TW202000640A - Method for producing diaminobenzoic acid ester - Google Patents

Method for producing diaminobenzoic acid ester Download PDF

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TW202000640A
TW202000640A TW108119739A TW108119739A TW202000640A TW 202000640 A TW202000640 A TW 202000640A TW 108119739 A TW108119739 A TW 108119739A TW 108119739 A TW108119739 A TW 108119739A TW 202000640 A TW202000640 A TW 202000640A
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anthranilate
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azide
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関雅彦
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日商德山股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/16—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C247/18—Compounds containing azido groups with azido groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract

Provided is a method by which a diaminobenzoic acid ester and a benzimidazole derivative can be more easily produced using a cheaper material. The present invention includes the following method: an azide form of anthranilate ester represented by formula (2) is produced by contacting an anthranilate ester represented by the formula (1) with an azidating agent in the presence of an oxidizing agent and a copper compound, after producing the azide form of anthranilate ester represented by formula (2), the obtained azide form of the anthranilate ester is reduced to produce a diaminobenzoate ester represented by the formula (3). (In the formula, R1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms.).

Description

二胺基苯甲酸酯的製造方法 Method for manufacturing diaminobenzoate

本發明係有關一種可使用作為化學製品、原料藥等之中間體的二胺基苯甲酸酯之新穎的製造方法。更且，有關一種新穎之製造方法，係以該二胺基苯甲酸酯之新穎的製造方法製造二胺基苯甲酸酯之後，由所得二胺基苯甲酸酯製造苯并咪唑衍生物之方法。 The present invention relates to a novel manufacturing method of diaminobenzoate which can be used as an intermediate of chemicals, APIs and the like. Furthermore, a novel manufacturing method is to manufacture a benzimidazole derivative from the obtained diaminobenzoate after the diaminobenzoate is manufactured by the novel manufacturing method of the diaminobenzoate Method.

苯并咪唑衍生物作為化學製品、原料藥之中間體的利用價值極高。例如：下述式(5)所示之苯并咪唑衍生物作為坎地沙坦酯(candesartan cilexetil，沙壓錠)等沙坦系原料藥之中間體等，其工業上的利用價值極高(例如參照專利文獻1至3)。 Benzimidazole derivatives are extremely valuable as intermediates for chemicals and APIs. For example, the benzimidazole derivative represented by the following formula (5) is used as an intermediate of a sartan raw material drug such as candesartan cilexetil (sand pressure tablets), etc., and its industrial utilization value is extremely high (for example Refer to Patent Documents 1 to 3).

Figure 108119739-A0202-12-0001-5
Figure 108119739-A0202-12-0001-5

(式中，R1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基；R2為碳數1至6之烷基或碳數1至6之烷氧基)。 (In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms. ; R 2 is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms).

通常，屬於上述式(5)所示之苯并咪唑衍生物之一的BIM係以下述方法合成。 Generally, BIM, which is one of the benzimidazole derivatives represented by the above formula (5), is synthesized by the following method.

Figure 108119739-A0202-12-0002-6
Figure 108119739-A0202-12-0002-6

首先，通過鄰苯二甲酸1至3步驟，得到2-胺基-3-硝基苯甲酸酯4。接著，將該2-胺基-3-硝基苯甲酸酯4進行還原，得到二胺基體5。進一步使該二胺基體5環化以合成BIM。 First, through steps 1 to 3 of phthalic acid, 2-amino-3-nitrobenzoate 4 is obtained. Next, the 2-amino-3-nitrobenzoate 4 is reduced to obtain a diamine base 5. The diamine matrix 5 is further cyclized to synthesize BIM.

然而，由於本方法之步驟長，並且使用在高溫下處理危險的醯基疊氮之庫爾提斯(Curtius)重排(化合物2→3)，因此在工業製造方法方面並不見得令人滿意。更且，將上述2-胺基-3-硝基苯甲酸酯4之胺基進行還原時，在現有技術中，目前係使用高價的鎳觸媒(參照專利文獻1)或鈀觸媒(參照專利文獻2)、或使用高毒性的錫化合物(參照專利文獻3)。 However, due to the long steps of this method, and the use of Curtius rearrangement (compound 2→3) that handles the dangerous azide at high temperature, it is not satisfactory in terms of industrial manufacturing methods . Furthermore, when reducing the amine group of the above 2-amino-3-nitrobenzoate 4, in the prior art, an expensive nickel catalyst (refer to Patent Document 1) or a palladium catalyst ( Refer to Patent Document 2), or use a highly toxic tin compound (refer to Patent Document 3).

為了由二胺基苯甲酸酯、及上述式(5)所示之苯并咪唑衍生物製造如坎地沙坦酯之原料藥，此後需要非常大量的步驟。因此，希望盡 可能地使用價廉且容易處理的試藥而合成該等中間體。此點在現有技術中仍有改進的空間。 In order to manufacture a drug substance such as candesartan cilexetil from a diaminobenzoate ester and a benzimidazole derivative represented by the above formula (5), a very large number of steps are required thereafter. Therefore, it is desirable to use cheap and easy-to-handle reagents to synthesize these intermediates as much as possible. This point still has room for improvement in the prior art.

非專利文獻1係揭示一種使用銅化合物作為觸媒在鄰位及/或對位具有預定取代基之苯胺衍生物的疊氮化反應。 Non-Patent Document 1 discloses a azidation reaction of an aniline derivative having a predetermined substituent in the ortho and/or para position using a copper compound as a catalyst.

[先前技術文獻] [Prior Technical Literature] [專利文獻] [Patent Literature]

[專利文獻1]國際公開第2006/015134號 [Patent Literature 1] International Publication No. 2006/015134

[專利文獻2]國際公開第2015/173970號 [Patent Literature 2] International Publication No. 2015/173970

[專利文獻3]國際公開第2012/018325號 [Patent Document 3] International Publication No. 2012/018325

[非專利文獻] [Non-patent literature]

[非專利文獻1]Conghui Tang and Ning Jiao, Journal of the American Chemical Society, 2012, 134, pp 18924-18927 [Non-Patent Literature 1] Conghui Tang and Ning Jiao, Journal of the American Chemical Society, 2012, 134, pp 18924-18927

因鑒於上述情況，本發明之目的係提供一種製造方法，係使用較價廉之材料而可更簡便地製造二胺基苯甲酸酯及苯并咪唑衍生物之方法。 In view of the above circumstances, the object of the present invention is to provide a manufacturing method which is a method for manufacturing diaminobenzoic acid esters and benzimidazole derivatives more easily using less expensive materials.

本發明者等為了解決上述課題，精心進行檢討。其結果發現將價廉且容易取得之鄰胺苯甲酸酯作為起始原料，藉由在銅化合物及氧化劑的存在下使鄰胺苯甲酸酯與疊氮化劑接觸，即可將胺基之α位疊氮化，遂而完成本發明。 In order to solve the above-mentioned problems, the inventors of the present invention conducted careful examination. As a result, it was found that anthranilate, which is inexpensive and easily available, can be used as a starting material, by contacting anthranilate with an azide in the presence of a copper compound and an oxidizing agent, the amine group can be The α-position azide completes the present invention.

亦即，(1)本案第一個發明係一種二胺基苯甲酸酯之製造方法，其係藉由使下述式(1)所示之鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，

Figure 108119739-A0202-12-0004-7
That is, (1) The first invention of the present case is a method for producing a diamino benzoate by using an anthranilate represented by the following formula (1) and an azide agent in Contact in the presence of oxidants and copper compounds,
Figure 108119739-A0202-12-0004-7

(式中，R1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基)。 (In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms. ).

製造下述式(2)所示之鄰胺苯甲酸酯之疊氮體之後，

Figure 108119739-A0202-12-0004-9
After manufacturing the azido of anthranilate represented by the following formula (2),
Figure 108119739-A0202-12-0004-9

(式中，R1與上述式(1)之R1同義) (In the formula, R 1 is synonymous with R 1 of the above formula (1))

將所得的該鄰胺苯甲酸酯之疊氮體進行還原，製造下述式(3)所示之二胺基苯甲酸酯，

Figure 108119739-A0202-12-0005-10
The obtained azide of the anthranilate is reduced to produce a diaminobenzoate represented by the following formula (3),
Figure 108119739-A0202-12-0005-10

(式中，R1與上述式(1)之R1同義)。 (In the formula, R 1 is synonymous with R 1 in the above formula (1)).

(2)本案第二個發明係一種下述式(2)所示之鄰胺苯甲酸酯之疊氮體，

Figure 108119739-A0202-12-0005-13
(2) The second invention of the present case is an azide of anthranilate represented by the following formula (2),
Figure 108119739-A0202-12-0005-13

(式中，R1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基)。 (In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms. ).

(3)本案第三個發明係一種鄰胺苯甲酸酯之疊氮體的製造方法，其係藉由使下述式(1)所示之鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，

Figure 108119739-A0202-12-0005-14
(3) The third invention of the present case is a method for producing an anthranilate azide by using an anthranilate represented by the following formula (1) and an azide agent in Contact in the presence of oxidants and copper compounds,
Figure 108119739-A0202-12-0005-14

(式中，R1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基)。 (In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms. ).

製造下述式(2)所示之鄰胺苯甲酸酯之疊氮體，

Figure 108119739-A0202-12-0006-15
The azido of anthranilate represented by the following formula (2) is produced,
Figure 108119739-A0202-12-0006-15

(式中，R1與上述式(1)之R1同義)。 (In the formula, R 1 is synonymous with R 1 in the above formula (1)).

(4)本案第四個發明係一種二胺基苯甲酸酯之製造方法，其係將下述式(2)所示之鄰胺苯甲酸酯之疊氮體進行還原，

Figure 108119739-A0202-12-0006-18
(4) The fourth invention of the present case is a method for producing diaminobenzoate, which reduces the azide of o-aminobenzoate represented by the following formula (2),
Figure 108119739-A0202-12-0006-18

(式中，R1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基)。 (In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms, or an alkoxyaralkyl group having 8 to 11 carbon atoms. ).

製造下述式(3)所示之二胺基苯甲酸酯，

Figure 108119739-A0202-12-0006-19
The diaminobenzoate represented by the following formula (3) is produced,
Figure 108119739-A0202-12-0006-19

(式中，R1與上述式(2)之R1同義)。 (In the formula, R 1 is synonymous with R 1 in the above formula (2)).

(5)本案第五個發明係一種苯并咪唑衍生物之製造方法，其係依上述本案第一個發明之製造方法或上述本案第四個發明之製造方法製 造上述式(3)所示之二胺基苯甲酸酯後，在酸的存在下，藉由使所得二胺基苯甲酸酯與下述式(4)所示之原酯衍生物接觸，

Figure 108119739-A0202-12-0007-20
(5) The fifth invention of the present case is a method for producing a benzimidazole derivative, which is produced according to the above method of the first invention of the present case or the fourth method of the present invention of the above formula (3) After the diaminobenzoate, the resulting diaminobenzoate is brought into contact with the original ester derivative represented by the following formula (4) in the presence of an acid,
Figure 108119739-A0202-12-0007-20

(式中，R2為碳數1至6之烷基或碳數1至6之烷氧基，R3為碳數1至6之烷基，可互為相同或相異之基)。 (In the formula, R 2 is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and R 3 is an alkyl group having 1 to 6 carbon atoms, which may be the same or different groups).

製造下述式(5)所示之苯并咪唑衍生物，

Figure 108119739-A0202-12-0007-21
To produce a benzimidazole derivative represented by the following formula (5),
Figure 108119739-A0202-12-0007-21

(式中，R1與上述式(1)之R1同義、R2與上述式(4)之R2同義)。 (Wherein, R 1 is and R in the above formula (1) of the same meaning as 1, R 2 2 R synonymous with the above-described formula (4) of).

依據本發明，可用價廉且容易取得之鄰胺苯甲酸酯作為起始原料，以比目前的合成方法更短(較少)的步驟製造二胺基苯甲酸酯。 According to the present invention, anthranilate, which is inexpensive and easily available, can be used as a starting material to produce diaminobenzoate in shorter (less) steps than current synthetic methods.

而且，不用經過在高溫下處理危險的醯基疊氮之庫爾提斯重排而可安全地得到二胺基苯甲酸酯。 Moreover, the diamino benzoate can be obtained safely without undergoing Kurtish rearrangement for handling dangerous amide azide at high temperature.

所得之上述二胺基苯甲酸酯係可藉由與原酯衍生物的接觸而容易製造苯并咪唑衍生物。所得苯并咪唑衍生物可作為各種化學製品、 如坎地沙坦酯之原料藥的中間體使用，因此本發明在工業上的利用價值極高。 The obtained diaminobenzoate can be easily produced by contacting with the original ester derivative. The obtained benzimidazole derivatives can be used as intermediates of various chemical products, such as candesartan cilexetil, and the industrial application value of the present invention is extremely high.

本發明之二胺基苯甲酸酯之製造方法，係藉由使鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，在鄰胺苯甲酸酯之胺基的α位上導入疊氮基之後，使導入的疊氮基還原成胺基者。為了將疊氮基導入鄰胺苯甲酸酯中，可混合鄰胺苯甲酸酯、疊氮化劑、氧化劑及銅化合物。 The method for producing diaminobenzoate of the present invention is by contacting o-aminobenzoate with an azide agent in the presence of an oxidizing agent and a copper compound. After introducing an azide group at the α position, the introduced azide group is reduced to an amine group. In order to introduce an azido group into anthranilate, anthranilate, an azide agent, an oxidizing agent, and a copper compound can be mixed.

以下依序進行說明。 The following will explain in order.

<鄰胺苯甲酸酯之疊氮體的製造> <Manufacture of azide of anthranilate>

[原料化合物] [Raw material compound]

(鄰胺苯甲酸酯) (Anthranilate)

本發明中，作為原料使用之鄰胺苯甲酸酯係下述式(1)：

Figure 108119739-A0202-12-0008-23
In the present invention, the anthranilate used as the raw material is the following formula (1):
Figure 108119739-A0202-12-0008-23

所示之化合物。 The compound shown.

上述式(1)中，R1係碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基。其中，為 了作為各種物質、原料藥之中間體使用，以碳數1至5之烷基為佳。而且，R1為碳數1至5之烷基時，該化合物可適合作為坎地沙坦酯之原料使用。 In the above formula (1), R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxy alkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or an alkoxy group having 8 to 11 carbon atoms Aralkyl. Among them, an alkyl group having 1 to 5 carbon atoms is preferred for use as an intermediate for various substances and APIs. Moreover, when R 1 is an alkyl group having 1 to 5 carbon atoms, the compound can be suitably used as a raw material for candesartan cilexetil.

式(1)所示之鄰胺苯甲酸酯可使用市售品。而且，可利用習知方法製造。 As the anthranilate represented by the formula (1), commercially available products can be used. Moreover, it can be manufactured by a conventional method.

(疊氮化劑) (Azide agent)

本發明中，藉由疊氮化劑將疊氮基導入式(1)所示之鄰胺苯甲酸酯中，製造下述式(2)所示之鄰胺苯甲酸酯之疊氮體。 In the present invention, an azido group is introduced into the anthranilate represented by formula (1) by an azide to produce an azido of anthranilate represented by the following formula (2) .

Figure 108119739-A0202-12-0009-24
Figure 108119739-A0202-12-0009-24

(式中，R1與上述式(1)之R1同義)。 (In the formula, R 1 is synonymous with R 1 in the above formula (1)).

本發明中使用之疊氮化劑例如為有機疊氮化物，即可使用而無限制。有機疊氮化物如為有機化合物之疊氮化中使用的習知物，即可使用而無限制。 The azide used in the present invention is, for example, an organic azide, which can be used without limitation. The organic azide may be used without limitation as long as it is a conventional substance used in the azide of organic compounds.

疊氮化劑方面，可列舉如：三甲基矽基疊氮(TMSN3)、苯磺醯基疊氮(PhSO2N3)、對甲苯磺醯基疊氮(p-TolSO2N3)、二苯基磷醯基疊氮(DPPA)等有機疊氮化物，從產率、安全性及價格之觀點，以三甲基矽基疊氮為佳。 Examples of the azide agent include trimethylsilyl azide (TMSN 3 ), benzenesulfonyl azide (PhSO 2 N 3 ), p-toluenesulfonyl azide (p-TolSO 2 N 3 ) , Diphenylphosphoryl azide (DPPA) and other organic azides. From the viewpoint of yield, safety and price, trimethylsilyl azide is preferred.

疊氮化劑之使用量並無特別限制。為了提高安全性與減少成本而降低使用量以及實現高轉化率，相對於上述鄰胺苯甲酸酯1莫耳，疊 氮化劑以使用1至10莫耳為佳，以使用1至5莫耳更佳，以使用1至3莫耳又更佳。 The amount of azide used is not particularly limited. In order to improve safety and reduce cost, reduce the amount of use and achieve high conversion rate, relative to the above 1 mol of anthranilate, it is better to use 1 to 10 mol for the azide agent and 1 to 5 mol Ears are better, with 1 to 3 moles better.

本發明中，藉由疊氮化劑而進行的疊氮化係在後述氧化劑及銅化合物之存在下進行。 In the present invention, the azide by the azide agent is performed in the presence of an oxidizing agent and a copper compound described later.

(氧化劑) (Oxidant)

本發明中，與疊氮化劑共存的氧化劑並無特別限制。 In the present invention, the oxidizing agent coexisting with the azide agent is not particularly limited.

氧化劑方面，從產率、成本及安全性之觀點，可列舉如：三級丁基氫過氧化物(TBHP、tert-BuO2H)、二-三級丁基氫過氧化物(tert-BuO2 tert-Bu)、異丙苯氫過氧化物(CMHP)等氫過氧化物、二乙酸碘苯(PIDA)等超價碘化合物、過氧化氫等，以TBHP、CMHP、PIDA為佳。 In terms of oxidants, from the viewpoint of yield, cost and safety, for example, tertiary butyl hydroperoxide (TBHP, tert-BuO 2 H), tertiary butyl hydroperoxide (tert-BuO 2 tert-Bu), hydroperoxides such as cumene hydroperoxide (CMHP), supervalent iodine compounds such as iodobenzene diacetate (PIDA), hydrogen peroxide, etc., preferably TBHP, CMHP, PIDA.

氧化劑之使用量並無特別限制。為了使後述銅化合物之觸媒的氧化再生以及苯環的氧化等疊氮化反應進行，相對於上述鄰胺苯甲酸酯1莫耳，氧化劑係以使用0.1至10莫耳為佳，以使用0.5至5莫耳更佳，以使用0.8至4莫耳又更佳。該使用量之下限值係以1為佳。 The amount of oxidant used is not particularly limited. In order to carry out the azide reaction such as the oxidation regeneration of the copper compound catalyst described later and the oxidation of the benzene ring, it is preferred to use 0.1 to 10 moles for the oxidizing agent relative to 1 mole of the anthranilate. 0.5 to 5 moles is better, and 0.8 to 4 moles is better. The lower limit of the amount used is preferably 1.

(銅化合物) (Copper compound)

本發明中，與疊氮化劑共存的銅化合物並無特別限制。 In the present invention, the copper compound coexisting with the azide agent is not particularly limited.

銅化合物方面，可列舉如：氯化銅(I)(CuCl)、氯化銅(II)(CuCl2)、溴化銅(I)(CuBr)、溴化銅(II)(CuBr2)、碘化銅(I)(CuI)、碘化銅(II)(CuI2)等銅鹽及其水合物或溶媒合物；氧化銅(I)(Cu2O)等銅氧化物等。從產率、成本之觀點，銅化合物係以溴化銅(I)(CuBr)、氯化銅(I)(CuCl)、氯化銅(II)(CuCl2)為佳，以溴化銅(I)(CuBr)、氯化銅(I)(CuCl)更佳，以溴化銅(I)(CuBr)為特佳。 Examples of copper compounds include copper (I) (CuCl), copper (II) (CuCl 2 ), copper (I) (CuBr), and copper (II) (CuBr 2 ), Copper salts such as copper (I) (CuI), copper (II) (CuI 2 ) and their hydrates or solvent compounds; copper oxides such as copper (I) (Cu 2 O), etc. From the viewpoint of yield and cost, the copper compound is preferably copper (I) (CuBr), copper chloride (I) (CuCl), copper (II) chloride (CuCl 2 ), and copper bromide ( I) (CuBr) and copper chloride (I) (CuCl) are more preferred, with copper bromide (I) (CuBr) being particularly preferred.

銅化合物之使用量並無特別限制。為了提高轉化率，相對於上述鄰胺苯甲酸酯1莫耳，銅化合物係以使用0.001至4莫耳為佳，以使用0.01至3莫耳更佳，以使用0.1至2莫耳又更佳。 The amount of copper compound used is not particularly limited. In order to improve the conversion rate, relative to the above 1 mol of anthranilate, the copper compound is preferably 0.001 to 4 mol, more preferably 0.01 to 3 mol, and more preferably 0.1 to 2 mol. good.

(製造疊氮體時之反應條件) (Reaction conditions when manufacturing azide)

(反應溶媒) (Reaction solvent)

本發明中，為了使上述鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，係以將上述鄰胺苯甲酸酯與疊氮化劑在反應溶媒中攪拌混合而使兩者充分接觸者為佳。 In the present invention, in order to contact the anthranilate and the azide agent in the presence of an oxidizing agent and a copper compound, the anthranilate and the azide agent are stirred and mixed in a reaction solvent. It is better to make the two fully contact.

本發明中，所使用之反應溶媒如為不會對上述鄰胺苯甲酸酯、疊氮化劑、氧化劑及銅化合物造成不良影響，並可順利地製造疊氮體之溶媒，則無特別限制。其中，如考量上述鄰胺苯甲酸酯、疊氮化劑、氧化劑、銅化合物以及所得鄰胺苯甲酸酯之疊氮體的溶解度、安定性、反應性、成本、安全性等之觀點，可列舉如：乙酸乙酯、乙酸甲酯、乙酸丁酯、乙酸異丙酯等乙酸酯類；乙腈、丙腈等脂肪族腈類；四氫呋喃(THF)、2-甲基四氫呋喃(2-甲基THF)、1,4-二噁烷、三級丁基甲基醚、二甲氧基乙烷、二甘二甲醚(diglyme)等醚類；丙酮、二乙基酮、甲基乙基酮等酮類；二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、氯苯等鹵化烴類；甲苯、二甲苯等芳香族烴；己烷、庚烷等脂肪族烴；二甲亞碸(DMSO)等非質子性極性溶媒等。該等溶媒亦可作為混合溶媒使用。 In the present invention, the reaction solvent used is not particularly limited as long as it does not adversely affect the anthranilate, azide agent, oxidizing agent, and copper compound, and can smoothly produce azide. . Among them, considering the viewpoints of solubility, stability, reactivity, cost, safety, etc. of the above anthranilate, azide, oxidizing agent, copper compound, and the azide of the obtained anthranilate, Examples include: acetates such as ethyl acetate, methyl acetate, butyl acetate, and isopropyl acetate; aliphatic nitriles such as acetonitrile and propionitrile; tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl THF), 1,4-dioxane, tertiary butyl methyl ether, dimethoxyethane, diglyme and other ethers; acetone, diethyl ketone, methyl ethyl ketone and other ketones Halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene; aromatic hydrocarbons such as toluene and xylene; aliphatic hydrocarbons such as hexane and heptane; Aprotic polar solvents such as DMSO. These solvents can also be used as mixed solvents.

該等之中，為了提高所得鄰胺苯甲酸酯之疊氮體的純度、產率，以使用單獨一種乙腈、單獨一種DMSO，或者乙腈或DMSO的任一者 與此外的上述反應溶媒之混合溶媒為佳。尤其是，以使用乙腈或乙腈與甲苯之混合溶媒為佳。 Among these, in order to improve the purity and yield of the obtained anthranilate azide, a single acetonitrile, a single DMSO, or any one of acetonitrile or DMSO is mixed with the above-mentioned reaction solvent Solvent is better. In particular, it is preferable to use acetonitrile or a mixed solvent of acetonitrile and toluene.

本發明中，在使用反應溶媒時，以使用各成分可充分地混合之溶媒量為佳。具體而言，相對於上述鄰胺苯甲酸酯，以使用1至100倍容量之反應溶媒為佳，以使用1至50倍容量更佳，以使用2至30倍容量又更佳。而且，在使用混合溶媒作為反應溶媒時，混合溶媒的總量滿足上述範圍者即可。 In the present invention, when a reaction solvent is used, it is preferable to use a solvent amount in which each component can be sufficiently mixed. Specifically, relative to the above anthranilate, it is better to use a reaction solvent with a capacity of 1 to 100 times, more preferably to use a capacity of 1 to 50 times, and still more preferably to use a capacity of 2 to 30 times. In addition, when a mixed solvent is used as the reaction solvent, the total amount of the mixed solvent may suffice if it meets the above range.

(將原料導入反應系內的方法) (Method of introducing raw materials into the reaction system)

本發明中，將上述鄰胺苯甲酸酯、疊氮化劑、氧化劑、銅化合物及反應溶媒導入反應系內(反應容器內等進行反應之處)之方法並無特別限制。亦即，可為任意的導入順序，然而為了促進銅鹽對胺基的配位，較佳者係預先在反應系內饋入鄰胺苯甲酸酯，在此導入銅化合物並進行攪拌、混合之後，導入反應溶媒使其溶解，更在其後導入疊氮化劑與氧化劑。因應所需，氧化劑可在反應溶媒中溶解後導入反應系內。 In the present invention, the method of introducing the anthranilate, azide agent, oxidizing agent, copper compound, and reaction solvent into the reaction system (where the reaction takes place in a reaction vessel, etc.) is not particularly limited. That is, any introduction order may be used. However, in order to promote the coordination of the copper salt to the amine group, it is preferable to feed anthranilate into the reaction system in advance, and then introduce the copper compound and stir and mix After that, a reaction solvent is introduced to dissolve it, and then an azide agent and an oxidizing agent are introduced. The oxidant can be introduced into the reaction system after being dissolved in the reaction medium as required.

(反應溫度) (temperature reflex)

反應溫度可依所使用的溶媒而適當地決定。具體而言，係以-30℃以上，且在包含上述鄰胺苯甲酸酯、疊氮化劑、氧化劑及銅化合物之狀態的反應溶媒之回流溫度以下者為佳。更具體而言，係以-30℃以上100℃以下為佳，以10℃以上80℃以下更佳，以20℃以上60℃以下又更佳，以30℃以上50℃以下為特佳。藉由在該溫度下進行反應，可促進反應並可抑制產物的分解，且可更高產率地獲得更高純度的鄰胺苯甲酸酯之疊氮體。 The reaction temperature can be appropriately determined according to the solvent used. Specifically, it is preferably -30° C. or higher and below the reflux temperature of the reaction medium in the state of containing the anthranilate, azide agent, oxidizing agent, and copper compound. More specifically, it is preferably -30°C or more and 100°C or less, more preferably 10°C or more and 80°C or less, even more preferably 20°C or more and 60°C or less, and particularly preferably 30°C or more and 50°C or less. By carrying out the reaction at this temperature, the reaction can be promoted and the decomposition of the product can be suppressed, and the azido of anthranilate can be obtained with higher purity in a higher yield.

(其它條件) (Other conditions)

本發明中，其它反應條件係以採用以下條件者為佳。反應時間可根據上述鄰胺苯甲酸酯之消耗量、上述鄰胺苯甲酸酯之疊氮體的產量、反應規模等而適當地決定，一般可為30分鐘以上24小時以下，以1小時以上17小時以下為佳。 In the present invention, the other reaction conditions are preferably those using the following conditions. The reaction time can be appropriately determined according to the consumption of the anthranilate, the output of the azide of the anthranilate, the scale of the reaction, etc., and it can generally be 30 minutes or more and 24 hours or less and 1 hour More than 17 hours is better.

本發明中，反應氣體環境的條件並無特別限制，可在空氣環境下、非活性氣體環境下或氫氣環境下之任一種氣體環境下。其中，考慮抑制濕氣的混入等，以在氮氣等非活性氣體環境下為佳。 In the present invention, the conditions of the reaction gas environment are not particularly limited, and may be in any gas environment under an air environment, an inert gas environment, or a hydrogen environment. Among them, it is preferable to suppress the mixing of moisture, etc., and it is preferably in an inert gas environment such as nitrogen.

而且，反應系內可為大氣壓下、加壓下、減壓下之任一者。其中，以在大氣壓下實施為佳。 Furthermore, the reaction system may be any of atmospheric pressure, pressurized, and reduced pressure. Among them, it is preferably carried out under atmospheric pressure.

(鄰胺苯甲酸酯之疊氮體之精製/取出方法) (Method for refining/removing azido of anthranilate)

藉由在如上述之條件下進行反應，可將上述鄰胺苯甲酸酯轉化成下述式(2)所示之鄰胺苯甲酸酯之疊氮體，

Figure 108119739-A0202-12-0013-25
By carrying out the reaction under the above conditions, the anthranilate can be converted into the azido of anthranilate represented by the following formula (2),
Figure 108119739-A0202-12-0013-25

(式中，R1與上述式(1)之R1同義)。 (In the formula, R 1 is synonymous with R 1 in the above formula (1)).

依上述反應條件所得的鄰胺苯甲酸酯之疊氮體係以藉由以下方法從反應系內取出者為佳。具體而言，較佳者係使如乙酸乙酯、三氯甲烷、二氯甲烷之水溶性差的有機溶媒與所得反應溶液接觸，在該水溶性差的有機溶媒中萃取上述鄰胺苯甲酸酯之疊氮體。然後，較佳者係以水清 洗含有上述鄰胺苯甲酸酯之疊氮體的水溶性差之有機溶媒並去除銅鹽及無機鹽。 The azido system of anthranilate obtained under the above reaction conditions is preferably taken out of the reaction system by the following method. Specifically, it is preferable to contact a poorly water-soluble organic solvent such as ethyl acetate, chloroform, and dichloromethane with the resulting reaction solution, and extract the anthranilate from the poorly water-soluble organic solvent. Azide. Then, it is preferred to wash the poorly water-soluble organic solvent containing the azide of the anthranilate with water and remove the copper and inorganic salts.

而且，所得鄰胺苯甲酸酯之疊氮體亦可藉由管柱分離及再結晶等習知方法進行更高的純化。 Furthermore, the obtained azido of anthranilate can be further purified by conventional methods such as column separation and recrystallization.

<由鄰胺苯甲酸酯之疊氮體製造二胺基苯甲酸酯的方法> <Method for producing diaminobenzoate from azido of anthranilate>

接著，對於將所得鄰胺苯甲酸酯之疊氮體還原以製造二胺基苯甲酸酯之方法進行說明。鄰胺苯甲酸酯之疊氮體之還原可採用習知的還原方法而無特別限制。具體而言，藉由使鄰胺苯甲酸酯之疊氮體與氫、甲酸或甲酸銨、或鋅粉接觸，或者藉由使鄰胺苯甲酸酯之疊氮體與膦接觸以成為為鄰胺苯甲酸酯之亞胺基正膦體之後經水解等，即可將鄰胺苯甲酸酯之疊氮體進行還原。 Next, a method of reducing the obtained azide of anthranilate to produce a diaminobenzoate will be described. The reduction of the azido of anthranilate can be carried out by a conventional reduction method without particular limitation. Specifically, by contacting the azide of anthranilate with hydrogen, formic acid or ammonium formate, or zinc powder, or by contacting the azide of anthranilate with phosphine to become After the imidophosphorane body of the anthranilate is hydrolyzed and the like, the azide of the anthranilate can be reduced.

<使用氫之疊氮體的還原方法> <Reduction method of azide using hydrogen>

本發明中，為了還原鄰胺苯甲酸酯之疊氮體而與氫接觸的方法方面，可列舉如：在鈀碳、鈀黑等鈀觸媒或雷氏鎳等鎳觸媒等之觸媒的存在下，使氫氣與鄰胺苯甲酸酯之疊氮體接觸之方法。 In the present invention, the method of contacting with hydrogen in order to reduce the azide of anthranilate may include catalysts such as palladium catalysts such as palladium carbon and palladium black, nickel catalysts such as Raney nickel, etc. The method of bringing hydrogen gas into contact with the azide of anthranilate in the presence of.

氫氣如能在1氣壓至100氣壓的壓力範圍內供給至鄰胺苯甲酸酯之疊氮體的溶液中即可，以1至80氣壓為佳，以1至50氣壓更佳。 Hydrogen gas can be supplied to the solution of anthranilate azide within a pressure range of 1 to 100 atmospheres, preferably 1 to 80 atmospheres, more preferably 1 to 50 atmospheres.

觸媒的使用量並無別限制，惟相對於鄰胺苯甲酸酯之疊氮體1莫耳，以觸媒中的金屬原子計算，係以0.0001至10莫耳為佳，以0.0005至5莫耳更佳，以0.001至2莫耳又更佳。 The amount of catalyst used is not limited, but relative to 1 mole of azide of anthranilate, calculated from metal atoms in the catalyst, it is preferably 0.0001 to 10 moles, and 0.0005 to 5 Moles are better, with 0.001 to 2 moles being better.

本發明中，為了使鄰胺苯甲酸酯之疊氮體與氫接觸以進行上述還原，係以將兩者攪拌混合為佳。在攪拌混合時，以在溶媒中實施為佳。 所使用的溶媒方面，如為不影響還原反應者即可而無特別限制。具體而言，可列舉如：甲醇、乙醇、異丙醇等醇；1,4-二噁烷、1,2-二甲氧基乙烷(DME)、THF、水或水與上述溶媒之混合溶媒。 In the present invention, in order to contact the azide of the anthranilate with hydrogen to perform the above reduction, it is preferable to stir the two to mix. When stirring and mixing, it is preferably carried out in a solvent. The solvent used is not particularly limited as long as it does not affect the reduction reaction. Specific examples include alcohols such as methanol, ethanol, and isopropanol; 1,4-dioxane, 1,2-dimethoxyethane (DME), THF, water, or a mixture of water and the above-mentioned solvents Solvent.

進行還原反應時之溫度並無特別限制者，以0至120℃為佳，以20至100℃更佳。反應時間亦無特別限制，可依轉化率而適當地決定。氣體環境亦無特別限制，可為空氣環境下、或非活性氣體環境下之任一種氣體環境下。其中，考量到操作性等，則以空氣環境下為佳。 The temperature at which the reduction reaction is carried out is not particularly limited, preferably 0 to 120°C, more preferably 20 to 100°C. The reaction time is also not particularly limited, and can be appropriately determined according to the conversion rate. The gas environment is also not particularly limited, and it can be any of the gas environment under the air environment or the inert gas environment. Among them, considering the operability, etc., it is better to be in an air environment.

<使用甲酸或甲酸銨之疊氮體的還原方法> <Reduction method of azide using formic acid or ammonium formate>

本發明中，使鄰胺苯甲酸酯之疊氮體與甲酸或甲酸銨接觸以進行還原時，甲酸或甲酸銨之使用量並無特別限制，惟相對於鄰胺苯甲酸酯之疊氮體1莫耳，係以1至100莫耳為佳，以1至50莫耳更佳，以1至10莫耳又更佳。 In the present invention, when the azide of anthranilate is contacted with formic acid or ammonium formate for reduction, the amount of formic acid or ammonium formate is not particularly limited, but it is relative to the azide of anthranilate The body is 1 mol, preferably 1 to 100 mol, more preferably 1 to 50 mol, and 1 to 10 mol.

為了使鄰胺苯甲酸酯之疊氮體與甲酸或甲酸銨接觸，係以將兩者攪拌混合為佳。在攪拌混合時，以在溶媒中實施為佳。所使用的溶媒方面，如為不影響還原反應者即可而無特別限制。具體而言，可列舉如：甲醇、乙醇、異丙醇等醇；1,4-二噁烷、1,2-二甲氧基乙烷(DME)、THF、水或水與上述溶媒之混合溶媒。 In order to contact the azido of anthranilate with formic acid or ammonium formate, it is better to stir the two together. When stirring and mixing, it is preferably carried out in a solvent. The solvent used is not particularly limited as long as it does not affect the reduction reaction. Specific examples include alcohols such as methanol, ethanol, and isopropanol; 1,4-dioxane, 1,2-dimethoxyethane (DME), THF, water, or a mixture of water and the above-mentioned solvents Solvent.

進行還原反應時之溫度並無特別限制者，以0至120℃為佳，以20至100℃更佳。反應時間亦無特別限制，可依轉化率而適當地決定。氣體環境亦無特別限制，可為空氣環境下、或非活性氣體環境下之任一種氣體環境下。其中，考量到操作性等，則以空氣環境下為佳。 The temperature at which the reduction reaction is carried out is not particularly limited, preferably 0 to 120°C, more preferably 20 to 100°C. The reaction time is also not particularly limited, and can be appropriately determined according to the conversion rate. The gas environment is also not particularly limited, and it can be any of the gas environment under the air environment or the inert gas environment. Among them, considering the operability, etc., it is better to be in an air environment.

<使用鋅之疊氮體的還原方法> <Reduction method of azide using zinc>

本發明中，使鄰胺苯甲酸酯之疊氮體與鋅粉接觸以進行還原時，係在氯化銨、鹽酸或硫酸等酸性物質之存在下使鄰胺苯甲酸酯之疊氮體與鋅粉接觸。酸性物質係以氯化銨為佳。 In the present invention, when the azide of anthranilate is brought into contact with zinc powder for reduction, the azide of anthranilate is used in the presence of acidic substances such as ammonium chloride, hydrochloric acid or sulfuric acid Contact with zinc powder. The acidic substance is preferably ammonium chloride.

鋅粉之使用量並無特別限制，惟相對於鄰胺苯甲酸酯之疊氮體1莫耳，係以1至10莫耳為佳，以1至8莫耳更佳，以1至5莫耳又更佳。在使用氯化銨作為酸性物質時，相對於鋅粉1莫耳，氯化銨之使用量係以1至10莫耳為佳。 The amount of zinc powder used is not particularly limited, but it is preferably 1 to 10 moles relative to 1 mole of azide of anthranilate, more preferably 1 to 8 moles, and 1 to 5 Moore is better. When using ammonium chloride as the acidic substance, the amount of ammonium chloride is preferably 1 to 10 moles relative to 1 mole of zinc powder.

與用氫進行還原時相同，鄰胺苯甲酸酯之疊氮體、鋅粉及酸性物質以在溶媒中進行攪拌混合為佳。所使用之溶媒如為不影響還原反應者即可，並無特別限制。具體而言，可列舉如：乙酸乙酯、乙酸甲酯、乙酸丁酯、乙酸異丙酯、乙腈、丙腈、甲醇、乙醇、丙醇、異丙醇、丁醇、2-丁醇、三級丁醇、THF、2-甲基THF、1,4-二噁烷、三級丁基甲基醚、二甲氧基乙烷、二甘二甲醚、丙酮、二乙基酮、甲基乙基酮、二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、氯苯、甲苯、DMSO、水或該等溶媒之混合溶媒。其中，從反應加速性、成本及安全性等之觀點，以使用乙醇與水之混合溶媒為佳。 As in the reduction with hydrogen, the azide of anthranilate, zinc powder and acidic substances are preferably stirred and mixed in a solvent. The solvent used is not particularly limited as long as it does not affect the reduction reaction. Specifically, for example, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, acetonitrile, propionitrile, methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, tris Butanol, THF, 2-methyl THF, 1,4-dioxane, tertiary butyl methyl ether, dimethoxyethane, diglyme, acetone, diethyl ketone, methyl ethyl Ketone, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene, toluene, DMSO, water or mixed solvents of these solvents. Among them, it is preferable to use a mixed solvent of ethanol and water from the viewpoint of reaction acceleration, cost, and safety.

相對於鄰胺苯甲酸酯之疊氮體，以使用1至200倍容量之溶媒為佳，以使用1至100倍容量更佳，以使用1至50倍容量又更佳。 Relative to the azide of anthranilate, it is better to use a solvent with a capacity of 1 to 200 times, more preferably with a capacity of 1 to 100 times, and even better with a capacity of 1 to 50 times.

將鄰胺苯甲酸酯之疊氮體、鋅粉、酸性物質及反應溶媒導入反應系內(反應容器內等進行反應之處)之方法並無特別限制。亦即，可為任意之導入順序。例如：可預先在反應系內饋入鄰胺苯甲酸酯之疊氮體與酸性物質，在此導入溶媒使混合物溶解後，再導入鋅粉開始進行還原反應。 The method of introducing the azide of anthranilate, zinc powder, acidic substance, and reaction solvent into the reaction system (where the reaction takes place in the reaction vessel, etc.) is not particularly limited. That is, it can be any import order. For example, the azide and acidic substance of anthranilate can be fed into the reaction system in advance, after introducing a solvent to dissolve the mixture, and then introducing zinc powder to start the reduction reaction.

以鋅粉進行還原反應時之溫度並無特別限制，惟以0至150℃為佳，以10至100℃更佳。反應時間亦無特別限制，以0.5至24小時為佳，以1至17小時更佳。氣體環境亦無特別限制，可為空氣環境下、或非活性氣體環境下之任一種氣體環境下。其中，考量到操作性等，則以空氣環境下為佳。 The temperature during the reduction reaction with zinc powder is not particularly limited, but it is preferably 0 to 150°C, more preferably 10 to 100°C. The reaction time is also not particularly limited, preferably 0.5 to 24 hours, more preferably 1 to 17 hours. The gas environment is also not particularly limited, and it can be any of the gas environment under the air environment or the inert gas environment. Among them, considering the operability, etc., it is better to be in an air environment.

反應結束後，可藉由濾出殘渣並將濾液進行水洗而得到二胺基苯甲酸酯。 After the reaction is completed, the residue can be filtered off and the filtrate can be washed with water to obtain diaminobenzoate.

(使用膦之疊氮體的還原方法) (Reduction method using phosphine azide)

本發明中，還原反應可藉由使鄰胺苯甲酸酯之疊氮體與膦接觸以製造鄰胺苯甲酸酯之亞胺基正膦體後經水解而進行。 In the present invention, the reduction reaction can be carried out by contacting the azide of the anthranilate with the phosphine to produce the iminophosphorane body of the anthranilate followed by hydrolysis.

膦方面，可列舉如：三苯基膦(PPh3)等芳香族膦、三丁基膦等烷基膦。從反應性、成本、安全性之觀點，以使用三苯基膦為佳。 Examples of phosphines include aromatic phosphines such as triphenylphosphine (PPh 3 ) and alkylphosphines such as tributylphosphine. From the viewpoint of reactivity, cost, and safety, it is preferable to use triphenylphosphine.

三苯基膦之使用量並無特別限制，惟相對於鄰胺苯甲酸酯之疊氮體1莫耳，係以1至10莫耳為佳，以1至8莫耳更佳，以1至5莫耳又更佳。 The amount of triphenylphosphine used is not particularly limited, but it is preferably 1 to 10 moles relative to 1 mole of azide of anthranilate, more preferably 1 to 8 moles, 1 To 5 moles is better.

使鄰胺苯甲酸酯之疊氮體與膦接觸時，以將該等在溶媒中進行攪拌混合為佳。所使用之溶媒如為不影響還原反應者即可，並無特別限制。具體而言，可列舉如：乙酸乙酯、乙酸甲酯、乙酸丁酯、乙酸異丙酯、乙腈、丙腈、THF、2-甲基THF、1,4-二噁烷、三級丁基甲基醚、二甲氧基乙烷、二甘二甲醚、丙酮、二乙基酮、甲基乙基酮、二氯甲烷、三氯甲烷、四氯化碳、1,2-二氯乙烷、氯苯、甲苯、二甲苯、己烷、庚烷、DMSO、水 或該等溶媒之混合溶媒。其中，從產率、成本及安全性之觀點，以使用水、或THF與水之混合溶媒為佳。 When the azide of anthranilate is brought into contact with phosphine, it is preferable to stir and mix these in a solvent. The solvent used is not particularly limited as long as it does not affect the reduction reaction. Specifically, for example, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, acetonitrile, propionitrile, THF, 2-methyl THF, 1,4-dioxane, tertiary butyl methyl Ether, dimethoxyethane, diglyme, acetone, diethyl ketone, methyl ethyl ketone, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, Chlorobenzene, toluene, xylene, hexane, heptane, DMSO, water or mixed solvents of these solvents. Among them, it is preferable to use water or a mixed solvent of THF and water from the viewpoint of productivity, cost, and safety.

相對於鄰胺苯甲酸酯之疊氮體，以使用1至200倍容量之溶媒為佳，以使用1至100倍容量更佳，以使用1至50倍容量又更佳。 Relative to the azide of anthranilate, it is better to use a solvent with a capacity of 1 to 200 times, more preferably with a capacity of 1 to 100 times, and even better with a capacity of 1 to 50 times.

進行還原反應時的溫度並無特別限制，以0至120℃為佳，以10至100℃更佳。反應時間亦無無特別限制，以0.1至48小時為佳，以1至24小時更佳。氣體環境亦無特別限制，可為空氣環境下、或非活性氣體環境下之任一種氣體環境下。其中，考量到操作性等，則以空氣環境下為佳。 The temperature at which the reduction reaction is carried out is not particularly limited, preferably 0 to 120°C, more preferably 10 to 100°C. The reaction time is also not particularly limited, preferably 0.1 to 48 hours, more preferably 1 to 24 hours. The gas environment is also not particularly limited, and it can be any of the gas environment under the air environment or the inert gas environment. Among them, considering the operability, etc., it is better to be in an air environment.

接著，經由上述鄰胺苯甲酸酯之疊氮體與膦之反應所得的亞胺基正膦體進行水解而合成二胺基苯甲酸酯。所得亞胺基正膦體可分離再水解，亦可不經分離而直接存在於反應液中進行水解。 Next, the iminophosphorane body obtained by the reaction of the azide of the anthranilate and the phosphine is hydrolyzed to synthesize the diaminobenzoate. The obtained iminophosphorane body can be separated and then hydrolyzed, or it can be directly present in the reaction solution for hydrolysis without separation.

亞胺基正膦體的水解可藉由使亞胺基正膦體與酸接觸而進行。 The hydrolysis of the iminophosphorane body can be performed by contacting the iminophosphorane body with an acid.

水解中使用的酸方面，並無特別限制，可列舉如：習知之酸。從產率、成本及安全性之觀點，以鹽酸、硫酸、甲磺酸、對甲苯磺酸、磷酸為佳，以鹽酸更佳。 The acid used in the hydrolysis is not particularly limited, and examples include conventional acids. From the viewpoint of yield, cost and safety, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, and phosphoric acid are preferred, and hydrochloric acid is more preferred.

酸的添加量並無特別限制，惟以使反應液之pH在4以下而將亞胺基正膦體進行水解者為佳。 The amount of acid added is not particularly limited, but it is preferable to hydrolyze the iminophosphorane body so that the pH of the reaction solution is 4 or less.

為了使亞胺基正膦體與酸接觸以進行水解，係以將兩者攪拌混合為佳。在攪拌混合時，以在溶媒中實施為佳。在不分離亞胺基正膦體且在持續進行鄰胺苯甲酸酯之疊氮體與膦之反應後進行水解時，可在反應 後的溶液中加入酸。將亞胺基正膦體分離並進行水解時，所使用的溶媒方面，可使用與鄰胺苯甲酸酯之疊氮體與膦之反應中所使用的溶媒為相同溶媒。 In order to bring the iminophosphorane body into contact with an acid for hydrolysis, it is better to stir and mix the two. When stirring and mixing, it is preferably carried out in a solvent. When the iminophosphorane body is not separated and hydrolysis is continued after the reaction of the azide of the anthranilate ester with the phosphine, an acid may be added to the solution after the reaction. When the iminophosphorane body is separated and hydrolyzed, the solvent used can be the same as the solvent used in the reaction between the azido of anthranilate and phosphine.

水解時必須有水的存在，溶媒係使用水或水與其它溶媒的混合溶媒。在持續進行鄰胺苯甲酸酯之疊氮體與膦之反應後進行水解時，當溶媒不含水的情況下，可在水解時另外添加水。水的添加量並無特別限制，惟相對於亞胺基正膦體，係以0.01至200倍容量者為佳。 Water must be present during hydrolysis. The solvent system uses water or a mixed solvent of water and other solvents. When the reaction between the azido of anthranilate and the phosphine is continued and the hydrolysis is performed, when the solvent does not contain water, additional water may be added during the hydrolysis. The amount of water added is not particularly limited, but it is preferably 0.01 to 200 times the volume relative to the iminophosphorane body.

進行水解時的溫度並無特別限制，惟以20至120℃為佳，以10至150℃更佳。反應時間亦無特別限制，惟以0.5至48小時為佳，以1至24小時更佳。氣體環境亦無特別限制，可為空氣環境下、或非活性氣體環境下之任一種氣體環境下。其中，考量到操作性等，則以空氣環境下為佳。 The temperature during the hydrolysis is not particularly limited, but it is preferably 20 to 120°C, more preferably 10 to 150°C. The reaction time is also not particularly limited, but it is preferably 0.5 to 48 hours, more preferably 1 to 24 hours. The gas environment is also not particularly limited, and it can be any of the gas environment under the air environment or the inert gas environment. Among them, considering the operability, etc., it is better to be in an air environment.

將水解結束後的反應液使用鹼作成鹼性後，藉由溶劑萃取等而可得到二胺基苯甲酸酯。 After the reaction solution after the hydrolysis is made alkaline using an alkali, diaminobenzoate can be obtained by solvent extraction or the like.

上述鄰胺苯甲酸酯之疊氮體經還原而得的二胺基苯甲酸酯亦可依再結晶、管柱分離等習知方法進一步高度純化。 The diaminobenzoate obtained by reducing the azide of the anthranilate can be further highly purified by conventional methods such as recrystallization and column separation.

<由二胺基苯甲酸酯製造苯并咪唑衍生物之方法> <Method for producing benzimidazole derivatives from diaminobenzoate>

接著，對於在酸的存在下使所得二胺基苯甲酸酯與原酯衍生物接觸以製造苯并咪唑衍生物之方法進行說明。藉由二胺基苯甲酸酯與原酯衍生物的接觸以合成苯并咪唑衍生物之反應本身為習知，可採用專利文獻1等記載之方法。 Next, a method of producing a benzimidazole derivative by contacting the obtained diaminobenzoate with an orthoester derivative in the presence of an acid will be described. The reaction itself to synthesize the benzimidazole derivative by contacting the diaminobenzoate with the original ester derivative is known, and the method described in Patent Document 1 or the like can be used.

<原酯衍生物> <orthoester derivative>

本發明中，與上述二胺基苯甲酸酯反應之原酯衍生物係由下述式(4)：

Figure 108119739-A0202-12-0020-26
In the present invention, the original ester derivative reacted with the diaminobenzoate is represented by the following formula (4):
Figure 108119739-A0202-12-0020-26

所示。 As shown.

上述式中，R2為碳數1至6之烷基或碳數1至6之烷氧基。R2為烷氧基時，係成為具有4個烷氧基之化合物。R2之中，為了將所得苯并咪唑衍生物作為坎地沙坦酯之中間體使用，以乙氧基為佳。 In the above formula, R 2 is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms. When R 2 is an alkoxy group, it becomes a compound having 4 alkoxy groups. Among R 2 , in order to use the obtained benzimidazole derivative as an intermediate of candesartan cilexetil, ethoxy is preferred.

R3為碳數1至6之烷基，可互為相同或相異之基。 R 3 is an alkyl group having 1 to 6 carbon atoms, which may be the same or different from each other.

此種原酯衍生物可使用市售品。 Commercial products can be used as such orthoester derivatives.

上述二胺基苯甲酸酯與上述原酯衍生物之反應中，該原酯衍生物之使用量並無特別限制，惟相對於上述二胺基苯甲酸酯1莫耳，係以0.5至10莫耳為佳，以0.95至2莫耳更佳。 In the reaction between the diaminobenzoate and the original ester derivative, the amount of the original ester derivative used is not particularly limited, but it is 0.5 to 1 mole relative to the above diaminobenzoate. 10 moles is better, and 0.95 to 2 moles is better.

(酸) (Acid)

上述二胺基苯甲酸酯與上述原酯衍生物之反應係在酸的存在下進行，然而該酸並無特別限制，可使用鹽酸、硫酸等無機酸；甲酸、乙酸、甲磺酸、對甲苯磺酸等有機酸，其中，從處理的容易度之觀點，以使用乙酸等有機酸為佳。此時，亦可將所使用之酸作為反應溶媒。 The reaction between the diaminobenzoate and the original ester derivative is carried out in the presence of an acid. However, the acid is not particularly limited, and inorganic acids such as hydrochloric acid and sulfuric acid can be used; formic acid, acetic acid, methanesulfonic acid, Among organic acids such as toluenesulfonic acid, it is preferable to use organic acids such as acetic acid from the viewpoint of ease of handling. At this time, the acid used may also be used as a reaction solvent.

酸之使用量並無特別限制，惟在將酸作為反應溶媒使用時，可添加過量的酸。然而，如考量反應後的後處理等，相對於上述二胺基苯甲酸酯1g，以使用0.5至10mL之酸為佳，以使用0.5至5mL更佳。而 且，當使用有機溶媒作為反應溶媒使用時，考量反應進行性、後處理等，相對於上述二胺基苯甲酸酯1莫耳，以0.1至10莫耳為佳，以0.5至3莫耳更佳。 The amount of acid used is not particularly limited, but when the acid is used as a reaction medium, an excess amount of acid can be added. However, for example, considering the post-treatment after the reaction, it is preferable to use 0.5 to 10 mL of acid relative to 1 g of the above-mentioned diaminobenzoate, and more preferably 0.5 to 5 mL. Furthermore, when using an organic solvent as the reaction solvent, considering the progress of the reaction, post-treatment, etc., it is preferably 0.1 to 10 mol, and 0.5 to 3 mol relative to 1 mol of the above-mentioned diaminobenzoate. Better.

(苯并咪唑衍生物之製造條件) (Production conditions of benzimidazole derivatives)

本發明之苯并咪唑衍生物之製造方法係使上述二胺基苯甲酸酯與上述原酯衍生物在酸的存在下接觸。 The method for producing a benzimidazole derivative of the present invention is to contact the diaminobenzoate and the orthoester derivative in the presence of an acid.

將有機溶媒作為反應溶媒使用時，有機溶媒如為不會對上述二胺基苯甲酸酯、上述酸及上述原酯衍生物造成不良影響者即可，而無特別限制。然而，為了提高反應溫度、縮短反應時間、方便後處理，反應溶媒係以乙酸乙酯、甲苯、四氫呋喃(THF)等為佳，尤以甲苯為特佳。 When an organic solvent is used as a reaction solvent, the organic solvent is not particularly limited as long as it does not adversely affect the diaminobenzoate, the acid, and the original ester derivative. However, in order to increase the reaction temperature, shorten the reaction time, and facilitate post-treatment, the reaction solvent system is preferably ethyl acetate, toluene, tetrahydrofuran (THF), etc., particularly toluene.

上述二胺基苯甲酸酯與上述原酯衍生物之反應係發生胺基與烷氧基之縮合反應，接著，產生環化反應，得到下述式(5)所示之苯并咪唑衍生物，

Figure 108119739-A0202-12-0021-27
The reaction between the diaminobenzoate and the original ester derivative is a condensation reaction of an amine group and an alkoxy group, followed by a cyclization reaction to obtain a benzimidazole derivative represented by the following formula (5) ,
Figure 108119739-A0202-12-0021-27

(式中，R1與上述式(1)之R1同義、R2與上述式(4)之R2同義)。 (Wherein, R 1 is and R in the above formula (1) of the same meaning as 1, R 2 2 R synonymous with the above-described formula (4) of).

本反應中，反應溫度可依所設定之反應條件而適當地決定，惟以0至150℃為佳，以10至100℃更佳，以10至50℃為特佳。藉由滿足該範圍，可減低反應所副產生之不純物量。而且，反應時間如為0.5至5 小時即為充分。氣體環境亦無特別限制，如為空氣環境下即可。更且，反應可在減壓下、加壓下、大氣壓下之任一種狀態下進行。 In this reaction, the reaction temperature can be appropriately determined according to the set reaction conditions, but it is preferably 0 to 150°C, more preferably 10 to 100°C, and particularly preferably 10 to 50°C. By satisfying this range, the amount of impurities generated by the reaction can be reduced. Furthermore, a reaction time of 0.5 to 5 hours is sufficient. The gas environment is also not particularly limited, as long as it is in an air environment. Furthermore, the reaction can be carried out in any state under reduced pressure, under pressure, or under atmospheric pressure.

所得苯并咪唑衍生物可用習知方法從反應系內取出。而且，該苯并咪唑衍生物可用習知方法精製。 The obtained benzimidazole derivative can be taken out of the reaction system by a conventional method. Moreover, the benzimidazole derivative can be purified by a conventional method.

而且，所得苯并咪唑衍生物可適合作為如坎地沙坦酯之沙坦系原料藥的中間體(原料)使用。 Moreover, the obtained benzimidazole derivative can be suitably used as an intermediate (raw material) of a satan-based drug substance such as candesartan cilexetil.

[實施例] [Example]

以下列舉實施例以詳細說明本發明，然而本發明並不受該等具體例所限定。 The following examples are given to illustrate the present invention in detail, but the present invention is not limited by these specific examples.

另外，實施例中之純度評定係以使用以下高效液相層析(HPLC)之方法進行。 In addition, the purity evaluation in the examples was performed using the following high-performance liquid chromatography (HPLC) method.

<HPLC之測定條件> <Measurement conditions of HPLC>

裝置：高效液相層析儀(HPLC) Device: High-performance liquid chromatography (HPLC)

檢測器：紫外線吸光光度計(測定波長：254nm) Detector: ultraviolet absorption photometer (measurement wavelength: 254nm)

管柱：XBridge C18、內徑4.6mm、長度15cm(粒徑5μm)(Waters公司製造) Column: XBridge C18, inner diameter 4.6mm, length 15cm (particle size 5μm) (made by Waters)

管柱溫度：恆定在30℃ Column temperature: constant at 30℃

試樣溫度：恆定在25℃ Sample temperature: constant at 25℃

流速：1.0ml/分鐘 Flow rate: 1.0ml/min

測定時間：20分鐘 Measurement time: 20 minutes

移動相A：乙腈 Mobile phase A: acetonitrile

移動相B：水 Mobile phase B: water

流動相的送液：根據測定對象，如下述變更移動相A、B的混合比來控制濃度梯度。 Liquid feeding of mobile phase: According to the measurement object, the mixing ratio of mobile phases A and B is changed as follows to control the concentration gradient.

測定對象：2,3-二胺基苯甲酸甲酯2-乙氧基-1H-苯并咪唑-7-甲酸甲酯 Measurement object: methyl 2,3-diaminobenzoate 2-ethoxy-1H-benzimidazole-7-methyl formate

流動相A、B的混合比：20至100%乙腈(0至20分鐘) Mixing ratio of mobile phases A and B: 20 to 100% acetonitrile (0 to 20 minutes)

上述條件中，2,3-二胺基苯甲酸甲酯(上述二胺基苯甲酸酯)在約5.9分鐘確認波峰，而2-乙氧基-1H-苯并咪唑-7-甲酸甲酯(上述苯并咪唑衍生物)在約7.3分鐘確認波峰。 Under the above conditions, methyl 2,3-diaminobenzoate (the above-mentioned diaminobenzoate) confirmed the peak at about 5.9 minutes, while methyl 2-ethoxy-1H-benzimidazole-7-carboxylate (The above-mentioned benzimidazole derivative) The peak was confirmed in about 7.3 minutes.

測定對象：鄰胺苯甲酸甲酯3-疊氮基鄰胺苯甲酸酯 Measurement object: Methyl anthranilate 3-azido anthranilate

流動相A、B的混合比：50至100%乙腈(0至20分鐘) Mixing ratio of mobile phases A and B: 50 to 100% acetonitrile (0 to 20 minutes)

上述條件中，鄰胺苯甲酸甲酯(上述鄰胺苯甲酸酯)在約3.7分鐘確認波峰，而3-疊氮基鄰胺苯甲酸酯(上述鄰胺苯甲酸酯之疊氮體)在約5.8分鐘確認波峰。 Under the above conditions, methyl anthranilate (the above anthranilate) confirmed the peak at about 3.7 minutes, and 3-azido anthranilate (the azido of the above anthranilate) ) Confirm the peak in about 5.8 minutes.

以下實施例中，上述鄰胺苯甲酸酯、上述鄰胺苯甲酸酯之疊氮體、上述二胺基苯甲酸酯、上述苯并咪唑衍生物的各純度全部係在上述條件下測定之各化合物的波峰面積值相對於所有波峰(排除源自溶媒之波峰)的面積值之總和而言的比率。 In the following examples, the purity of the anthranilate, the azide of the anthranilate, the diaminobenzoate, and the benzimidazole derivative are all measured under the above conditions The ratio of the peak area value of each compound to the sum of the area values of all peaks (excluding peaks derived from the solvent).

[實施例1](使用三級丁基氫過氧化物作為氧化劑，由鄰胺苯甲酸酯製造鄰胺苯甲酸酯之疊氮體) [Example 1] (Using tertiary butyl hydroperoxide as an oxidant to produce an azide of anthranilate from anthranilate)

使用三級丁基氫過氧化物作為氧化劑，進行下述式之反應。 Using tertiary butyl hydroperoxide as an oxidizing agent, the reaction of the following formula proceeds.

Figure 108119739-A0202-12-0024-28
Figure 108119739-A0202-12-0024-28

在鄰胺苯甲酸甲酯(0.5g、3.30mmol)中加入CuBr(0.05g、0.35mmol)，在氮氣環境下攪拌30分鐘之後，加入乙腈(5mL)使其溶解。在該溶液中加入三甲基矽基疊氮(0.76g、6.60mmol)、42.2%三級丁基氫過氧化物甲苯溶液(1.4g、6.60mmol)，在50℃下攪拌7小時。將反應液進行HPLC分析，發現含有3-疊氮基鄰胺苯甲酸甲酯(415mg、65.4%)及鄰胺苯甲酸甲酯(153mg、30.6%)。 CuBr (0.05 g, 0.35 mmol) was added to methyl anthranilate (0.5 g, 3.30 mmol), and after stirring for 30 minutes under a nitrogen atmosphere, acetonitrile (5 mL) was added to dissolve it. To this solution, trimethylsilyl azide (0.76 g, 6.60 mmol) and 42.2% tertiary butyl hydroperoxide toluene solution (1.4 g, 6.60 mmol) were added, and the mixture was stirred at 50°C for 7 hours. The reaction solution was analyzed by HPLC and found to contain methyl 3-azidoanthranilate (415 mg, 65.4%) and methyl anthranilate (153 mg, 30.6%).

在反應液中加入乙酸乙酯(200mL)加以過濾。將濾液濃縮後，藉由在矽膠管柱(己烷/乙酸乙酯=20：1)精製，得到3-疊氮基鄰胺苯甲酸甲酯之結晶(由質量所求得的產率：58.9%、在高效液相層析(HPLC)求得之由鄰胺苯甲酸甲酯轉化為3-疊氮基鄰胺苯甲酸甲酯之轉化率：68.1%、由HPLC所得之純度為95%)。3-疊氮基鄰胺苯甲酸甲酯之分析值係如下所述。 Ethyl acetate (200 mL) was added to the reaction liquid and filtered. After concentrating the filtrate, it was purified on a silica gel column (hexane/ethyl acetate = 20:1) to obtain crystals of methyl 3-azidoanthranilate (yield obtained from mass: 58.9 %, the conversion rate from methyl anthranilate to methyl 3-azido anthranilate determined by high performance liquid chromatography (HPLC): 68.1%, and the purity by HPLC is 95%) . The analysis values of 3-azidoanthranilic acid methyl ester are as follows.

融點：61至63℃ Melting point: 61 to 63°C

IR(KBr)：2116、1685cm-1 IR(KBr): 2116, 1685cm -1

1H-NMR(CDCl3)δ3.85(s,3H),6.00(brs,2H),6.5-6.90(m,1H),7.00-7.40(m,1H),7.60-7.90(m,1H) 1 H-NMR (CDCl 3 ) δ 3.85 (s, 3H), 6.00 (brs, 2H), 6.5-6.90 (m, 1H), 7.00-7.40 (m, 1H), 7.60-7.90 (m, 1H)

[實施例2](使用二乙酸碘苯作為氧化劑，由鄰胺苯甲酸酯製造鄰胺苯甲酸酯之疊氮體) [Example 2] (The azido of anthranilate was produced from anthranilate using iodobenzene diacetate as the oxidant)

在鄰胺苯甲酸甲酯(0.5g、3.30mmol)中加入CuBr(0.15g、1.05mmol)，在氮氣環境下攪拌30分鐘後，加入乙腈(5mL)使其溶解。在20℃下花費15分鐘在該溶液中加入三甲基矽基疊氮(0.76g、6.60mmol)、二乙酸碘苯(PIDA、1.06g、3.30mmol)，並在相同溫度下攪拌5小時。將反應液進行HPLC分析，發現含有3-疊氮基鄰胺苯甲酸甲酯(283mg、44.7%)及鄰胺苯甲酸甲酯(229mg、45.9%)。 CuBr (0.15 g, 1.05 mmol) was added to methyl anthranilate (0.5 g, 3.30 mmol), and after stirring for 30 minutes under a nitrogen atmosphere, acetonitrile (5 mL) was added to dissolve it. Trimethylsilyl azide (0.76 g, 6.60 mmol) and iodobenzene diacetate (PIDA, 1.06 g, 3.30 mmol) were added to the solution at 20°C for 15 minutes, and stirred at the same temperature for 5 hours. The reaction solution was analyzed by HPLC and found to contain methyl 3-azidoanthranilate (283 mg, 44.7%) and methyl anthranilate (229 mg, 45.9%).

以與實施例1之相同操作進行精製，得到3-疊氮基鄰胺苯甲酸甲酯之結晶(由質量所求得的產率：40.2%、在高效液相層析(HPLC)求得之由鄰胺苯甲酸甲酯轉化為3-疊氮基鄰胺苯甲酸甲酯之轉化率：44.4%、由HPLC所得之純度為95%)。 Purification was carried out in the same manner as in Example 1 to obtain crystals of methyl 3-azidoanthranilate (yield obtained from mass: 40.2%, obtained by high performance liquid chromatography (HPLC) Conversion rate from methyl anthranilate to methyl 3-azido anthranilate: 44.4%, purity by HPLC is 95%).

[實施例3](使用CMHP作為氧化劑，由鄰胺苯甲酸酯製造鄰胺苯甲酸酯之疊氮體) [Example 3] (Azide of anthranilate is produced from anthranilate using CMHP as oxidant)

在鄰胺苯甲酸甲酯(0.5g、3.30mmol)中加入CuBr(0.15g、1.05mmol)，在氮氣環境下攪拌30分鐘後，加入乙腈(5mL)使其溶解。在20℃下花費1小時在該溶液中加入三甲基矽基疊氮(0.76g、6.60mmol)、80%異丙苯氫過氧化物(CMHP、1.26g、6.60mmol)，並在40℃下攪拌3小時。將反應液進行HPLC分析，發現含有3-疊氮基鄰胺苯甲酸甲酯(287mg、45.3%)及鄰胺苯甲酸甲酯(252mg、50.5%)。 CuBr (0.15 g, 1.05 mmol) was added to methyl anthranilate (0.5 g, 3.30 mmol), and after stirring for 30 minutes under a nitrogen atmosphere, acetonitrile (5 mL) was added to dissolve it. Add 1 hour of trimethylsilyl azide (0.76g, 6.60mmol) and 80% cumene hydroperoxide (CMHP, 1.26g, 6.60mmol) to this solution at 1 Stir for 3 hours. The reaction solution was analyzed by HPLC and found to contain methyl 3-azidoanthranilate (287 mg, 45.3%) and methyl anthranilate (252 mg, 50.5%).

以與實施例1之相同操作進行精製，得到3-疊氮基鄰胺苯甲酸甲酯之結晶(由質量所求得的產率：40.8%、在高效液相層析(HPLC)求得之由鄰胺苯甲酸甲酯轉化為3-疊氮基鄰胺苯甲酸甲酯之轉化率：45.4%、由HPLC所得之純度為95%)。 Purification was carried out in the same manner as in Example 1 to obtain crystals of methyl 3-azidoanthranilate (yield obtained from mass: 40.8%, obtained by high performance liquid chromatography (HPLC) Conversion rate from methyl anthranilate to methyl 3-azido anthranilate: 45.4%, purity by HPLC is 95%).

[實施例4](使用CuCl作為銅化合物，由鄰胺苯甲酸酯製造鄰胺苯甲酸酯之疊氮體) [Example 4] (Using CuCl as a copper compound to produce an azide of anthranilate from anthranilate)

在鄰胺苯甲酸甲酯(0.5g、3.30mmol)中加入CuCl(65.3g、0.66mmol)，在氮氣環境下攪拌30分鐘後，加入乙腈(5mL)使其溶解。在該溶液中加入三甲基矽基疊氮(0.76g、6.60mmol)、42.2%三級丁基氫過氧化物甲苯溶液(1.4g、6.60mmol)，在50℃下攪拌7小時。將反應液進行HPLC分析，發現含有3-疊氮基鄰胺苯甲酸甲酯(302mg、47.6%)及鄰胺苯甲酸甲酯(92.3mg、18.5%)。 CuCl (65.3 g, 0.66 mmol) was added to methyl anthranilate (0.5 g, 3.30 mmol), and after stirring for 30 minutes under a nitrogen atmosphere, acetonitrile (5 mL) was added to dissolve. To this solution, trimethylsilyl azide (0.76 g, 6.60 mmol) and 42.2% tertiary butyl hydroperoxide toluene solution (1.4 g, 6.60 mmol) were added, and the mixture was stirred at 50°C for 7 hours. The reaction solution was analyzed by HPLC and found to contain methyl 3-azidoanthranilate (302 mg, 47.6%) and methyl anthranilate (92.3 mg, 18.5%).

以與實施例1之相同操作進行精製，得到3-疊氮基鄰胺苯甲酸甲酯之結晶(由質量所求得的產率：42.8%、在高效液相層析(HPLC)求得之由鄰胺苯甲酸甲酯轉化為3-疊氮基鄰胺苯甲酸甲酯之轉化率：72%、由HPLC所得之純度為95%)。 Purification was carried out in the same manner as in Example 1 to obtain crystals of methyl 3-azidoanthranilate (yield from mass: 42.8%, obtained by high performance liquid chromatography (HPLC) Conversion rate from methyl anthranilate to methyl 3-azido anthranilate: 72%, purity by HPLC is 95%).

[實施例5](使用CuCl2作為銅化合物，由鄰胺苯甲酸酯製造鄰胺苯甲酸酯之疊氮體) [Example 5] (Using CuCl 2 as a copper compound to produce an azide of anthranilate from anthranilate)

除了銅化合物係使用CuCl2以外，以與實施例4之相同操作進行反應。在該反應液中發現含有3-疊氮基鄰胺苯甲酸甲酯(211mg、33.3%)及鄰胺苯甲酸甲酯(92.8mg、18.6%)。 The reaction was carried out in the same manner as in Example 4 except that CuCl 2 was used as the copper compound. The reaction solution was found to contain methyl 3-azidoanthranilate (211 mg, 33.3%) and methyl anthranilate (92.8 mg, 18.6%).

以與實施例1之相同操作進行精製，得到3-疊氮基鄰胺苯甲酸甲酯之結晶(由質量所求得的產率：30%、在高效液相層析(HPLC)求得之由鄰胺苯甲酸甲酯轉化為3-疊氮基鄰胺苯甲酸甲酯之轉化率：64.2%、由HPLC所得之純度為95%)。 Purification was carried out in the same manner as in Example 1 to obtain crystals of methyl 3-azidoanthranilate (yield obtained from mass: 30%, obtained by high performance liquid chromatography (HPLC) Conversion rate of methyl anthranilate to methyl 3-azido anthranilate: 64.2%, purity by HPLC is 95%).

[實施例6](使用鋅粉作為還原劑，由鄰胺苯甲酸酯之疊氮體製造二胺基苯甲酸酯) [Example 6] (Zinc powder is used as a reducing agent to produce diaminobenzoate from an azide of anthranilate)

使用鋅粉作為還原劑進行下述式之反應。 The reaction of the following formula is carried out using zinc powder as a reducing agent.

Figure 108119739-A0202-12-0027-29
Figure 108119739-A0202-12-0027-29

在實施例1中所得的3-疊氮基鄰胺苯甲酸甲酯(10mg、0.05mmol)與氯化銨(7mg、0.13mmol)中加入乙醇(1mL)及水(0.3mL)使其溶解。在該溶液中加入鋅粉(5mg、0.07mmol)並在室溫下攪拌16小時，由於起始原料之3-疊氮基鄰胺苯甲酸甲酯的殘留，故在此進而加入氯化銨(7mg、0.13mmol)及鋅粉(5mg、0.07mmol)並在室溫下攪拌4小時。將反應液經乙酸乙酯稀釋後加以過濾，將所濾取的固體以乙酸乙酯清洗。將濾液及清洗液合併，再以飽和食鹽水清洗後，在硫酸鎂上脫水過濾，將濾液進行HPLC分析。由3-疊氮基鄰胺苯甲酸甲酯轉化為2,3-二胺基苯甲酸甲酯之轉化率為99.7%。 To the methyl 3-azidoanthranilate (10 mg, 0.05 mmol) and ammonium chloride (7 mg, 0.13 mmol) obtained in Example 1, ethanol (1 mL) and water (0.3 mL) were added and dissolved. Zinc powder (5 mg, 0.07 mmol) was added to this solution and stirred at room temperature for 16 hours. Since the starting material 3-methyl-azido-anthranilic acid methyl ester remained, ammonium chloride ( 7mg, 0.13mmol) and zinc powder (5mg, 0.07mmol) and stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate and filtered, and the filtered solid was washed with ethyl acetate. The filtrate and the washing solution were combined, washed with saturated saline, and then dehydrated and filtered on magnesium sulfate, and the filtrate was analyzed by HPLC. The conversion rate of methyl 3-azidoanthranilate to methyl 2,3-diaminobenzoate was 99.7%.

將該濾液減壓濃縮後，藉由在矽膠管柱(己烷/乙酸乙酯=1：1)精製，得到2,3-二胺基苯甲酸甲酯(由質量所求得的產率：99%、在高效液相層析(HPLC)求得之由3-疊氮基鄰胺苯甲酸甲酯轉化為2,3-二胺基苯甲酸甲酯之轉化率：99.7%、由HPLC所得之純度為95%)。所得2,3-二胺基苯甲酸甲酯之分析值係如下所述。 After concentrating the filtrate under reduced pressure, it was purified on a silica gel column (hexane/ethyl acetate = 1:1) to obtain methyl 2,3-diaminobenzoate (yield obtained from mass: 99%, conversion rate from methyl 3-azido-anthranilate to methyl 2,3-diaminobenzoate determined by high-performance liquid chromatography (HPLC): 99.7%, obtained by HPLC The purity is 95%). The analysis value of the obtained methyl 2,3-diaminobenzoate is as follows.

IR(KBr)：1693cm-1 IR(KBr): 1693cm -1

1H-NMR(CDCl3)δ 7.30-7.80(m,1H),6.40-7.10(m.2H),1.45(brs,2H),3.85(s,3H),3.40(brs,2H) 1 H-NMR(CDCl 3 )δ 7.30-7.80(m,1H),6.40-7.10(m.2H),1.45(brs,2H),3.85(s,3H),3.40(brs,2H)

[實施例7](使用三苯基膦作為還原劑，由鄰胺苯甲酸酯之疊氮體製造二胺基苯甲酸酯) [Example 7] (Use of triphenylphosphine as a reducing agent to produce diaminobenzoate from an azide of anthranilate)

使用三苯基膦(PPh3)作為還原劑進行下述式之反應。 The reaction of the following formula was carried out using triphenylphosphine (PPh 3 ) as a reducing agent.

Figure 108119739-A0202-12-0028-30
Figure 108119739-A0202-12-0028-30

在實施例1中所得的3-疊氮基鄰胺苯甲酸甲酯(10mg、0.05mmol)之THF(0.5mL)溶液中加入三苯基膦(16mg、0.06mmol)及水(0.01g)，在55℃下攪拌16小時使反應。直到THF及水不噴濺為止將反應液進行減壓濃縮，加入水(1mL)及乙酸乙酯(1mL)後，再加入鹽酸至pH為1進行水解。將經分液所得的水層以24%NaOH調整pH成為10，以乙酸乙酯萃取後，將有機層藉由減壓濃縮而得到2,3-二胺基苯甲酸甲酯。 To a solution of methyl 3-azidoanthranilate (10 mg, 0.05 mmol) in THF (0.5 mL) obtained in Example 1, triphenylphosphine (16 mg, 0.06 mmol) and water (0.01 g) were added. The reaction was stirred at 55°C for 16 hours. The reaction solution was concentrated under reduced pressure until THF and water were not splashed. After adding water (1 mL) and ethyl acetate (1 mL), hydrochloric acid was further added to pH 1 for hydrolysis. The aqueous layer obtained by liquid separation was adjusted to pH 10 with 24% NaOH, extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure to obtain methyl 2,3-diaminobenzoate.

進行與實施例6之相同操作，得到精製之2,3-二胺基苯甲酸甲酯(由質量所求得的產率：95%、在高效液相層析(HPLC)求得之由3-疊氮基鄰胺苯甲酸甲酯轉化為2,3-二胺基苯甲酸甲酯之轉化率：99%、由HPLC所得之純度為95%)。 The same operation as in Example 6 was carried out to obtain purified methyl 2,3-diaminobenzoate (yield from mass: 95%, obtained from high performance liquid chromatography (HPLC) from 3 -Conversion rate of methyl azidoanthranilate to methyl 2,3-diaminobenzoate: 99%, purity by HPLC is 95%).

[實施例8](由二胺基苯甲酸酯製造苯并咪唑衍生物) [Example 8] (Production of benzimidazole derivatives from diaminobenzoate)

使用原酯衍生物進行下述式之反應。 The reaction of the following formula is carried out using orthoester derivatives.

Figure 108119739-A0202-12-0029-31
Figure 108119739-A0202-12-0029-31

將實施例6中所得的2,3-二胺基苯甲酸甲酯(10mg、0.06mmol二胺基苯甲酸酯)溶解於甲苯(1mL)，在室溫下加入乙酸(4mg、0.07mmol)及四乙氧基甲烷(10mg、0.08mmol；原酯衍生物)並在100℃下攪拌2小時使反應。將反應液進行HPLC分析，由2,3-二胺基苯甲酸甲酯轉化為苯并咪唑衍生物之轉化率為100%。 The methyl 2,3-diaminobenzoate (10 mg, 0.06 mmol diaminobenzoate) obtained in Example 6 was dissolved in toluene (1 mL), and acetic acid (4 mg, 0.07 mmol) was added at room temperature. And tetraethoxymethane (10mg, 0.08mmol; original ester derivatives) and stirred at 100 ° C for 2 hours to react. The reaction solution was analyzed by HPLC, and the conversion rate from methyl 2,3-diaminobenzoate to benzimidazole derivatives was 100%.

藉由將水(0.5mL)加入反應液中進行結晶、過濾，得到2-乙氧基-1H-苯并咪唑-7-甲酸甲酯(11.9mg、產率：90%)。而且，經HPLC確認2-乙氧基-1H-苯并咪唑-7-甲酸甲酯之純度為95%。 By adding water (0.5 mL) to the reaction solution for crystallization and filtration, 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (11.9 mg, yield: 90%) was obtained. Moreover, it was confirmed by HPLC that the purity of methyl 2-ethoxy-1H-benzimidazole-7-carboxylate was 95%.

Figure 108119739-A0202-11-0002-4
Figure 108119739-A0202-11-0002-4

Claims (5)

一種二胺基苯甲酸酯之製造方法，其係藉由使下述式(1)所示之鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，
Figure 108119739-A0202-13-0001-32
 式中，R 1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基，製造下述式(2)所示之鄰胺苯甲酸酯之疊氮體之後，
Figure 108119739-A0202-13-0001-33
 式中，R 1與上述式(1)之R 1同義，將所得的該鄰胺苯甲酸酯之疊氮體進行還原，製造下述式(3)所示之二胺基苯甲酸酯，
Figure 108119739-A0202-13-0001-34
 式中，R 1與上述式(1)之R 1同義。 A method for producing diaminobenzoate by contacting o-aminobenzoate represented by the following formula (1) with an azide agent in the presence of an oxidizing agent and a copper compound,
Figure 108119739-A0202-13-0001-32
 In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or an alkoxyaralkyl group having 8 to 11 carbon atoms, After manufacturing the azido of anthranilate represented by the following formula (2),
Figure 108119739-A0202-13-0001-33
 In the formula, R 1 and R in the above formula (1) of a synonym, the resulting azido-o-benzoate of the body is reduced to produce (3) amino acid esters of bis following formula ,
Figure 108119739-A0202-13-0001-34
 In the formula, R 1 is synonymous with R 1 in the above formula (1). 一種下述式(2)所示之鄰胺苯甲酸酯之疊氮體，
Figure 108119739-A0202-13-0002-36
 式中，R 1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基。 An azide of anthranilate represented by the following formula (2),
Figure 108119739-A0202-13-0002-36
 In the formula, R 1 is an alkyl group having 1 to 6 carbons, an alkoxyalkyl group having 2 to 12 carbons, an aralkyl group having 7 to 10 carbons, or an alkoxyaralkyl group having 8 to 11 carbons. 一種鄰胺苯甲酸酯之疊氮體的製造方法，其係藉由使下述式(1)所示之鄰胺苯甲酸酯與疊氮化劑在氧化劑及銅化合物之存在下接觸，
Figure 108119739-A0202-13-0002-41
 式中，R 1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基，製造下述式(2)所示之鄰胺苯甲酸酯之疊氮體，
Figure 108119739-A0202-13-0002-37
 式中，R 1與上述式(1)之R 1同義。 A method for producing an azide of anthranilate by contacting an anthranilate represented by the following formula (1) with an azide agent in the presence of an oxidizing agent and a copper compound,
Figure 108119739-A0202-13-0002-41
 In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or an alkoxyaralkyl group having 8 to 11 carbon atoms, The azido of anthranilate represented by the following formula (2) is produced,
Figure 108119739-A0202-13-0002-37
 In the formula, R 1 is synonymous with R 1 in the above formula (1). 一種二胺基苯甲酸酯之製造方法，其係將下述式(2)所示之鄰胺苯甲酸酯之疊氮體進行還原，
Figure 108119739-A0202-13-0002-38
 式中，R 1為碳數1至6之烷基、碳數2至12之烷氧基烷基、碳數7至10之芳烷基或碳數8至11之烷氧基芳烷基，製造下述式(3)所示之二胺基苯甲酸酯，
Figure 108119739-A0202-13-0003-40
 式中，R 1與上述式(2)之R 1同義。 A method for producing diaminobenzoate, which reduces the azide of ortho-aminobenzoate represented by the following formula (2),
Figure 108119739-A0202-13-0002-38
 In the formula, R 1 is an alkyl group having 1 to 6 carbon atoms, an alkoxyalkyl group having 2 to 12 carbon atoms, an aralkyl group having 7 to 10 carbon atoms or an alkoxyaralkyl group having 8 to 11 carbon atoms, The diaminobenzoate represented by the following formula (3) is produced,
Figure 108119739-A0202-13-0003-40
 In the formula, R 1 is synonymous with R 1 in the above formula (2). 一種苯并咪唑衍生物之製造方法，其係依申請專利範圍第1項或第4項所述之製造方法而製造上述式(3)所示之二胺基苯甲酸酯後，在酸的存在下，藉由使所得該二胺基苯甲酸酯與下述式(4)所示之原酯衍生物接觸，
Figure 108119739-A0202-13-0003-39
 式中，R 2為碳數1至6之烷基或碳數1至6之烷氧基，R 3為碳數1至6之烷基，可互為相同或相異之基，製造下述式(5)所示之苯并咪唑衍生物，
Figure 108119739-A0202-13-0003-35
 式中，R 1與上述式(1)之R 1同義、R 2與上述式(4)之R 2同義。 A method for manufacturing a benzimidazole derivative, which is based on the manufacturing method described in item 1 or item 4 of the patent application scope, after the diaminobenzoate represented by the above formula (3) is manufactured, In the presence of this, by contacting the obtained diaminobenzoate with an orthoester derivative represented by the following formula (4),
Figure 108119739-A0202-13-0003-39
 In the formula, R 2 is an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms, and R 3 is an alkyl group having 1 to 6 carbon atoms, which may be the same or different groups. The benzimidazole derivative represented by formula (5),
Figure 108119739-A0202-13-0003-35
 Formula, R 1 is and R in the above formula (1) of the same meaning as 1, R 2 2 R synonymous with the above-described formula (4) of.
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