WO2017131213A1

WO2017131213A1 - Method for producing 1h-tetrazole derivative

Info

Publication number: WO2017131213A1
Application number: PCT/JP2017/003066
Authority: WO
Inventors: 大輔市成; 今川　務; 廣川　賢一; 史孝増井
Original assignee: 日本曹達株式会社
Priority date: 2016-01-29
Filing date: 2017-01-27
Publication date: 2017-08-03
Also published as: CN108473446A

Abstract

Provided is a method for producing, at a high yield, a 1H-tetrazole derivative using a flow reactor and using an azide compound and a cyanide compound as starting materials. The method of producing a 1H-tetrazole derivative of the present invention entails reacting, in a flow reactor, an azide compound represented by general formula (2) (in the formula, Y¹ represents an alkyl group or the like) with a cyanide compound represented by formula (3) (in the formula, Z represents -CO- or the like, and R¹² represents an optionally substituted aryl group), to obtain the 1H-tetrazole derivative represented by formula (1). 0.8-1.2 mol. equivalent of the cyanide compound represented by formula (3) is used with respect to the azide compound represented by formula (2), and the initial concentration in the reaction solution of the azide compound represented by formula (2) is at least 5% by mass.

Description

Method for producing 1H-tetrazole derivative

The present invention relates to a method for producing a 1H-tetrazole derivative using a flow reactor.

The following formula (II)

(In the formula (II), Y represents an alkyl group, an aryl group, an arylalkyl group, a silyl group having a substituent, or a silylalkyl group having a substituent) and the following formula ( III)

(In the formula (III), Z is —CO—, —SO ₂ —, or —CR ^a R ^b — (wherein R ^a and R ^b are each independently a hydrogen atom, an alkyl group, or Represents an unsubstituted or substituted aryl group.), P represents 0 or 1, q represents 0 or 1, r represents 0 or 1, and R ¹ represents a case where q is 0. Represents an alkyl group or a hydrogen atom, represents an alkylene group when q is 1, and R ² represents an unsubstituted or substituted aryl group, provided that when p is 0, q is 1. , R is 0, q is 1.) and a cyanide compound represented by the following formula (I):

(In the formula (I), Y is the same as in the formula (II), and Z, R ¹ , R ² , p, q, and r are the same as in the formula (III)). A process for producing 1H-tetrazole derivatives is known. (See Patent Document 1)

International Publication No. 2013/187327

In the above method, the yield is obtained at a medium level of 60 to 80%, but a large excess (140 to 400 mol%) of methylazide having a high risk is used, which is not satisfactory industrially.
An object of the present invention is to provide a method for producing a 1H-tetrazole derivative with a high yield using a flow reactor by using an azide compound and a cyanide compound as raw materials.

As a result of intensive studies to solve the above problems, the present inventors can produce a 1H-tetrazole derivative with high yield by controlling the ratio of the azide compound and cyanide compound to be used and the initial concentration of the azide compound in the reaction solution. As a result, the present invention has been completed.

That is, the present invention
[1] The following formula (2)

(In Formula (2), Y ¹ represents an alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted arylalkyl group, a substituted silyl group, or a substituted silylalkyl. An azide compound represented by the following formula (3):

(In the formula (3), Z ¹ represents —CO—, —SO ₂ —, or —CR ^a1 R ^b1 — (wherein R ^a1 and R ^b1 each independently represents a hydrogen atom or an alkyl group) Or an unsubstituted or substituted aryl group, which may be bonded to each other to form a ring.], P1 represents 0 or 1, q1 represents 0 or 1, and r1 represents Represents 0 or 1, R ¹¹ represents an alkyl group or a hydrogen atom when q1 is 0, represents an alkylene group when q1 is 1, and R ¹² represents an unsubstituted or substituted aryl group. However, when p1 is 0, q1 is 1, and when r1 is 0, q1 is 1.) The following formula obtained by reacting with a cyanide compound represented by a flow reactor: (1)

(In Formula (1), Y ¹ is the same as in Formula (2), and Z ¹ , R ¹¹ , R ¹² , p1, q1, and r1 are the same as in Formula (3)). A method for producing a 1H-tetrazole derivative represented by claim 1, wherein 0.8 to 1.2 mol of the cyanide compound represented by the formula (3) is added to the azide compound represented by the formula (2). The present invention relates to a method for producing a 1H-tetrazole derivative represented by the formula (1), which is used in an equivalent range and the initial concentration of the azide compound represented by the formula (2) in the reaction solution is 5% by mass or more.
[2] A method for producing a 1H-tetrazole derivative represented by the formula (1) according to [1], wherein an initial concentration of the azide compound represented by the formula (2) in the reaction solution is 10% by mass or more,
[3] The method for producing a 1H-tetrazole derivative represented by the formula (1) according to [1] or [2], wherein Y ¹ represents an alkyl group,
[4] R ¹² is represented by the following formula (s11)

(In the formula (s11), A ¹ represents a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylsulfonyl group, an unsubstituted or substituted aryl group, a cyano group, or a nitro group. N1 represents an integer of 0 to 5. When n1 is 2 or more, A ¹ may be the same as or different from each other. , When p1 is 1, it binds to R ¹¹ , when p1 is 0 and r1 is 1, it binds to Z ¹ , and when p1 and r1 are 0, it binds to the carbon atom of the cyanide group A method for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of [1] to [3],
[5] The process for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of [1] to [4], wherein the reaction temperature of the reaction is 150 to 250 ° C.
[6] The method for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of [1] to [5], wherein the solvent of the reaction solution is toluene or N-methylpyrrolidone,
About.

By using the method of the present invention, the 1H-tetrazole derivative represented by the formula (1) can be produced in an industrially satisfactory yield.

It is the schematic diagram which showed one Embodiment of the flow reactor used for the manufacturing method of this invention.

[Azide Compound Represented by Formula (2)]
In Formula (2), Y ¹ represents an alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted arylalkyl group, a substituted silyl group, or a substituted silyl group. Represents an alkyl group.

The alkyl group may be a linear alkyl group, a branched alkyl group, or a cyclic alkyl group. The alkyl group is preferably a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 3 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms. Specifically, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl Group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.

The unsubstituted or substituted aryl group may be monocyclic or polycyclic. In the polycyclic aryl group, as long as at least one ring is an aromatic ring, the remaining ring may be a saturated ring, an unsaturated ring, or an aromatic ring. In the case where Y ¹ in the formula (2) is an aryl group having a substituent, the substituent is not particularly limited as long as it is chemically acceptable. Specifically, the following (1) to (1) The substituent illustrated in (85) can be mentioned. Among the aryl groups, an aryl group having 6 to 10 carbon atoms is preferable, and a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an azulenyl group, an indanyl group, or a tetralinyl group (1,2,3,4-tetrahydronaphthyl group) ) Is more preferable, and a phenyl group is more preferable.

An unsubstituted or substituted arylalkyl group means a group in which at least one hydrogen atom of an alkyl group is substituted with an unsubstituted or substituted aryl group. The alkyl group substituted with the aryl group may be a linear alkyl group, a branched alkyl group, or a cyclic alkyl group. The alkyl group is preferably a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 3 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms, and has 1 to 8 carbon atoms. The linear alkyl group is more preferable. Examples of the aryl group that serves as a substituent of the alkyl group include the same aryl groups as those described above that are unsubstituted or have a substituent. Among them, it is preferable that one hydrogen atom of a linear alkyl group having 1 to 8 carbon atoms is a group that is unsubstituted or substituted with an aryl group having 6 to 10 carbon atoms having a substituent. More preferably, one hydrogen atom of the straight chain alkyl group of 8 is a group substituted with an unsubstituted or substituted phenyl group, and one hydrogen atom of the straight chain alkyl group of 1 to 8 carbon atoms is A group substituted with an unsubstituted phenyl group is more preferable, and a benzyl group is still more preferable.

A silyl group having a substituent is a group in which at least one hydrogen atom of the silyl group is substituted. The substituent is not particularly limited as long as it is chemically acceptable. Specific examples include the substituents exemplified in the following (1) to (85). When 2 or 3 hydrogen atoms are substituted, the substituents may be the same or different from each other. Among them, a silyl group in which 1 to 3 hydrogen atoms are substituted with the same or different alkyl groups is preferable, and a silyl group in which three hydrogen atoms are substituted with the same or different alkyl groups is more preferable. , A trimethylsilyl group, a triethylsilyl group, an ethyldimethylsilyl group, or a t-butyldimethylsilyl group is more preferable, and a trimethylsilyl group is still more preferable.

A silylalkyl group having a substituent is a group in which at least one hydrogen atom of an alkyl group is substituted with a silyl group having a substituent. The alkyl group substituted with the silyl group may be a linear alkyl group, a branched alkyl group, or a cyclic alkyl group. The alkyl group is preferably a linear alkyl group having 1 to 8 carbon atoms, a branched alkyl group having 3 to 8 carbon atoms, or a cyclic alkyl group having 3 to 8 carbon atoms, and has 1 to 8 carbon atoms. The linear alkyl group is more preferable. Examples of the silyl group that serves as a substituent for the alkyl group include the same silyl groups having the above substituent. Among them, one hydrogen atom of a linear alkyl group having 1 to 8 carbon atoms is preferably a group substituted with a silyl group having a substituent, and one hydrogen atom of a linear alkyl group having 1 to 8 carbon atoms. More preferably, the atom is a group in which 1 to 3 hydrogen atoms are substituted with a silyl group substituted by the same or different alkyl groups, and 1 hydrogen atom of a linear alkyl group having 1 to 3 carbon atoms is , A trimethylsilyl group, a triethylsilyl group, an ethyldimethylsilyl group, or a group substituted with a t-butyldimethylsilyl group is more preferable, and a trimethylsilylmethyl group is still more preferable.

Examples of the azide compound represented by the formula (2) include linear alkyl azides having 1 to 8 carbon atoms, branched alkyl azides having 3 to 8 carbon atoms, cyclic alkyl azides having 3 to 8 carbon atoms, and unsubstituted alkyl azides. Or a phenyl azide having a substituent, or an unsubstituted or substituted benzyl azide, preferably a linear alkyl azide having 1 to 6 carbon atoms, a branched alkyl azide having 3 to 6 carbon atoms, More preferred are cyclic alkyl azides having 3 to 6 carbon atoms, more preferred are linear alkyl azides having 1 to 3 carbon atoms, and methyl azide is particularly preferred.

The azide compound represented by the formula (2) can be synthesized from a known compound using a known chemical reaction. For example, among the azide compounds represented by the formula (2), methyl azide can be synthesized by adding dimethyl sulfate dropwise to sodium azide in the presence of a base at 80 ° C. (for example, (See Journal of Organic Chemistry, 1990, vol. 55, pages 2304-2306.)

[Cyanide Compound Represented by Formula (3)]
In the formula (3), Z ¹ is —CO— (carbonyl group), —SO ₂ — (sulfonyl group), or —CR ^a1 R ^b1 — (in the left formula, R ^a1 and R ^b1 are each independently A hydrogen atom, an alkyl group, or an unsubstituted or substituted aryl group, which may be bonded to each other to form a ring, and r1 represents 0 or 1. However, when r1 is 0, q1 is always 1. In the case where R ^a1 or R ^{b1 in} Z ¹ is an alkyl group, specifically, the same alkyl groups as those exemplified for Y ¹ in the formula (2) can be exemplified as unsubstituted or In the case of an aryl group having a substituent, specific examples are the same as those of the unsubstituted or substituted aryl group exemplified for Y ¹ in the formula (2).

As —CR ^a1 R ^b1 —, specifically, either a methylene group (—CH ₂ —) in which R ^a1 and R ^b1 are both hydrogen atoms, one of R ^a1 and R ^b1 is a hydrogen atom, and the other is A group that is an alkyl group, a group in which any one of R ^a1 and R ^b1 is a hydrogen atom, and the other is an unsubstituted or substituted aryl group, R ^a1 and R ^b1 are each independently an alkyl group , A group that is an unsubstituted or substituted aryl group, or a group in which R ^a1 and R ^b1 are bonded to each other to form a cycloalkylene group, and more specifically, a divalent group shown below. Groups can be exemplified.

Z ¹ is preferably —CO— or —SO ₂ — rather than —CR ^a1 R ^b1 —. Compared to alkyl nitrile and benzyl cyanide derivatives in which a cyano group is directly bonded to an alkyl group or an alkyl aryl group, by using a cyanide derivative in which a cyano group and an alkyl group are bonded via a carbonyl group or a sulfonyl group as a raw material The reaction proceeds efficiently.

In general, cyanide derivatives in which the group adjacent to the cyano group is a carbonyl group tend to be less reactive than the cyanide derivatives in which the group adjacent to the cyano group is a sulfonyl group. In the production method of the present invention, since the reaction is carried out in a flow reactor, even when a cyanide derivative in which the group adjacent to the cyano group is a carbonyl group is used as a raw material, the reaction efficiency is sufficiently high and the time is shorter. The 1H-tetrazole derivative can be prepared with

In the formula (3), when q1 is 0, R ¹¹ is an alkyl group or a hydrogen atom. Specific examples of the alkyl group include the same groups as those described above for Y ¹ in the formula (2). A linear alkyl group having 1 to 8 carbon atoms, 3 to 3 carbon atoms, and the like. It is preferably a branched alkyl group having 8 or a cyclic alkyl group having 3 to 8 carbon atoms.

In the formula (3), when q1 is 1, R ¹¹ is an alkylene group. The alkylene group may be a linear alkylene group, a branched chain alkylene group, or a cyclic alkylene group. The alkylene group is preferably a linear alkylene group having 1 to 8 carbon atoms, a branched alkylene group having 3 to 8 carbon atoms, or a cyclic alkylene group having 3 to 8 carbon atoms, and 1 to 6 carbon atoms. And a straight chain alkylene group, a branched chain alkylene group having 3 to 6 carbon atoms, or a cyclic alkylene group having 3 to 6 carbon atoms. Specifically, methylene group, ethylene group, 1,3-propylene group, 1,2-propylene group, 1,1-propylene group, 2,2-propylene group, 1,5-pentylene group, 1,6- Hexylene, 1,2-cyclopropylene, 1,1-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclo Examples thereof include a pentylene group and a 1,4-cyclohexylene group. Among them, a linear alkylene group having 1 to 3 carbon atoms or a branched alkylene group having 3 carbon atoms is preferable. A straight chain alkylene group of 1 to 3 is more preferable, and a methylene group is more preferable.

As the cyanide compound represented by the formula (3), [— (R ¹¹ ) _p1 — (R ¹² ) _q1 ] is preferably a group having a strong electron-withdrawing property from the viewpoint of increasing the reaction yield. For this reason, among the compounds represented by the formula (3), p1 is 1 and q1 is 0 in both of the compound in which r1 is 0 and the compound in which r1 is 1. A compound having 0 or 1 and q1 being 1 is preferable, and a compound having p1 being 0 and q1 being 1 is more preferable.

In the formula (3), R ¹² represents an unsubstituted or substituted aryl group, and q 1 represents 0 or 1. However, when p1 is 0, q1 is 1. The aryl group may be monocyclic or polycyclic. In the polycyclic aryl group, as long as at least one ring is an aromatic ring, the remaining ring may be a saturated ring, an unsaturated ring, or an aromatic ring. In the case where R ¹² is an aryl group having a substituent, the substituent is not particularly limited as long as it is chemically acceptable, and is specifically exemplified in (1) to (85) below. A substituent can be mentioned.

R ¹² is preferably an aryl group having 6 to 10 carbon atoms, more preferably a phenyl group, and specifically, a group represented by the following general formula (s11) is particularly preferable.

In the formula (s11), n1 is an integer of 0 to 5, preferably an integer of 0 to 3, more preferably 0. Note that when n1 is 2 or more, A ¹ each other may be identical to each other, may be different from each other.

Specific examples of A ¹ include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group and i-butyl group. Alkyl groups such as s-butyl group, t-butyl group, n-pentyl group and n-hexyl group (the number of carbon atoms constituting the alkyl group is preferably 1 to 8), fluoromethyl group, chloromethyl group, Bromomethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, trifluoroethyl, pentafluoroethyl, 3,3,3,2,2-pentafluoropropyl, 2,2,2 A haloalkyl group such as trifluoro-1-trifluoromethylethyl group (the number of carbon atoms constituting the haloalkyl group is preferably 1 to 8), a methoxy group, an ethoxy group Alkoxy groups such as n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group, n-hexyloxy group (the number of carbons constituting the alkoxy group is Haloalkoxy groups such as 2-chloro-n-propoxy group, 2,3-dichlorobutoxy group and trifluoromethoxy group (the number of carbons constituting the haloalkoxy group is preferably 1 to 8). ), Alkylsulfonyl groups such as methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, t-butylsulfonyl group (the number of carbons constituting the alkylsulfonyl group is preferably 1-8. ), Unsubstituted or substituted, such as phenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, indanyl group, tetralinyl group An aryl group (an aryl group means a monocyclic or polycyclic aryl group. In addition, if at least one ring is an aromatic ring, the remaining ring is a saturated ring, an unsaturated ring, or Any of aromatic rings may be used, and among aryl groups, aryl groups having 6 to 10 carbon atoms are preferred), cyano groups, and nitro groups.

The “substituent” in the aryl group having a substituent is not particularly limited as long as it is chemically acceptable. Specific examples include the substituents exemplified below.
(1) Halogen atoms such as fluorine atom, chlorine atom, bromine atom, iodine atom; (2) methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i- Alkyl groups such as butyl, t-butyl, n-pentyl and n-hexyl; (3) cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; (4) Alkoxy groups such as methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t-butoxy group; (5) vinyl group, 1-propenyl group 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 2- Nthenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group , An alkenyl group such as a 5-hexenyl group;

(6) Cycloalkenyl groups such as 2-cyclopropenyl group, 2-cyclopentenyl group, 3-cyclohexenyl group, 4-cyclooctenyl group; (7) vinyloxy group, allyloxy group, 1-propenyloxy group, 2-butenyloxy group (8) ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-methyl-2-propynyl group, 2-methyl- 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 2-methyl-3-pentynyl group, 1-hexynyl group, 1, Alkynyl groups such as 1-dimethyl-2-butynyl group; (9) alkynyloxy groups such as ethynyloxy group and propargyloxy group; Group, 1-naphthyl group, aryl groups such as 2-naphthyl group;

(11) Aryloxy groups such as phenoxy group and 1-naphthoxy group; (12) Aralkyl groups such as benzyl group and phenethyl group; (13) Aralkyloxy groups such as benzyloxy group and phenethyloxy group; (14) Formyl group Acyl groups such as acetyl group, propionyl group, benzoyl group, cyclohexylcarbonyl group, phthaloyl group; (15) methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butoxycarbonyl group, alkoxycarbonyl group such as t-butoxycarbonyl group; (16) carboxyl group; (17) hydroxyl group; (18) chloromethyl group, chloroethyl group, 1,2-dichloro-n-propyl group, 1-fluoro-n-butyl Haloalkyl such as perfluoro-n-pentyl group (19) haloalkoxy groups such as 2-chloro-n-propoxy group, 2,3-dichlorobutoxy group, trifluoromethoxy group; (20) 2-chloro-1-propenyl group, 2-fluoro-1-butenyl (21) haloalkynyl groups such as 4,4-dichloro-1-butynyl group, 4-fluoro-1-pentynyl group, 5-bromo-2-pentynyl group;

(22) haloalkenyloxy groups such as 2-chloro-1-propenyloxy group and 3-bromo-2-butenyloxy group; (23) haloalkynyl groups such as 3-chloro-propargyl group and 3-iodo-propargyl group; (24) haloalkynyloxy groups such as 3-chloro-propargyloxy group and 3-iodo-propargyloxy group; (25) haloaryl groups such as 4-chlorophenyl group, 4-fluorophenyl group and 2,4-dichlorophenyl group; (26) Haloaryloxy groups such as 4-fluorophenoxy group and 4-chloro-1-naphthoxy group; (27) Halogen-substituted acyls such as chloroacetyl group, trifluoroacetyl group, trichloroacetyl group and 4-chlorobenzoyl group Group: (28) methoxymethyl group, ethoxymethyl group, 1-ethoxyethyl group, 2 Alkoxyalkyl groups such as ethoxyethyl group; (29) methoxymethoxy group, ethoxymethoxy group, 1-ethoxyethoxy group, 2-alkoxyalkoxy groups such as ethoxyethoxy group; (30) a cyano group;

(31) Isocyano group; (32) Nitro group; (33) Isocyanato group; (34) Cyanato group; (35) Amino group (NH ₂ group); (36) Methylamino group, dimethylamino group, diethylamino group, etc. (37) arylamino groups such as anilino group, naphthylamino group and anthranylamino group; (38) aralkylamino groups such as benzylamino group and phenethylamino group; (39) methylsulfonylamino group, ethylsulfonylamino An alkylsulfonylamino group such as a group, n-propylsulfonylamino group, i-propylsulfonylamino group, n-butylsulfonylamino group; (40) an arylsulfonylamino group such as a phenylsulfonylamino group;

(41) Heteroarylsulfonylamino groups such as pyrazinylsulfonylamino group; (42) Acylamino groups such as formylamino group, acetylamino group, propanoylamino group, butyrylamino group, i-propylcarbonylamino group, benzoylamino group, etc. (43) alkoxycarbonylamino groups such as methoxycarbonylamino group and ethoxycarbonylamino group; (44) fluoromethylsulfonylamino group, chloromethylsulfonylamino group, bromomethylsulfonylamino group, difluoromethylsulfonylamino group, dichloromethylsulfonyl; Amino group, 1,1-difluoroethylsulfonylamino group, trifluoromethylsulfonylamino group, 2,2,2-trifluoroethylsulfonylamino group, pentafluoroethylsulfonylamino group (45) bis (methylsulfonyl) amino group, bis (ethylsulfonyl) amino group, (ethylsulfonyl) (methylsulfonyl) amino group, bis (n-propylsulfonyl) amino group, bis ( bis (alkylsulfonyl) amino groups such as i-propylsulfonyl) amino group, bis (n-butylsulfonyl) amino group, bis (t-butylsulfonyl) amino group;

(46) Bis (fluoromethylsulfonyl) amino group, bis (chloromethylsulfonyl) amino group, bis (bromomethylsulfonyl) amino group, bis (dichloromethylsulfonyl) amino group, bis (1,1-difluoroethylsulfonyl) amino A bis (haloalkylsulfonyl) amino group such as a group, bis (trifluoromethylsulfonyl) amino group, bis (2,2,2-trifluoroethylsulfonyl) amino group, bis (pentafluoroethylsulfonyl) amino group; An unsubstituted or substituted hydrazino group such as a hydrazino group, an N′-phenylhydrazino group, an N′-methoxycarbonylhydrazino group, an N′-acetylhydrazino group, an N′-methylhydrazino group; ) Aminocarbonyl group, dimethylaminocarbonyl group, phen An unsubstituted or substituted aminocarbonyl group such as a ruaminocarbonyl group or N-phenyl-N-methylaminocarbonyl group; (49) hydrazinocarbonyl group, N′-methylhydrazinocarbonyl group, N′-phenyl An unsubstituted or substituted hydrazinocarbonyl group such as a hydrazinocarbonyl group; (50) N-methyliminomethyl group, 1-N-phenyliminoethyl group, N-hydroxyiminomethyl group, N-methoxyiminomethyl An unsubstituted or substituted iminoalkyl group such as a group;

(51) thiol group; (52) isothiocyanato group; (53) thiocyanato group; (54) methylthio group, ethylthio group, n-propylthio group, i-propylthio group, n-butylthio group, i-butylthio group, s-butylthio group Groups, alkylthio groups such as t-butylthio groups; (55) alkenylthio groups such as vinylthio groups and allylthio groups; (56) alkynylthio groups such as ethynylthio groups and propargylthio groups; (57) phenylthio groups and naphthylthio groups; (58) heteroarylthio groups such as 2-pyridylthio group and 3-pyridazylthio group; (59) aralkylthio groups such as benzylthio group and phenethylthio group; (60) 2-pyridylmethylthio group and 2-furylmethylthio; A heteroarylalkylthio group such as a group; (61) methylthiocarbo Group, ethylthiocarbonyl group, n-propylthiocarbonyl group, i-propylthiocarbonyl group, n-butylthiocarbonyl group, i-butylthiocarbonyl group, s-butylthiocarbonyl group, t-butylthiocarbonyl group, etc. An alkylthiocarbonyl group of

(62) alkylthioalkyl groups such as methylthiomethyl group and 1-methylthioethyl group; (63) arylthioalkyl groups such as phenylthiomethyl group and 1-phenylthioethyl group; (64) methylthiomethoxy group and 1-methylthioethoxy group. Alkylthioalkoxy groups such as groups; (65) arylthioalkoxy groups such as phenylthiomethoxy groups and 1-phenylthioethoxy groups; (66) alkylsulfinyl groups such as methylsulfinyl groups, ethylsulfinyl groups and t-butylsulfinyl groups; (67) alkenylsulfinyl group such as allylsulfinyl group; (68) alkynylsulfinyl group such as propargylsulfinyl group; (69) arylsulfinyl group such as phenylsulfinyl group; (70) 2-pyridylsulfinyl group, 3-pyridyls group Heteroaryl arylsulfinyl group such Finiru group; (71) benzyl-sulfinyl group, phenethyl Rusuru Fini aralkyl sulfinyl group such as Le group; (72) 2-pyridyl-methyl sulfinyl group, a heteroaryl alkylsulfinyl group such as 3-pyridyl methylsulfinyl group;

(73) alkylsulfonyl groups such as methylsulfonyl group, ethylsulfonyl group, t-butylsulfonyl group; (74) alkenylsulfonyl groups such as allylsulfonyl group; (75) alkynylsulfonyl groups such as propargylsulfonyl group; (76) phenyl Arylsulfonyl groups such as sulfonyl groups; (77) heteroarylsulfonyl groups such as 2-pyridylsulfonyl groups and 3-pyridylsulfonyl groups; (78) aralkylsulfonyl groups such as benzylsulfonyl groups and phenethylsulfonyl groups; Heteroarylalkylsulfonyl groups such as a pyridylmethylsulfonyl group and a 3-pyridylmethylsulfonyl group; (80) furan-2-yl group, furan-3-yl group, thiophen-2-yl group, thiophen-3-yl group, Pyrrol-2-yl group, pyro Ru-3-yl group, oxazol-2-yl group, oxazol-4-yl group, oxazol-5-yl group, thiazol-2-yl group, thiazol-4-yl group, thiazol-5-yl group, iso Oxazol-3-yl group, isoxazol-4-yl group, isoxazol-5-yl group, isothiazol-3-yl group, isothiazol-4-yl group, isothiazol-5-yl group, imidazole-2 -Yl group, imidazol-4-yl group, imidazol-5-yl group, pyrazol-3-yl group, pyrazol-4-yl group, pyrazol-5-yl group, 1,3,4-oxadiazole-2 -Yl group, 1,3,4-thiadiazol-2-yl group, 1,2,3-triazol-4-yl group, 1,2,4-triazol-3-yl group, 1,2,4-tri Unsaturated heterocyclic 5-membered ring groups such as a 5-yl group;

(81) Pyridin-2-yl group, pyridin-3-yl group, pyridin-4-yl group, 5-chloro-3-pyridyl group, 3-trifluoromethyl-2-pyridyl group, pyridazin-3-yl group Such as pyridazin-4-yl group, pyrazin-2-yl group, pyrimidin-5-yl group, 1,3,5-triazin-2-yl group, 1,2,4-triazin-3-yl group, etc. (82) tetrahydrofuran-2-yl group, tetrahydropyran-4-yl group, piperidin-3-yl group, pyrrolidin-2-yl group, morpholino group, piperidino group, N-methylpiperazino group, Saturated or partially unsaturated heterocyclic group such as oxazolin-2-yl group; (83) heterocyclic oxy group such as 2-pyridyloxy group and 3-isoxazolyloxy group; (84) 2-pyridylmethyl , 3-heteroarylalkyl group pyridylmethyl and the like; (85) 2-pyridylmethoxy group, 3-pyridyl heteroarylalkoxy group Jill methoxy like.
These substituents exemplified in (1) to (85) can further have substituents exemplified in (1) to (85) therein in a chemically acceptable range.

Specific examples of the aryl group having a substituent include 4-fluorophenyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, and 2,6-difluorophenyl. Group, 4-trifluoromethylphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4-methylenedioxyphenyl group, 4-trifluoromethoxyphenyl group, 4-methoxy-1-naphthyl group , 4-ethoxyphenyl group, 4-methylphenyl group and the like.

As the formula (s11), among them, n1 is any integer of 0 to 3, and A ¹ is preferably a halogen atom, an alkyl group, or an alkoxy group, and n is 0 to 3 is preferred. A compound in which any integer and A ¹ is a halogen atom is more preferable, and a compound in which n 1 is 0 is more preferable.

As the cyanide compound represented by the formula (3), r1 is 0 or 1, p1 is 0 or 1, and R ¹¹ is a linear alkylene group having 1 to 3 carbon atoms or a branched chain having 3 carbon atoms. Compounds having a chain alkylene group, q1 of 1 and R ¹² being a group represented by the general formula (s11) are preferred, and compounds represented by the following formulas (3-1) to (3-48) And more preferably compounds represented by the following general formulas (3-1) to (3-32), and the following formulas (3-1), (3-9), (3- 17) or (3-25) is more preferred, and compounds represented by the following general formula (3-1) or (3-9) are particularly preferred. In the general formulas (3-1) to (3-48), R ¹¹ ′ represents a linear alkylene group having 1 to 3 carbon atoms or a branched alkylene group having 3 carbon atoms, and X represents a halogen atom.

The cyanide compound represented by the formula (3) can be synthesized from a known compound using a known chemical reaction. For example, among the cyanide compounds represented by the formula (3), Z ¹ is a carbonyl group, p 1 is 0, q 1 is 1, r 1 is 1, and R ¹² is the general formula (s11 ) Can be produced by reacting a benzoyl halide derivative with a cyanide derivative.

[Flow reactor]
In the production method of the present invention, a cyanide compound represented by the above formula (3) (hereinafter sometimes simply referred to as “cyanide compound”) and an azide compound represented by the above formula (2) (hereinafter simply referred to as “cyanide compound”). A flow reactor is used as a reaction vessel with azide compound.

The flow reactor used in the production method of the present invention includes a raw material inlet, a product outlet, and a flow path that connects these. The raw material is supplied from the raw material introduction port, and the product obtained by the reaction in the flow path is taken out from the product discharge port. The flow path may include an introduction path, and at least one of a mixer section and a reactor section (retention section) as necessary. When the flow reactor has a mixer part, the part of the flow path that connects the raw material inlet and the mixer part is called the introduction path, and when there is no mixer part, the flow part that connects the raw material inlet and the reactor part is introduced. It is called a road. Moreover, the raw material inlet is usually connected to a container filled with the raw material. You may connect the container for storing a product to a product discharge port as needed.

The mixer part is a part having a function of mixing a plurality of liquids by diffusion, and the solutions supplied from the plurality of raw material inlets are joined at the mixer part. The reactor section is a site where a reaction for synthesizing a product from a plurality of raw material compounds (cyanide compound and azide compound in the production method of the present invention) is performed. When both the mixer section and the reactor section are provided, the mixer section is provided on the raw material inlet side. In the case where a reaction solution in which all the raw material compounds are mixed in advance is supplied from one raw material introduction port, the mixer section may not be provided. Further, when the time required for the reaction for synthesizing the product is short and the reaction can be completed only by passing through the mixer section, it is not necessary to provide a reactor section.

When the flow reactor includes a plurality of raw material introduction ports and introduction paths, the upstream side of the flow reactor has a structure branched according to the number of introduction paths, and further includes at least one mixer section. Prepare. There is no restriction | limiting in particular as the number of a raw material introduction port and introduction paths, According to the objective, it can select suitably. In the case of having three or more raw material introduction ports and introduction paths, the structure may be such that the liquids supplied from all the introduction paths are merged in one mixer section, and are merged in stages by two or more mixer sections. Also good. For example, after the liquid supplied from the two introduction paths is merged in the first mixer section, the mixed liquid discharged from the mixer section and the liquid introduced from the remaining introduction path are merged in the second mixer section. be able to.

In addition, a part of the raw material may be charged in advance in the flow reactor channel (for example, a mixer unit), and the remaining raw material may be supplied from one or a plurality of raw material introduction ports.

There is no restriction | limiting in particular as a material of the said flow reactor, According to requirements, such as heat resistance, pressure resistance, solvent resistance, and processability, it can select suitably. Examples of the material include stainless steel, titanium, copper, nickel, aluminum, silicon, fluororesin such as Teflon (registered trademark), PFA (perfluoroalkoxy resin), TFAA (trifluoroacetamide), PEEK (polyether). Ether ketone resin).
Moreover, the material may be substantially the same in all the flow paths, and may be different in each of the introduction path, the mixer section, and the reactor section.

The cross-sectional shape of the flow path is not particularly limited, and may be a square, a rectangle including a rectangle, a polygon including a triangle, a pentagon, etc., a star shape, a semicircle, or a circle including an ellipse. The cross-sectional shape of the channel need not be constant. The “cross section of the flow path” means a cross section perpendicular to the flow direction of the reaction solution or the like in the flow path, and the “cross sectional area” means the area of the cross section.

The cross-sectional area and the channel length of the channel are not particularly limited, and are appropriately adjusted in consideration of the viscosity and flow rate of the reaction solution, the reaction temperature, the reaction time, and the like. If the cross-sectional area of the flow path is too small, the pressure loss increases, and it becomes difficult to supply the raw material and flow the reaction solution. On the other hand, if it is too large, the heat exchange efficiency is lowered, temperature distribution and the like occur, and the features of the flow reactor are reduced. The cross-sectional areas of the flow paths may be substantially the same in all the flow paths, and the cross-sectional areas may be different in each of the introduction path, the mixer section, and the reactor section. When the flow reactor has a plurality of introduction paths, the cross-sectional areas of the introduction paths may be different from each other or the same.

The mixer section has a function of mixing a plurality of liquids by diffusion and a function of removing reaction heat.
There is no restriction | limiting in particular as a liquid mixing system in a mixer part, According to the objective, it can select suitably. For example, mixing by laminar flow and mixing by turbulent flow can be mentioned.

The mixer section is not particularly limited as long as it has a structure capable of mixing a plurality of liquids, and can be appropriately selected according to the purpose. For example, a cheese tube, a micro mixer, a branched tube, etc. are mentioned. As the shape of the mixer section, when the number of introduction paths is two, for example, a T-shape or a Y-shape can be used. When the number of introduction paths is three, for example, a cross shape is used. Can be used.

The cross-sectional area of the mixer section is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately adjusted in consideration of the mixing method and the like. Since both the function of mixing a plurality of liquids by diffusion and the function of removing heat of reaction can be satisfactorily performed, the mixer section has an inner diameter of about 10 μm to about 5 cm when the cross-sectional shape is circular. It is preferable that Moreover, although the cross-sectional area of a mixer part may be the same as other parts, such as an introduction path, the one larger than an introduction path is preferable from the point of mixing efficiency.

The flow path length of the mixer section is not particularly limited, and can be appropriately adjusted in consideration of the mixing method, the type and amount of liquid supplied from each introduction path, the presence or absence of a reactor section, and the like. For example, when the cross-sectional shape is circular, the inner diameter is about 10 μm to about 5 cm, and the flow path length can be 10 cm to 50 m.

The flow path length of the mixer section is preferably long enough for the liquids introduced from the plurality of introduction paths to be mixed by diffusion, but when a separate reactor section is provided, the flow path length is more It may be short. On the other hand, when the reaction is completed and the product is obtained when it passes through the mixer section without providing a separate reactor section, the flow path length of the mixer section is appropriately adjusted in consideration of the optimum reaction time. It is preferable to do.

The reactor part is a part for adjusting the length of the flow path and precisely controlling the time required for performing the reaction (residence time control). In the flow reactor, the reaction time corresponds to the residence time in the flow path of the reaction solution in which all raw materials are mixed. Since the residence time is proportional to the channel length, the reaction time is adjusted by adjusting the channel length.

The configuration of the cross-sectional area, inner diameter, outer diameter, flow path length, material, and the like of the flow path of the reactor section can be appropriately selected according to the desired reaction. For example, the material of the reactor part is not particularly limited, and those exemplified as the material of the flow reactor can be suitably used.

The mixer section, the introduction path, and the reactor section are each provided with connecting means for connecting to each other as necessary. The connection method in the connection means is not particularly limited, and can be appropriately selected from known tube connection methods according to the purpose. For example, a screw type, a union type, a butt welding type, a plug welding type, Examples include a socket welding type, a flange type, a biting type, a flare type, and a mechanical type.

The configuration other than the introduction path, the mixer unit, and the reactor unit is not particularly limited and can be appropriately selected depending on the purpose. Examples of the configuration include a pump used for liquid feeding, a temperature adjusting means, a reaction promoting means, a sensor, a pressure adjusting valve, and a tank for storing the produced compound.

The pump is not particularly limited and may be appropriately selected from those that can be used industrially. Especially, what does not produce a pulsation at the time of liquid feeding is preferable, for example, a plunger pump, a gear pump, a rotary pump, a diaphragm pump etc. are mentioned.

The temperature adjusting means is not particularly limited and can be appropriately selected depending on the reaction temperature. For example, a thermostatic bath, a circulation circulator, a heat exchanger, etc. are mentioned.

[Reaction conditions for azide compound and cyanide compound]
The solvent of the reaction solution in the flow reactor (the solution after all the raw materials have been mixed) dissolves both the cyanide compound and the azide compound, and inhibits the cycloaddition reaction of the azide compound to the cyanide group of the cyanide compound. If it does not, it will not specifically limit. Examples of the solvent include hydrocarbon solvents such as pentane, hexane, heptane, benzene, toluene and xylene; nitrile solvents such as acetonitrile and propiononitrile; ether solvents such as diethyl ether, dioxane and tetrahydrofuran; N, N Amide solvents such as dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone (NMP); sulfoxide solvents such as dimethyl sulfoxide; water; and mixed solvents thereof. Moreover, what added acids, such as an acetic acid, to these organic solvents may be used. In the production method of the present invention, a hydrocarbon solvent or an amide solvent is preferably used, and toluene or NMP is more preferably used.

The content ratio of the cyanide compound and the azide compound in the reaction solution in the flow reactor (the solution after all the raw materials are mixed) is not particularly limited as long as the target reaction can proceed. Specifically, the content of the cyanide compound with respect to the azide compound is preferably 0.5 to 2.0 times molar equivalent, more preferably 0.8 to 2.0 times molar equivalent, and 0.9 to 1. A 5-fold molar equivalent is more preferred, and a 1.1-1.3 molar equivalent is even more preferred.
The initial concentration of the azide compound in the reaction solution in the flow reactor is preferably a certain concentration or more, preferably 5% by mass or more, more preferably 10% by mass or more, and further preferably 20% by mass or more.

The reaction temperature of the reaction solution in the flow reactor (the solution after all the raw materials have been mixed) is not particularly limited as long as it can sufficiently suppress the risk of decomposition of the azide compound and the product. For example, it is preferably performed in the range of 150 to 250 ° C, more preferably in the range of 150 to 220 ° C.

Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

[Example 1]
65.01 g (1 mol) of sodium azide and 159.2 g of pure water were added to a 1 L four-necked flask to prepare a 29% by mass aqueous solution of sodium azide. To the four-necked flask, 71.4 g of 28 mass% sodium hydroxide aqueous solution (50 mol%) was further added and heated to 80 ° C.

While maintaining the liquid temperature at 80 ° C., 222.58 g of dimethyl sulfate (176 mol%) and 19.3 g of 28% by mass aqueous sodium hydroxide solution (8.4 mol%) were added dropwise, and further at 80 ° C. for 20 minutes. Reacted. Completion of the reaction was confirmed by HPLC. Toluene (56.03 g) was added to the produced methyl azide, and the organic layer was separated. This methyl azidotoluene solution was washed with a 4% by mass aqueous sodium hydroxide solution (10 ml) and cold water (10 ml) and separated. When the separated methyl azide toluene solution was analyzed, 56.24 g of methyl azide (yield: 98.5 mol%) toluene solution was obtained as a pure amount.

Among these, 25.52 g of toluene was added to 33.92 g of methyl azide toluene solution, and a 24 mass% methyl azide-containing toluene solution was obtained.
50 g (0.38 mol) of benzoyl cyanide was dissolved in 6.7 g of toluene to obtain a benzoyl cyanide toluene solution having a benzoyl cyanide concentration of 88.1% by mass.
55.6 g of the benzoyl cyanide toluene solution was mixed with 59.0 g of the methyl azide toluene solution, and toluene was further added so that the total volume became 140 ml. The total weight at that time was 128.4 g. The concentration of methyl azide in this reaction solution was 11% by mass.

As a reaction part to a high-performance liquid chromatography (HPLC) pump, a SUS304 1/8 tube (inner diameter: 1.775 mm), 12.8 m was connected, and the outlet part was connected to a back pressure valve. The Teflon tube connected to was impregnated in the toluene solution of methyl azide and benzoyl cyanide prepared above. A SUS304 1/16 tube (inner diameter: 1.0 mm), 2 m was connected to the outlet side of the back pressure valve, and an apparatus for separating the reaction solution while cooling the outflow part was set.

The toluene solution prepared above was immersed in the suction part of the HPLC pump, the flow rate of 0.8 ml / min, the temperature of the reaction part was set to 200 ° C., the pressure of the back pressure valve was set to about 50 kg / cm ² , and liquid feeding was started. . The set residence time of only the reaction part is 39 min, and after the start of liquid feeding, the fraction from 70 min to 80 min is divided into 2 fractions (fraction 1 and fraction 2) of 5 min each in a 30 ml sample bottle, and the reaction yield of that fraction The residual ratio of the raw material was determined by HPLC and gas chromatography (GC) analysis.
The yield analyzed by HPLC is shown in Table 1 below. MeN ₃ was quantified by GC analysis.

[Example 2] to [Example 6]
The concentration of methyl azide in the mixed solution of methyl azide toluene solution and benzoyl cyanide toluene solution prepared in Example 1 was adjusted to the value shown in Table 2, and the molar equivalent of benzoyl cyanide used was adjusted to the value shown in Table 2. The reaction was performed in the same manner as in Example 1 except that the reaction was performed at the temperature, flow rate, and residence time shown in Table 2. The results are shown in Table 2.

[Comparative Example 1]
The reaction was performed in the same manner as in Example 2 except that the concentration of methyl azide in the mixed solution was adjusted to the value shown in Table 2. The results are shown in Table 2.

[Example 7]
[Method of preparing methyl azide]
Sodium azide and dimethyl sulfate were reacted in the following flow reactor to synthesize methyl azide.
<Flow reactor>
A 1/16 tube of SUS316 (inner diameter: 1.00 mm) 1.0m is connected to 1/16 of cheese 1 (SUS material), and 1/8 tube of SUS316 ( Inner diameter: 2.18 mm) and 14.0 m are connected, and a back pressure valve is connected to the tip of the tube. Further, on the outlet side of the back pressure valve, a 1/8 tube of SUS304 (inner diameter: 2.18 mm), 2 0.0m was connected to form an outflow part, and a receiver was provided at the tip of the outflow part so that the effluent could be collected, and the receiver was ice-cooled to 0 ° C. Among the cheese 1, the remaining two openings not connected to the SUS pipe are connected to plunger pumps, and the Teflon tubes connected to the suction parts of the respective pumps are sulfuric acid in the following sodium azide aqueous solution. Impregnation in dimethyl solution. (Refer to FIG. 1) As shown in FIG. 1, the portion surrounded by a dotted line containing cheese 1 is immersed in a 120 ° C. oil bath and heated, and the portion before the back pressure valve (about 6 m) is 0 ° C. in an ice bath. Cooled down.

<Preparation of solution>
Sodium azide, 5% mol equivalent of 28% by weight sodium hydroxide aqueous solution with respect to sodium azide, and water were mixed to obtain an azide having a sodium azide concentration of 22.5% by mass (4.0 mol / L). A sodium chloride solution was prepared.
Further, dimethyl sulfate and toluene were mixed to prepare a dimethyl sulfate solution having a dimethyl sulfate concentration of 90.6% by mass (9.0 mol / L).

A Teflon tube connected to the suction part of the HPLC pump is immersed in each solution prepared above. The sodium azide solution is 15.3 ml / min, the dimethyl sulfate solution is 7.5 ml / min, and the pressure of the back pressure valve is 9 kg / min. It set to cm < ² > and liquid feeding was started. The set residence time of the heated part at 120 ° C. in the flow reactor was 1.3 minutes, and the solution was fed for 60 minutes, and the reaction solution was collected in a receiver. The receiver was charged with 40 ml of toluene to adjust the concentration of methyl azide obtained. The recovered reaction solution was separated into an aqueous layer and a toluene layer, and the amount of methyl azide contained in the toluene layer was quantified by high performance liquid chromatography (HPLC). As a result, methyl azide was obtained in a yield of 78%. As a result of the concentration analysis by HPLC described above, it was found that 65.8% by mass of methyl azide (170.2 g, 2.98 mol as a pure component) was contained in the obtained 259 g of methyl azide toluene solution.
416.9 g (3.13 mol) of benzoylcyanide was dissolved in 181.4 g of toluene. A benzoyl cyanide toluene solution having a benzoyl cyanide concentration of 69.7% by mass was obtained.
The whole amount of the benzoyl cyanide toluene solution was mixed with the methyl azide toluene solution. The concentration of methyl azide in this mixed solution was 20% by mass.

A SUS304 3/16 tube (inner diameter: 3.36 mm), 12 m was connected as a reaction part to a high performance liquid chromatography (HPLC) pump, and used as a flow reactor apparatus. 1/4 Tese (SUS material) is connected to this device, and the Teflon tube connected to the plunger pump is connected to the plunger pump in one opening not connected to the SUS pipe. Impregnation in toluene for dilution. The other opening was connected to a SUS304 1/4 tube (inner diameter: 4.35 mm), 0.3 m, to which a back pressure valve was attached. Furthermore, the outlet side of the back pressure valve was connected with a SUS304 1/8 tube (inner diameter: 2.18 mm), 2 m, and an apparatus for separating the reaction solution while allowing the outflow portion to cool was set.

The toluene solution prepared above is immersed in the suction part of the HPLC pump, the raw material mixture liquid flow rate is 1.77 ml / min, the diluted toluene flow rate is 7.17 ml / min, the reaction part temperature is 200 ° C., and the back pressure valve pressure is 80 kg. / Cm ² was set, and liquid feeding was started. The set residence time of only the reaction part is set to 60 minutes, and after the start of liquid feeding, the fraction from 90 to 110 minutes is divided into 2 fractions (fraction 1 and fraction 2) of 10 minutes each in a 110 ml sample bottle, and the reaction yield of the fractions The residual ratio of the raw material was determined by HPLC and gas chromatography (GC) analysis.
The average yield of the two fractions analyzed by HPLC is shown in Table 3 below.

[Example 8]
[Method of preparing methyl azide]
Sodium azide and dimethyl sulfate were reacted in the following flow reactor to synthesize methyl azide.
<Flow reactor>
A 1/16 tube of SUS304 (inner diameter: 1.00 mm) 1.0 m is connected to 1/16 cheese 1 (SUS material), and further, a 3/16 tube of SUS304 material (with a pipe joint ( 1/8 tube of SUS304 (inner diameter: 2.18 mm), 4.0 m connected to the back pressure valve via the pipe joint. It was connected and this part was immersed in a 0 ° C. ice water bath. Furthermore, on the outlet side of the back pressure valve, a SUS304 material 1/8 tube (inner diameter: 2.18 mm), 2.0 m is connected as an outflow part, a receiver is provided at the end of the outflow part, In addition to allowing separation, the outflow part and the receiver were ice-cooled to 0 ° C.

<Preparation of solution>
Sodium azide, 15% mol equivalent of 28% by weight sodium hydroxide aqueous solution with respect to sodium azide, and water were mixed to obtain an azide having a sodium azide concentration of 22.5% by mass (4.0 mol / L). A sodium chloride solution was prepared.
In addition, dimethyl sulfate and toluene were mixed to prepare a dimethyl sulfate solution having a dimethyl sulfate concentration of 48.3 mass% (4.0 mol / L).

A Teflon tube connected to the suction part of the plunger pump is immersed in each solution prepared above, the flow rate of the back pressure valve is 33.6 ml / min for the sodium azide solution and 35.2 ml / min for the dimethyl sulfate solution. Was set to 9 kg / cm ² and liquid feeding was started. The time until the effluent in the flow reactor passed through the pipe cooled to 0 ° C. (set residence time) was 1.3 minutes, and the liquid was fed for 65 minutes, and the reaction liquid was collected in a receiver. The recovered reaction solution was separated into an aqueous layer and a toluene layer, and the amount of methyl azide contained in the toluene layer was analyzed by HPLC. As a result, a toluene solution of methyl azide having a yield of 82% and a concentration of 24% by mass could be obtained.
The reaction was conducted in the same manner as in Example 7 except that the concentration of methyl azide in the mixed solution and the length of the tube in the reaction part were adjusted to the values shown in Table 3. The results are shown in Table 3.

[Example 9]
This was carried out in the same manner as the method for preparing methyl azide in Example 1, and 156.8 g of methyl azide (yield: 91.6 mol%) in toluene (59.6% by mass) was obtained with methyl azide as a pure amount.
The reaction was conducted in the same manner as in Example 7 except that the concentration of methyl azide in the mixed solution and the length of the tube in the reaction part were adjusted to the values shown in Table 3. The results are shown in Table 3.

[Example 10]
A SUS304 3/16 tube (inner diameter: 3.36 mm), 12 m was connected as a reaction unit to a high performance liquid chromatography (HPLC) pump, and used as a flow reactor apparatus. 1/4 Tese (SUS material) is connected to this device, and the Teflon tube connected to the plunger pump is connected to the plunger pump in one opening not connected to the SUS pipe. Impregnation in toluene for dilution. The other opening is connected to a SUS304 1/4 tube (inner diameter: 4.35 mm), 0.3 m, to which a back pressure valve is attached. Further, an SUS304 1/8 tube (inner diameter: 2.18 mm), 2 m was connected to the outlet side of the back pressure valve, and an apparatus for separating the reaction solution while cooling the outflow part was set.

The toluene solution prepared in the same manner as in Example 7 was immersed in the suction part of the HPLC pump, the raw material mixture liquid flow rate 1.77 ml / min, diluted toluene 6.22 ml / min flow rate, the reaction part temperature 200 ° C. The pressure of the pressure valve was set to about 30 kg / cm ² and liquid feeding was started. The set residence time of only the reaction part was set to 60 minutes, and the part from 50 minutes to 110 minutes after the start of liquid feeding was continuously collected. The pump of the raw material mixture is temporarily stopped, this mixed solution is switched to toluene, the raw material solution remaining in the pipe is washed out at a flow rate of 1.77 ml / min, and sent to 190 min (washing for 80 min). did. The effluent from 50 min to 110 min and the washing effluent from 110 min to 190 min were collected, and the reaction yield and the residual ratio of raw materials were determined by HPLC and gas chromatography (GC) analysis. The results are shown in Table 4.

[Example 11]
Concentration analysis by HPLC of 151.53 g of methyl azide toluene solution prepared in the same manner as in Example 7 confirmed that the methyl azide concentration was 63.2% by mass (95.8 g, 1.68 mol as a pure amount).
231.0 g (1.76 mol) of benzoylcyanide was dissolved in 96.2 g of N-methylpiperidone (NMP). A benzoyl cyanide NMP solution having a benzoyl cyanide concentration of 70.6% by mass was obtained.
The benzoyl cyanide NMP solution was mixed with the methyl azide toluene solution. The concentration of methyl azide in this mixed solution was 20% by mass.
The reaction was performed in the same manner as in Example 10 except that the concentration of methyl azide in the mixed solution was adjusted to the value shown in Table 4. The results are shown in Table 4.

[Examples 12 and 13]
Except that the molar ratio of MeN ₃ and PhCOCN and the concentration of methyl azide in the mixed solution were adjusted to the values shown in Table 5, and the reactor piping used was changed to 3/8 inch (inner diameter: 7.53 mm). The reaction was conducted in the same manner as in Example 7. The results are shown in Table 5.

Claims

Following formula (2)

(In Formula (2), Y 1 represents an alkyl group, an unsubstituted or substituted aryl group, an unsubstituted or substituted arylalkyl group, a substituted silyl group, or a substituted silylalkyl. An azide compound represented by the following formula (3):

(In the formula (3), Z 1 represents —CO—, —SO 2 —, or —CR a1 R b1 — (wherein R a1 and R b1 each independently represents a hydrogen atom or an alkyl group) Or an unsubstituted or substituted aryl group, which may be bonded to each other to form a ring.], P1 represents 0 or 1, q1 represents 0 or 1, and r1 represents Represents 0 or 1, R 11 represents an alkyl group or a hydrogen atom when q1 is 0, represents an alkylene group when q1 is 1, and R 12 represents an unsubstituted or substituted aryl group. However, when p1 is 0, q1 is 1, and when r1 is 0, q1 is 1.) The following formula obtained by reacting with a cyanide compound represented by a flow reactor: (1)

(Wherein Y 1 is the same as in formula (2), and Z 1 , R 11 , R 12 , p1, q1, and r1 are the same as in formula (3)). A method for producing a tetrazole derivative, wherein the cyanide compound represented by the formula (3) is added in a range of 0.8 to 1.2 molar equivalents relative to the azide compound represented by the formula (2). A method for producing a 1H-tetrazole derivative represented by the formula (1), wherein the initial concentration of the azide compound represented by the formula (2) in the reaction solution is 5% by mass or more.
The method for producing a 1H-tetrazole derivative represented by the formula (1) according to claim 1, wherein the initial concentration of the azide compound represented by the formula (2) in the reaction solution is 10% by mass or more.
The method for producing a 1H-tetrazole derivative represented by the formula (1) according to claim 1 or 2, wherein Y 1 represents an alkyl group.
R 12 represents the following formula (s11)

(In the formula (s11), A 1 represents a halogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a haloalkoxy group, an alkylsulfonyl group, an unsubstituted or substituted aryl group, a cyano group, or a nitro group. N1 represents an integer of 0 to 5. When n1 is 2 or more, A 1 may be the same as or different from each other. , When p1 is 1, it binds to R 11 , when p1 is 0 and r1 is 1, it binds to Z 1 , and when p1 and r1 are 0, it binds to the carbon atom of the cyanide group A method for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of claims 1 to 3, which is a group represented by the formula:
The method for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of claims 1 to 4, wherein the reaction temperature of the reaction is 150 to 250 ° C.
The process for producing a 1H-tetrazole derivative represented by the formula (1) according to any one of claims 1 to 5, wherein the solvent of the reaction solution is toluene or N-methylpyrrolidone.