的其他保护基。经一次或多次反应后，保护基可用本领域公知的标准方法除去，例如用无机酸(如：盐酸)水解；卤素一代表氟、氯、溴或碘；三卤甲基一代表三氯甲基和三氟甲基；烷氧基一代表通过氧原子共键价连结的上文定义的烷基，例如：甲氧基、乙氧基、丙氧基、戊氧基、己氧基、癸氧基等；羧基一代表-COOH基团；且巯基一代表-SR’基团，其中R’代表烷基或芳基聚合硫烃一代表含硫、氢和碳原子的聚合物，硫原子以硫醚构型存在于聚合硫烃中，即，-C-S-C构型。Unless otherwise stated, the terms used herein are defined as follows: Alkyl-represents a straight-chain saturated hydrocarbon group having 1-10 carbon atoms, preferably 1-6 carbon atoms; or represents a branched hydrocarbon group containing 3-10 carbon atoms Chain hydrocarbon groups, preferably with 3-6 carbon atoms, such as: methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, dodecyl, etc.; "substituted alkyl The term "group" refers to an alkyl group with one or more hydrogen atoms substituted by halogen, hydroxyl, aryl or cycloalkyl; cycloalkyl-represents a saturated hydrocarbon ring containing 3-10 carbon atoms, preferably containing 3 - 6 carbon atoms, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. Acyl - represents a -CO-J group, wherein J represents an alkyl, cycloalkyl or aryl group. Aryl-represents a carbocyclic group containing at least one benzene-type ring, the aromatic ring part containing 6-14 carbon atoms, such as phenyl, naphthyl, indenyl, indanyl, etc.; the term "substituted aryl" is refers to an aryl group substituted by one to three substituents respectively selected from the group consisting of aryl, alkyl, alkoxy, halogen, trihalomethyl, cyano, nitro, -CONH ₂ , hydroxyl, Protected hydroxy, hydroxyalkyl, protected hydroxyalkyl, mercapto or carboxyl groups and salts or esters thereof. Aralkyl or substituted aralkyl-refers to a group formed by bonding an alkyl group to an aryl group or a substituted aryl group, for example: benzyl, 2-chlorophenethyl, etc. Heterocyclic group-represents a cyclic group containing at least one O, S and/or N atom in a carbocyclic ring, and has a sufficient number of delocalized π electrons to provide aromaticity. The aromatic heterocyclic group has 2-14 ( 2-16 better) carbon atoms. For example 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 1-, 2-, 4- or 5- Imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, 3- or 4-pyridazinyl, 3-, 5- or 6-(1,2,4-triazinyl), 3 - or 5-(1,2,4-thiadiazolyl), 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 1-, 2-, 3-, 4- , 5-, 6-, or 7-indolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, etc.; A group formed by bonding a group with a heterocyclic group; hydroxyalkyl-represents an alkyl group as defined above, wherein one of the hydrogen atoms is replaced by a hydroxyl group, for example: hydroxymethyl, 2-hydroxyethyl, etc.; Protected hydroxy or protected hydroxyalkyl-represents a hydroxy or hydroxyalkyl as defined above, wherein the hydroxy is converted into a protected group such as -OCH ₃ , -OCH ₂ phenyl, =OCOCH ₃ , -OSi( CH ₃ ) ₃ , -OSi(CH ₃ ) ₂ (tert-butyl),

etc. so as not to participate in the reaction. Of course other protecting groups known in the art may also be used. After one or more reactions, the protecting group can be removed by standard methods known in the art, such as hydrolysis with mineral acid (such as: hydrochloric acid); halogen - represents fluorine, chlorine, bromine or iodine; trihalomethyl - represents trichloromethane and trifluoromethyl; alkoxy - represents an alkyl group as defined above covalently bonded through an oxygen atom, for example: methoxy, ethoxy, propoxy, pentyloxy, hexyloxy, decyl Oxygen, etc.; carboxyl group - COOH group; and mercapto group - SR' group, where R' represents alkyl or aryl polymeric sulfur hydrocarbon - polymer containing sulfur, hydrogen and carbon atoms, sulfur atom in The thioether configuration exists in polymeric thiohydrocarbons, ie, the -CSC configuration.

This method and the intermediates relevant to the present invention are shown in the following reaction schemes, wherein Ar, Ar', R3 and R5 are defined by the above formulas (ⅪⅤ), (Ⅺ), (Ⅴ), (Ⅶ) and Hal is a halogen , L is the leaving group:

In the formula, Hal represents a halogen (such as chlorine, bromine or iodine) and ^R represents hydrogen, an alkyl or an aryl compound of formula (II) which can be obtained by combining a compound of formula (I) with a halogenating agent and a sulfoxide such as dimethyl sulfoxide contact to prepare. The halogenating agent used may be selected from a broad class of compounds capable of introducing a halogen element, preferably chlorine or bromine, into compound (1). Such halogenating agents include, but are not limited to, bromine ( _Br2 ), iodine ( _I2 ) chlorine ( _Cl2 ), hydrogen bromide (HBr) and hydrogen chloride (HCl). The halogenating agent is used in an amount of about 2 moles to a catalytic amount of the halogenating agent, preferably about 0.8 to about 0.4 moles, per mole of the compound (I). The reaction is best carried out under anhydrous or substantially anhydrous conditions. Methods for using such reagents are well known and can be found in J. March, Advanced Organic Chemistry. Reactions, Mechanisms and Structure, Third Edition, John Wiley and Sons, New York, (1985), 1346pp. mentioned. The sulfoxides used may be alkyl sulfoxides in which each alkyl substituent has one to four carbon _atoms , for example: dimethylsulfoxide (ie _CH3SOCH3 or DMSO), diethylsulfoxide, dipropylene sulfoxide and dibutyl sulfoxide, most preferably DMSO. The consumption of sulfoxide is from excess to about 2: 1 mole compound (1) [sulfoxide mole number: 1 mole compound (I)], preferably with about 20-4 mole sulfoxide, about 10-6 mole sulfoxide is better , preferably about 6 moles of sulfoxide. The compound of formula (II') can be prepared by contacting compound (I') with an acidic chloride of formula LCl in the presence of a base, wherein L is a leaving group, and typical leaving groups include tosyl, three For fluoromethanesulfonyl, p-bromophenylsulfonyl and methylsulfonyl, etc., see the above-mentioned J. March, pp. 444 and 628.

Acetal (VII) and hemiacetal (V) can be obtained by compound (II) or (II') with sulfoxide and alcohol ROH (wherein R is alkyl, cycloalkyl, hydroxyalkane as defined above group or aryl) by contacting, and the amount of sulfoxide used is similar to that of the above-mentioned preparation of compound (II). Alcohols used in the preparation of acetal (VII) and hemiacetal (V) can be a large class of organic compounds containing hydroxyl groups, see Condensed Chemical Dictionary (10th edition, rewritten by Gessner G. Hawley, Van Nostrand Reinhold Company , New York, 1981) definition. Alcohols can be monohydric (one -OH group) or dihydric (two -OH groups - diol) alcohols. Typical monohydric alcohols include methanol (ie, _CH3OH ), ethanol, propanol, isopropanol, n-butanol, n-hexanol, 4-methyl-2-pentanol, and the like. Monohydric alcohols also include C-3 to C-8 cyclic alcohols, such as: cyclohexanol, cycloheptanol, etc.; C-6 to C-15 aromatic alcohols, such as: phenol, benzyl alcohol, 1-naphthol, etc.; and hetero Cyclic alcohols, such as; 2-hydroxypyridine, furfuryl alcohol, etc. Diols may include C-2 to C-10 diols, such as ethylene glycol, propylene glycol, 1,2-butanediol, 1,4-butanediol, pentanediol, and the like. Where appropriate, mixtures of the aforementioned alcohols, such as mixtures of two or more monohydric alcohols or mixtures of monohydric and dihydric alcohols, may also be used. The amount of alcohol used can range from excess to about 2:1 (moles of ethanol: 1 mole of compound (II)), preferably about 30-10 moles of alcohol, most preferably about 20-15 moles of alcohol. In general, the use of a higher amount of alcohol tends to make the acetal acetal (VII) easier to form than the hemiacetal (V).

The reactants are usually stirred during the reaction. The reactants can be contacted for a sufficient time to complete the desired reaction, as observed by the disappearance of starting materials. This time will depend on the temperature and reagents used, and can range from about 15 minutes to 24 hours or longer, preferably about 1 hour.

Acetal (VII) and hemiacetal (V) can be recovered by conventional methods, such as: solvent extraction, filtration, phase separation, crystallization, etc. Generally, the mixture is added to ice water, and the precipitate is filtered to obtain the desired acetal (V) and hemiacetal (VII).

Arylglyoxal hydrate (IX) can be prepared by the conventional method of hydrolyzing acetal (VII) and hemiacetal (V) in the reaction mixture with inorganic or organic acid (such as: hydrochloric acid, sulfuric acid or acetic acid) . The amount of acid can range from excess to about 0.1 mol of acid per mole of acetal (VII) or hemiacetal (V), and about 10- 0.5 molar acid is better. Similarly, the acid can be contacted with any isolated or recovered acetal (VII) or hemiacetal (V) to give the arylglyoxal hydrate. When there is already sufficient acid for hydrolysis in the reaction mixture containing acetal (VII) and hemiacetal (V), it is not necessary to add additional acid to the reaction mixture.

上式中，R³最好是氢。Arylglyoxal hydrate (IX) can be transformed into its corresponding arylglyoxal (IX') after dehydration, as shown by the following equilibrium:

In the above formula, ^R3 is preferably hydrogen.

The process of the present invention is preferably carried out without the use of any solvent other than excess of the reactants themselves. However, when an external solvent is used, the solvent may include aromatic hydrocarbons, such as xylene, benzene, toluene, etc.; or alkanes with 6-10 carbon atoms. When additional solvent is used, the amount of solvent used ranges from an excess of either reactant to sufficient to at least partially solvate one or more reactants and/or the desired product. It is worth noting that the conversion of compound (I) to glyoxal hydrate (IX) can be conveniently carried out in a single kettle or reaction vessel with high yield, as described in Example 1 below.

Schiff base (XI) can be obtained by condensation of hemiacetal (V) or arylglyoxal hydrate (IX) with primary amine H ₂ NR ⁵ (X), wherein R ⁵ is as defined above. Preferably the reactants are equimolar or in excess of a less expensive reactant (usually an amine). Condensation can be carried out in the presence of a suitable solvent, including C-1 to C-6 alkanols, such as methanol, ethanol, hexanol, etc.; aromatic hydrocarbons as mentioned above; C-5 to C-10 aliphatic hydrocarbons; ethers , such as diethyl ether, ethylene glycol dimethyl ether (DME) or dioxane; tetrahydrofuran (THF); or any mixture of the above solvents. Alternatively the condensation can be carried out very neatly, wherein the used amine (X) is preferably DME or toluene. The organic solvent that is used to prepare Schiff base (XI) generally also should be used as the solvent of next step reaction, promptly uses the solvent of the reduction reaction of borane-thioether reagent (XII), and this is because after condensation, carry out in single kettle The reduction reaction is more economical. The condensation can be carried out at a temperature ranging from 0°C to the reflux temperature of the solvent, preferably at about room temperature.

式中R¹³和R¹⁵可以相同或不同，可以代表C-1至C-6烷基或与硫原子一起代表含3-6个碳原子的杂环，该杂环可以含1或2个硫或氧原子；或者R¹³和R¹⁵与硫一起代表聚合硫代烃。R¹³和R¹⁵是C-1至C-6烷基为好，是乙基更好，是甲基最好。R¹³和R¹⁵是甲基的硼烷-硫醚试剂称为硼烷-硫化二甲基(BMS₃)，是市售液体。优选的是R¹³和R¹⁵与硫原子一起代表美国专利4,029,706和3,928,293号所述的聚合硫烃。上述专利描述了硼烷硫聚合物络合物，即三氢化硼(BH₃)与不溶性交联硫烃聚合物固体粒子的络合物，更具体地说后者是含大量硫原子的、固体的、粒子的、不溶的、交联的脂肪族、环脂族或芳香族硫烃聚合物，所述硫原子是硫醚构型。聚合硼烷硫聚合物络合物的特征是硫烃聚合物中的大部分硫原子(至少80％)都与BH₃分子络合。硼烷硫聚合物络合物在室温下是稳定的。其稳定性及该络合物是固体的性质使其易于使用和回收(即通过过滤回收)。硼烷硫聚合物络合物可以通过将二硼烷气体与选定的聚醚接触制得，见美国专利4,029,706号和3,928,293号中所述，其中的关于制备方法的叙述作为对比文献并入本文。硼烷硫聚合物络合物的优点是大大减弱了含硫气味，Schiff碱与非聚合硼烷-硫醚试剂的反应会产生这种气味。而且，用过的硼烷硫聚合物试剂可以很方便地用常规方法(如过滤)从反应混合物中回收。Reduction of Schiff base (XI) with borane-thioether reagent (XII), followed by treatment with alcohol and acid can prepare a new boron-arylethanolamine complex (XIII). The borane-thioether reagent can have the following structure:

In the formula, ^R13 and ^R15 can be the same or different, and can represent a C-1 to C-6 alkyl group or, together with a sulfur atom, represent a heterocyclic ring containing 3-6 carbon atoms, and the heterocyclic ring can contain 1 or 2 sulfur atoms or an oxygen atom; or R ¹³ and R ¹⁵ together with sulfur represent a polymeric thiohydrocarbon. R ¹³ and R ¹⁵ are preferably C-1 to C-6 alkyl, more preferably ethyl, most preferably methyl. The borane-sulfide reagent in which R ¹³ and R ¹⁵ are methyl groups is called borane-sulfide dimethyl (BMS ₃ ), which is a commercially available liquid. It is preferred that R ¹³ and R ¹⁵ together with the sulfur atom represent polymeric thiohydrocarbons as described in US Patent Nos. 4,029,706 and 3,928,293. The aforementioned patents describe borane sulfur polymer complexes, that is, complexes of boron trihydride (BH ₃ ) with solid particles of insoluble cross-linked sulfur hydrocarbon polymers, more specifically solid Particle, insoluble, cross-linked aliphatic, cycloaliphatic or aromatic thiol hydrocarbon polymers, the sulfur atom is in thioether configuration. Polymeric borane sulfur polymer complexes are characterized in that a majority (at least 80%) of the sulfur atoms in the thiohydrocarbon polymer are complexed with _BH3 molecules. The borane sulfur polymer complex is stable at room temperature. Its stability and the fact that the complex is a solid make it easy to use and recover (ie by filtration). Borane sulfur polymer complexes can be prepared by contacting diborane gas with selected polyethers as described in U.S. Patent Nos. 4,029,706 and 3,928,293, the descriptions of which are incorporated herein by reference . The advantage of the borane sulfur polymer complex is that it greatly attenuates the sulfur-containing odor that is produced by the reaction of a Schiff base with a non-polymeric borane-thioether reagent. Furthermore, the spent boranethiopolymer reagent can be conveniently recovered from the reaction mixture by conventional means such as filtration.

其中，波浪线(

)表示硼烷-芳基乙醇胺络合物可以通过硼原子与其它硼-芳基乙醇胺络合物聚合。该聚合络合物通过任何方便的方法可断开成单个单体，如通过将含聚合络合物的反应混合物与适当的C-1至C-6醇接触。硼-芳基乙醇胺络合物(ⅩⅢ)-A或-B单体最好在醇的存在下向反应混合物中加入酸的方法而裂解为芳基乙醇胺(ⅪⅤ)。所用的酸可以是多种有机弱酸中的任一种，如乙酸、丙酸或丁酸，优选的是乙酸。优选的醇是C-1至C-6醇，最优选的是甲醇。酸的用量范围从过量到大约4当量[酸当量数：1当量硼-芳基乙醇胺络合物(ⅩⅢ)]，更优选约10-4当量酸。醇的用量范围从过量到大约10当量[醇当量数：1当量硼-芳基乙醇胺络合物(ⅩⅢ)]，优选的是用约1000-100当量醇。It is best to choose a suitable borane-thioether reagent (XII). The used boron and organosulfide reactants are easily removed: for example, the used methyl sulfide can be removed by distillation, and the used boron can be removed after the addition of methanol and acetic acid. It is then removed from the reaction mixture by distillation in the form of trimethyl borate. It is best to use anhydrous aprotic solvents, such as toluene, DME, THF, dioxane, xylene, etc. The amount of borane-thioether reagent (XII) ranges from excessive to about 1.7 moles [borane-thioether reagent (XII) moles: 1 mole of Schiff base (XI)], preferably about 5-2 moles, about 3-2 moles are more preferred, about 2 moles are most preferred. The temperature range of the reduction reaction can be from room temperature to the reflux temperature of the solvent, for example: 84° C. with DME as the solvent, and the reaction time is long enough to complete the desired reaction, such as 2-12 hours or longer. After the reaction of the Schiff base (XI) and the borane-thioether reagent (XII), the borane-aryl ether amine complex is considered to be in a polymeric form, as shown in the following formula

Among them, the tilde (

) means that the borane-arylethanolamine complex can be polymerized with other boron-arylethanolamine complexes through the boron atom. The polymeric complex can be cleaved into individual monomers by any convenient method, such as by contacting the reaction mixture containing the polymeric complex with the appropriate C-1 to C-6 alcohol. Boron-arylethanolamine complex (XIII)-A or -B monomer is preferably cleaved to arylethanolamine (XIV) by adding acid to the reaction mixture in the presence of alcohol. The acid used may be any of a variety of weak organic acids, such as acetic acid, propionic acid or butyric acid, preferably acetic acid. Preferred alcohols are C-1 to C-6 alcohols, most preferably methanol. The acid is used in an excess amount to about 4 equivalents [acid equivalent number: 1 equivalent of the boron-arylethanolamine complex (XIII)], more preferably about 10-4 equivalents of the acid. The amount of alcohol used ranges from an excess to about 10 equivalents [alcohol equivalent number: 1 equivalent of boron-arylethanolamine complex (XIII)], preferably about 1000-100 equivalents of alcohol.

The boron-arylethanolamine complex (XIII) generally exists in the reaction medium in the form of an instantaneous intermediate, as shown in brackets in the complex structure. The boron-arylethanol complex (XIII), wherein Y is -OH, can be recovered by any convenient method, for example, by adding water to the reaction mixture, followed by a water-immiscible solvent (such as ethyl acetate) extract. The boron-arylethanolamine (XIII) wherein Y is ^-OR6 can be recovered by adding an alcohol of formula ^HOR6 wherein ^R6 is as defined above to the reaction mixture followed by removal of excess solvent.

After addition of alcohol and acid, the boron used, eg trimethyl borate, is distilled off from the reaction mixture to leave the desired arylethanolamine (XIV). Distillation is carried out in vacuum at a temperature range of about 35°C-40°C and should be distilled for a sufficient time, for example about 2-12 hours or longer, to complete the desired reaction.

The desired arylethanolamine (XIV) can be recovered from the reaction mixture by conventional methods, such as solvent extraction, filtration, phase separation, distillation, crystallization and the like. Preferably dilute sulfuric acid is added to the reaction mixture containing arylethanolamine (XIV) together with a water-immiscible organic solvent such as 2-propanol. The arylethanolamine (XIV) precipitates out in the form of sulfate (eg salbutamol sulfate) and is separated from the reaction mixture by filtration.

It is noteworthy that the conversion of 5-glyoxyl-methyl salicylate hydrate to salbutamol sulfate can be conveniently carried out in a single kettle or reaction vessel with high yield, as described in Example 7 below.

The following examples illustrate the invention and its practice without limiting the general scope of the invention. Example 1:

在步骤(a)中，将6.23g(0.077mol)溴化氢气体通入处于500ml园底烧瓶中的180ml分子筛干燥过的异丙醇中。将12.5g 5-乙酰基-2-羟基苯甲酰胺(1)(MW 179.17,0.0698mol)和29.3mlDMSO(32.3g,0.413mol)加入该溶液中，得到的悬浮液在适当的搅拌下加热到约85℃，平缓蒸馏。在整个反应过程中蒸出的补充损失的异丙醇。反应过程用H’-核磁谱(NMR)和高压液相色谱(HPLG)监控。反应在三小时内完成，得到含70％的5-[双(1-甲基乙氧基)乙酰基]-2-羟基苯甲酰胺(2)和2-羟基-5-[羟基(1-甲基乙氧基]苯甲酰胺(3)的反应混合物。在步骤(b)中向反应混合物中加入1.8g浓硫酸和100ml水组成的溶液。同时，加热混合物馏出异丙醇。馏出90％的异丙醇后，另加入100ml水，将混合物冷却至50℃。剩下的异丙醇在减压下(300mmHg)馏出。搅拌下冷却至室温，出现结晶。滤出白色晶体，用水充分洗涤，在60℃的鼓风烘箱中干燥16小时，得12.2g标题化合物(10)(83％产率)。实施例2：5-(Diglycolyl)-2-hydroxybenzamide (10)

In step (a), 6.23 g (0.077 mol) of hydrogen bromide gas was bubbled into 180 ml of molecular sieve dried isopropanol in a 500 ml round bottom flask. 12.5g of 5-acetyl-2-hydroxybenzamide (1) (MW 179.17, 0.0698mol) and 29.3ml of DMSO (32.3g, 0.413mol) were added to the solution, and the resulting suspension was heated to About 85 ℃, gentle distillation. Isopropanol was evaporated throughout the reaction to make up for lost isopropanol. The reaction process was monitored by H'-nuclear magnetic spectrum (NMR) and high pressure liquid chromatography (HPLG). The reaction was completed within three hours to obtain 70% of 5-[bis(1-methylethoxy)acetyl]-2-hydroxybenzamide (2) and 2-hydroxyl-5-[hydroxyl(1- The reaction mixture of methyl ethoxy] benzamide (3).In step (b), in reaction mixture, add the solution that 1.8g vitriol oil and 100ml water form.Meanwhile, heating mixture distills isopropanol. Distillate After 90% isopropanol, add 100ml water in addition, the mixture is cooled to 50 ℃.The remaining isopropanol distills off under reduced pressure (300mmHg). Cooling to room temperature under stirring, crystallization occurs. Filter out white crystals, Fully washed with water, dried in a blast oven at 60° C. for 16 hours to obtain 12.2 g of the title compound (10) (83% yield).Example 2:

5-(Diglycolyl)-2-hydroxybenzamide (10)

On the 250ml three-neck flask at the bottom of the garden, a short condenser tube, an addition funnel and a thermometer were installed, and 12.5g (0.07mol) of 5-acetyl-2-hydroxyl-benzamide (1), 30mlDMSO and 50ml of normal Butanol was added to the bottle. The resulting slurry was heated to 95°C with stirring. A solution consisting of 4.5 g (0.056 mol) of HBr gas and 50 ml of n-butanol was added via an addition funnel, and the addition was complete in 20 minutes. During the addition, the reaction temperature rose to 98°C. The reaction progress was passed through 5-acetyl- Disappearance tracking of 2-hydroxybenzamide (1) (retention time (tr) = 2.23 min). After 20 minutes, remove the heat source, and use 100ml of ice to quench the mixture containing 5-(dibutoxyacetyl)-2-hydroxybenzamide (5) and 5-(butoxyhydroxyacetyl)-2-hydroxybenzene The reaction mixture of formamide (6) was stirred for 3 minutes. The resulting n-butanol layer was separated and washed with 100 ml of water, followed by the addition of 150 ml of water. n-Butanol was azeotropically distilled under vacuum at 32°C until 200 ml of distillate was collected. To the resulting solution was added 50 ml of isopropanol, and the suspension was stirred for 10 minutes and cooled to 20°C. To the resulting slurry was added 50 ml of concentrated hydrochloric acid via an addition funnel while controlling the temperature between 20-25°C, and the reaction mixture was then stirred at room temperature. When less than 0.5% 5-(dibutoxyacetyl)-2-hydroxybenzamide (5) (tr=6.7min) remains when detecting with HPLC, it is considered that the hydrolysis is complete (9.5 hours), which Add 250ml of water every 30 minutes. The reaction mixture was cooled to about 5° C., stirred for 20 minutes, filtered, and the filter cake was washed with 150 ml of water, 50 ml of isopropanol/water (1/l) and finally with 100 ml of water. The filter cake was dried in an oven at 45°C to obtain 12.6 g of the title compound (10) as a pale yellow solid (yield 85.5%). Example 3:

5-(Dimethoxyacetyl)-2-hydroxybenzamide (8)

Add 180ml DMSO and 100g (0.388mol) 5-(bromoacetyl)-2-hydroxybenzamide (7) successively in a 2-liter three-necked circular flask equipped with mechanical stirring and a reflux condenser at the neck of the bottle. The reaction mixture was stirred until a homogeneous solution was obtained. 1 L of methanol was added to the reaction mixture, and the mixture was heated to reflux at 85-90° C. in an oil bath under a nitrogen atmosphere. The progress of the reaction is monitored by HPLC or ¹ HNMR. When the reactant is consumed (about reflux for 22 hours), the reaction is considered complete. At this time, the reaction mixture contains about 70% 5-(dimethoxyacetyl)-2- Hydroxybenzamide and about 30% 2-hydroxy-5-(hydroxymethoxyacetyl)benzamide. About 1 liter of methanol was distilled off under reduced pressure, and the residue was poured into 1.5 liters of ice water. 5-(dimethoxyacetyl)-2-hydroxybenzamide was preferentially precipitated, which was filtered off, washed with water, and dried in vacuo to obtain 66 g (Yield 71%) Title Compound (8) Example 4:

5-(Dihydroxyacetyl)-2-hydroxybenzamide (10)

Add 33ml DMSO and 200ml molecular sieve-dried isopropanol to a 500ml three-necked round bottom flask equipped with mechanical stirring and a reflux condenser at the neck of the bottle, then add 20g (0.077mol) of 5-(bromoacetyl)-2-hydroxybenzene formamide, and the reaction mixture was heated to reflux in an oil bath for 5 hours, keeping the internal temperature of the reaction mixture at 85-90°C. 200 ml of water was added, and the isopropanol was distilled off as an azeotrope (130 ml) under normal pressure. Another 130ml of water was added, and the distillation under reduced pressure was continued until another 70ml of distillate was distilled out. The reaction mixture was cooled, and off-white crystals were filtered off, washed with water, and dried overnight in a forced air oven at 45° C. to obtain 15.14 g of the title compound (10) (yield 92%). Example 5:

Prepared with HBr gas

5-Glyoxyl-methyl salicylate hydrate

                5-Glyoxyl-methyl salicylate hydrate

A three-necked bottle containing 40 g (0.206 mol) of methyl 5-acetylsalicylate in 60 ml of dichloromethane was immersed in an oil bath, and 70 ml of isopropanol was added. Excess dichloromethane was distilled off. When the internal temperature reached 77°C, 126ml (1.77mol) DMSO was added to the mixture, and the reaction mixture was heated to 80°C. Keeping the temperature of the oil bath at about 85-90 °C, add HBr gas (10.85 g, 0.134 mol or 0.65 equivalent) to the mixture in 40 ml of isopropanol solution (exothermic) over a period of 20 minutes, when half of the HBr solution is added , stir the mixture, distill off dimethyl sulfide ((CH ₃ ) ₂ S) and isopropanol, monitor the distillate volume, after distilling off 82ml of solvent, slowly add isopropanol (IPA), while maintaining a stable distillate output rate. When HPLC determined that the reaction was complete, add 81ml of 2.4N sulfuric acid (H ₂ SO ₄ ) to the reaction mixture, lower the temperature to 75°C, vacuum distill to remove residual isopropanol, and keep an oil bath at 70-75°C during the whole distillation process temperature. After a total of 120 ml of distillate had been collected, the title compound started to precipitate. Water was added at 75°C with stirring. After stirring for 30 minutes, the reaction mixture was cooled to 15°C over 90 minutes to complete the precipitation. The reaction mixture was filtered, the filter cake was washed with water (3×60 ml), and dried at 50° C. for 16 hours to obtain 39.6 g of the title ketone aldehyde hydrate (yield 85%). Embodiment 6:

        Prepared with HBr aqueous solution

5-Glyoxyl-methyl salicylate hydrate

A three-necked bottle containing 40 g (0.206 mol) of methyl 5-acetylsalicylate in 6 ml of dichloromethane was immersed in an oil bath, and 82 ml of isopropanol was added. Excess dichloromethane was distilled off. When the internal temperature reached 77°C, 126ml (1.77mol or 8.6eq) of DMSO was added to the mixture, and the reaction mixture was heated to 85°C-90°C. Keep the oil bath temperature at about 95-100 ° C, add 33 ml (0.29 mol or 1.4 equivalents) of HBr aqueous solution (48%) to the mixture in 20 minutes (exothermic), when the HBr aqueous solution is added, start to distill methyl sulfide and isopropanol. The mixture was stirred and the distillate volume was monitored. After distilling off 82ml of solvent, 20ml of IPA was added slowly to maintain a steady distillation rate. After the completion of the reaction was detected by HPLC, 70ml of 2.4N sulfuric acid (H ₂ SO ₄ ) was added to the reaction mixture, the temperature was lowered to 75°C, and residual isopropanol was removed by vacuum distillation. After a total of 165 ml of distillate had been collected, the title compound started to precipitate. A mixture of 30 ml of acetonitrile (CH ₃ CN) and 70 ml of water was added at 75° C. with stirring. After stirring for 30 minutes, the reaction mixture was cooled to 15°C over 90 minutes to complete the precipitation. The reaction mixture was filtered, the filter cake was washed with water (3 x 300ml) and dried in a forced air oven at 50°C for 16 hours to give 39.5g of the title compound (85% yield). Embodiment 7:

沙丁胺醇硫酸酯Preparation of albuterol from 5-glyoxyl-methyl salicylate hydrate

salbutamol sulfate

tert-Butylamine (16.2 g, 0.221 mol) was added to a solution of 5-glyoxylmethyl salicylate hydrate (50 g, 0.221 mol) in DME (ethylene glycol diethyl ether, 400 ml) at room temperature. The resulting pale orange solution was stirred for 5 minutes until a clear solution formed. The clear solution was heated to reflux. Water and DME were removed by azeotropic distillation. After a total of 200 ml of distillate had been collected, the reaction solution was cooled to 25°C. The reaction mixture was slowly added to a 200ml DME solution containing 49ml (0.49mol) of 10.0M borane dimethyl sulfide (BMS) at 70°C. The resulting mixture was further refluxed for 25 hours. Monitored by HPLC, excess DME was removed by vacuum distillation after the reaction was complete. The residue containing boron and arylethanolamine complexes was then cooled to 0°C. The residue was treated with 300 mL of methanol to give the methyl borate of the arylethanolamine. Azeotropic distillation removes the borate ester as trimethyl borate (B(OCH)), leaving the desired arylethanolamine in the reaction mixture. A further 300 ml of methanol and acetic acid (85 ml) were added to ensure complete removal of trimethyl borate and vacuum distilled to near dryness. The residue containing boron-free arylethanolamine was cooled to 25°C, and a solution of concentrated sulfuric acid (10.4 g, 0.221 mol) in water (64 ml) and 570 ml of isopropanol were added successively. Salbutamol sulfate precipitated out as a white solid. The reaction mixture was stirred at room temperature for 12 hours and at 0° C. for 30 minutes. After that, albuterol sulfate was filtered off, washed with isopropanol (2×50 ml), and dried at 50° C. for 12 hours to obtain 49.75 g of the title compound (yield 78 %).

Claims (2)

1. The preparation method of acetal and semi-acetal of formula (VII) or (V), formula (VII) and (V) are as follows:

and

In the formula, Ar represents aryl or substituted aryl; R represents alkyl, substituted alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, Heterocyclyl or heterocycloalkyl, and R ³ represent hydrogen, alkyl, aryl or substituted aryl, the method includes contacting the compound of formula (II) with sulfoxide and alcohol ROH (R as defined above), formula ( Ⅱ) as follows: Wherein Ar and ^R3 have the same definition as above, L is a leaving group, or the compound of formula (I) is contacted with halogenating agent, sulfoxide and alcohol ROH to obtain formula (VII) or (V) acetal or semi-acetal Aldehyde, formula (I) is as follows:

Wherein Ar and R ³ are as defined above. 2. The preparation method of the glyoxal hydrate of formula (IX), formula (IX) is as follows: Wherein Ar and R ³ are as defined in claim 1, and the method comprises hydrolyzing the acetal or hemiacetal shown in formula (VII) and (V) of claim 1 respectively.