JP6540993B2 - Process for producing stereoselective alkenes - Google Patents
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本発明は立体選択的なアルケンの製造方法に関する。 The present invention relates to a process for the preparation of stereoselective alkenes.
1,2−2置換エチレンには2種類の異性体が存在するが、1,2−2置換エチレンを製造すると2種の異性体の混合物として得られる。1,2−2置換エチレンの2種の異性体(E体、Z体)はその構造の差異により、物性値が異なる。特に液晶組成物の成分として1,2−2置換エチレンを使用する場合には、Z体は添加した液晶組成物の液晶性を大きく低下させるため、Z体を除去し使用する必要がある。 Although there are two isomers in 1,2-disubstituted ethylene, the production of 1,2-disubstituted ethylene is obtained as a mixture of two isomers. The physical properties of the two isomers (E form, Z form) of 1,2-disubstituted ethylene are different due to the difference in their structures. In particular, when 1,2-disubstituted ethylene is used as a component of the liquid crystal composition, it is necessary to remove and use the Z form in order to greatly reduce the liquid crystallinity of the added liquid crystal composition.
このため、Z体を多く含むような製造工程を採用した場合、その後の精製工程で、多くのZ体を破棄することとなり効率的ではない。 For this reason, when a manufacturing process that contains many Z-forms is adopted, many Z-forms are discarded in the subsequent purification step, which is not efficient.
例えば、(E)−1,2−ビス(シクロヘキシル)エチレン誘導体は液晶組成物の粘度を低減させるために有用である(非特許文献1、特許文献1)。その製造法については、幾つかが知られている(特許文献1、特許文献2及び非特許文献2参照)。しかしながら、これらの製造方法は必ずしも実用的なものではない。例えば特許文献1及び特文献2では、Z体を過酸化物で酸化し、次いでジブロモトリフェニルホスホランで臭素化した後、亜鉛で還元することによってE体を得ているが、その収率は低い。また、非特許文献2では、1,2−ビス(トランス−4−アルキルシクロヘキシル)エタン−1,2−ジケトンをジヒドラゾンとし、これを1,2−ビス(トランス−4−アルキルシクロヘキシル)アセチレンに変換した後、これを還元することによってE−1,2−ビス(シクロヘキシル)エチレン誘導体を得ているが、毒性の高いヒドラジン及びヘキサメチルりん酸トリアミド(HMPT)を用いている他、発火性の金属リチウムを用いており、実用的なものではない。また、それら製造法のE体の選択率は十分であるとはいえず、更なる改良が求められていた。 For example, (E) -1,2-bis (cyclohexyl) ethylene derivative is useful for reducing the viscosity of a liquid crystal composition (Non-Patent Document 1, Patent Document 1). Several methods are known for their production (see Patent Document 1, Patent Document 2 and Non-patent Document 2). However, these manufacturing methods are not always practical. For example, in Patent Document 1 and Patent Document 2, the Z form is oxidized with peroxide, then brominated with dibromotriphenylphosphorane, and then reduced with zinc to obtain the E form, but the yield is Low. In Non-Patent Document 2, 1,2-bis (trans-4-alkylcyclohexyl) ethane-1,2-diketone is used as dihydrazone, which is converted to 1,2-bis (trans-4-alkylcyclohexyl) acetylene The product is then reduced to give an E-1,2-bis (cyclohexyl) ethylene derivative, but highly toxic hydrazine and hexamethylphosphoric acid triamide (HMPT) are used, as well as pyrophoric metal lithium. Is not practical. Moreover, the selectivity of E form of these production methods is not sufficient, and further improvement has been required.
また、E体及びZ体の混合物を得た後に、ベンゼンスルフィン酸等により異性化し、精製することによりE体を得る方法も知られている(特許文献3)が、この方法では、異性化の工程が必要となる。 In addition, there is also known a method of obtaining E form by isomerizing with a mixture of E form and Z form, then performing isomerization with benzenesulfinic acid or the like and purifying it (Patent Document 3). A process is required.
本願発明が解決しようとする課題は、効率的で立体選択的なアルケンの製造方法を提供するとともに有用な反応中間体を提供することである。 The problem to be solved by the present invention is to provide an efficient and stereoselective process for producing alkenes and to provide useful reaction intermediates.
本願発明者は上記課題を解決するために鋭意検討した結果本願発明の完成に至った。 The inventors of the present invention made earnest studies to solve the above problems, and as a result, achieved the present invention.
1種又は2種以上の一般式(1)で表される化合物と1種又は2種以上の一般式(2)で表される化合物と塩基を用いることにより、一般式(3)で表される化合物を高効率で立体選択的に製造することができる。併せて、該製造方法における重要中間体である一般式(2)で表される化合物を得た。 By using one or more compounds represented by formula (1) and one or more compounds represented by formula (2) and a base, it is represented by formula (3) Can be produced stereoselectively with high efficiency. In addition, a compound represented by the general formula (2), which is an important intermediate in the production method, was obtained.
(一般式(1)における、R11は、水素原子、炭素原子数炭素原子数1から8のアルキル基、炭素原子数炭素原子数1から8のアルコキシル基、炭素原子数炭素原子数2から8のアルケニル基又は炭素原子数炭素原子数2から8のアルケニルオキシル基を表し、基中の−CH2−又は隣接していない2個以上の−CH2−はそれぞれ独立的に−O−に置換されても良く、また、基中に存在する1個又は2個以上の水素原子はそれぞれ独立的にハロゲンに置換されても良く、
A11は、(a) シクロヘキサン−1,4−ジイル基(この基中に存在する1個の−CH2−又は隣接していない2個以上の−CH2−は−O−に置き換えられてもよい。)
(b) 1,4−フェニレン基(この基中に存在する1個の−CH=又は隣接していない2個以上の−CH=は−N=に置き換えられてもよい。)
(c) 1,4−シクロヘキセニレン基、1,4−ビシクロ(2.2.2)オクチレン基、ピペリジン−1,4−ジイル基、ナフタレン−2,6−ジイル基、デカヒドロナフタレン−2,6−ジイル基及び1,2,3,4−テトラヒドロナフタレン−2,6−ジイル基からなる群より選ばれる基を表し、上記の基(a)、基(b)又は基(c)中の水素原子はそれぞれ独立してハロゲンで置換されていても良く、
Z11は単結合、−CH2CH2−、−(CH2)4−、−OCH2−、−CH2O−、−COO−、−OCO−、−OCF2−、−CF2O−、−CH=CH−、−CF=CF−又は−C≡C−を表し、
n11は0〜10の自然数を表すが、n11が2〜10を表す場合に複数存在するA11は同一であっても異なっていてもよく、n11が2〜10を表す場合に複数存在するZ11は同一であっても異なっていてもよく、n11が0を表す場合にR11は水素原子を表すことはなく、
Sp11は単結合又は炭素原子数1〜20のアルキレン基を表し、基中の−CH2−又は隣接していない2個以上の−CH2−はそれぞれ独立的に−O−に置換されても良く、また、基中に存在する1個又は2個以上の水素原子はそれぞれ独立的にハロゲンに置換されても良く、
一般式(2)における、R21は水素原子又は一般式(4)で表される置換基を表し、R22は一般式(5)で表される置換基を表し、
(In General Formula (1), R 11 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, 2 to 8 carbon atoms) of an alkenyl group or an alkenyloxy Le group having a carbon number of carbon atoms from 2 to 8, -CH 2 in the radical - or nonadjacent two or more -CH 2 - are each independently substituted by -O- And one or more hydrogen atoms present in the group may be independently substituted with halogen, respectively.
A 11 is (a) a cyclohexane-1,4-diyl group (one —CH 2 — present in this group or two or more non-adjacent —CH 2 — is replaced by —O— Also good.)
(B) 1,4-phenylene group (one -CH = present in this group or two or more non-adjacent -CH = may be replaced by -N =)
(C) 1,4-cyclohexenylene group, 1,4-bicyclo (2.2.2) octyrene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 And a group selected from the group consisting of 6, 6-diyl group and 1, 2, 3, 4-tetrahydronaphthalene-2, 6-diyl group, and in the above group (a), group (b) or group (c) Each hydrogen atom may be independently substituted with halogen,
Z 11 is a single bond, -CH 2 CH 2 -, - (CH 2) 4 -, - OCH 2 -, - CH 2 O -, - COO -, - OCO -, - OCF 2 -, - CF 2 O- , -CH = CH-, -CF = CF- or -C≡C-,
n 11 represents a natural number of 0 to 10. However, when n 11 represents 2 to 10, a plurality of A 11 may be the same or different, and a plurality of n 11 represents 2 to 10 Z 11 present may be the same or different, and when n 11 represents 0, R 11 does not represent a hydrogen atom,
Sp 11 represents a single bond or an alkylene group of carbon atoms 1 to 20, -CH in group 2 - or nonadjacent two or more -CH 2 - may be replaced each independently -O- Also, one or more hydrogen atoms present in the group may be independently substituted with halogen, respectively.
In the general formula (2), R 21 represents a hydrogen atom or a substituent represented by the general formula (4), and R 22 represents a substituent represented by the general formula (5),
(一般式(4)及び(5)における、R41及びR51はそれぞれ独立して、一般式(1)におけるR11と同じ意味を表し、A41及びA51はそれぞれ独立して、一般式(1)におけるA11と同じ意味を表し、Z41及びZ51はそれぞれ独立して、一般式(1)におけるZ11と同じ意味を表し、n41及びn51はそれぞれ独立して、一般式(1)におけるn11と同じ意味を表し、Sp41及びSp51はそれぞれ独立して、一般式(1)におけるSp11と同じ意味を表す。)
R23は芳香環を表し、
一般式(3)における、R11は、一般式(1)におけるR11と同一の置換基を表し、A11は、一般式(1)におけるA11と同一の置換基を表し、Z11は、一般式(1)におけるZ11と同一の置換基を表し、n11は、一般式(1)におけるn11と同一の自然数を表し、Sp11は、一般式(1)におけるSp11と同一の自然数を表し、R21は、一般式(2)におけるR21と同一の置換基を表し、R22は、一般式(2)におけるR22と同一の置換基を表す。)
(In the general formulas (4) and (5), R 41 and R 51 each independently represent the same as R 11 in the general formula (1), and A 41 and A 51 each independently represent the general formula represents the same meaning as a 11 in (1), and each of Z 41 and Z 51 independently represent the same meaning as Z 11 in the general formula (1), n 41 and n 51 are each independently the general formula This represents the same meaning as n 11 in (1), and Sp 41 and Sp 51 each independently represent the same meaning as Sp 11 in General Formula (1).)
R 23 represents an aromatic ring,
In the general formula (3), R 11 has the general formula (1) represent the same substituent as R 11 in, A 11 represents the same substituent as A 11 in the general formula (1), Z 11 is represents a Z 11 and identical substituents in the general formula (1), n 11 represents an integer of same n 11 in the general formula (1), Sp 11 is identical to the Sp 11 in the general formula (1) It represents a natural number, R 21 represents the same substituent as R 21 in the general formula (2), R 22 represents the same substituent as R 22 in the general formula (2). )
本発明の製造方法により、効率的な製造が困難であったE−1,2−2置換エチレンの実用的な製造が可能となった。また、本願発明の製造方法により製造される化合物を含有する組成物は樹脂、オイル、オイルフィルター、油脂、インキ、医薬品、化粧品、洗剤、液晶材料、農薬、ポリマー、樹脂、顔料、染料、粘着剤接着剤、印刷物、食品、光学異方体、表示素子又は電子デバイスの用途に有用である。 According to the production method of the present invention, practical production of E-1,2-disubstituted ethylene which has been difficult for efficient production has become possible. Moreover, the composition containing the compound manufactured by the manufacturing method of this invention is resin, oil, oil filter, fats and oils, ink, pharmaceuticals, cosmetics, detergent, liquid crystal material, agrochemical, polymer, resin, pigment, dye, adhesive It is useful for adhesive, printed matter, food, optically anisotropic, display element or electronic device applications.
一般式(1)における、R11は、反応過程において目的の化合物を与えるものであれば特に制限は無いが、合成の容易さの観点及び液晶材料に使用する場合には液晶性の観点から、炭素原子数1から8のアルキル基、炭素原子数1から8のアルコキシル基、炭素原子数2から8のアルケニル基又は炭素原子数2から8のアルケニルオキシル基が好ましく、本発明の製造物である一般式(3)で表される化合物のネマチック相の安定性の観点からは、炭素原子数は5以下であることが好ましく、スメクチック相の安定性の観点からは炭素原子数6以上であることが好ましく、直鎖状であることが好ましい。 R 11 in the general formula (1) is not particularly limited as long as it gives a target compound in the reaction process, but from the viewpoint of easiness of synthesis and in the case of liquid crystal material, The alkyl group having 1 to 8 carbon atoms, the alkoxyl group having 1 to 8 carbon atoms, the alkenyl group having 2 to 8 carbon atoms or the alkenyloxyl group having 2 to 8 carbon atoms is preferable, which is a product of the present invention From the viewpoint of the stability of the nematic phase of the compound represented by the general formula (3), the number of carbon atoms is preferably 5 or less, and from the viewpoint of the stability of the smectic phase, it is 6 or more carbon atoms Is preferred and linear is preferred.
A11は、反応過程において目的の化合物を与えるものであれば特に制限は無いが、下記の構造であることがより好ましく、 A 11 is not particularly limited as long as it gives a target compound in the reaction process, but the following structure is more preferable,
下記の構造であることが更に好ましい。 The following structure is more preferable.
Z11は反応過程において目的の化合物を与えるものであれば特に制限は無いが、単結合、−CH2CH2−、−(CH2)4−、−OCH2−、−CH2O−、−OCF2−又は−CF2O−が好ましく、本発明の製造方法の収率に重点を置く場合には、単結合、−CH2CH2−、−OCH2−、−CH2O−、−OCF2−又は−CF2O−が好ましい。 Although Z 11 is not particularly limited as long as it gives the desired compounds in the reaction process, a single bond, -CH 2 CH 2 -, - (CH 2) 4 -, - OCH 2 -, - CH 2 O-, -OCF 2 - or -CF 2 O-are preferred, if the focus on the yield of the manufacturing method of the present invention is a single bond, -CH 2 CH 2 -, - OCH 2 -, - CH 2 O-, -OCF 2 - or -CF 2 O-it is preferred.
n11は反応過程において目的の化合物を与えるものであれば特に制限は無いが、本発明の製造方法を溶媒を用いた均一系で行う場合には、一般式(1)で表される化合物の溶媒に対する溶解度の関係から、4以下が好ましく、3以下が好ましい。一般式(3)の立体選択性を向上させるには1以上であることが好ましい。n11が2〜10を表す場合にはZ11は少なくとも1つ以上が単結合であることが好ましく、存在するZ11のうち1つを除きすべてが単結合であることが好ましく、すべてが単結合であることが好ましい。 n 11 is not particularly limited as long as it gives a target compound in the reaction process, but when the production method of the present invention is carried out in a homogeneous system using a solvent, the compound represented by the general formula (1) In view of solubility in a solvent, 4 or less is preferable, and 3 or less is preferable. In order to improve the stereoselectivity of the general formula (3), it is preferably at least 1. When n 11 represents 2 to 10, at least one or more of Z 11 is preferably a single bond, and it is preferable that all except one of Z 11 present be a single bond, all Preferably it is a bond.
Sp11は反応過程において目的の化合物を与えるものであれば特に制限は無く、単結合及び炭素原子数1〜20のアルキレン基が好ましく、単結合及び炭素原子数1〜8のアルキレン基が好ましく、単結合及び炭素原子数1〜4のアルキレン基が好ましく、単結合及び炭素原子数1〜2のアルキレン基が好ましい。 Sp 11 is not particularly limited as long as it gives a target compound in the reaction process, and a single bond and an alkylene group having 1 to 20 carbon atoms are preferable, and a single bond and an alkylene group having 1 to 8 carbon atoms are preferable. A single bond and an alkylene group having 1 to 4 carbon atoms are preferable, and a single bond and an alkylene group having 1 to 2 carbon atoms are preferable.
一般式(2)で表される化合物中、R22はR21と比較して嵩高い置換基である。このR21とR22の嵩高さの相違により、特定の立体構造を有する一般式(3)で表される化合物を製造することができる。 In the compound represented by the general formula (2), R 22 is a bulky substituent compared to R 21 . By the difference in bulkiness of R 21 and R 22 , a compound represented by General Formula (3) having a specific steric structure can be produced.
一般式(2)における、R21は、反応過程において目的の化合物を与えるものであれば特に制限は無く、水素原子又は一般式(4)で表される置換基であることが好ましい。しかし、一般式(2)で表される当該化合物の合成の容易さの観点、一般式(3)で表される化合物の立体選択性及び液晶材料に使用する場合には液晶性の観点から、水素原子であることがより好ましい。 R 21 in the general formula (2) is not particularly limited as long as it gives the target compound in the reaction process, and is preferably a hydrogen atom or a substituent represented by the general formula (4). However, from the viewpoint of the easiness of synthesis of the compound represented by the general formula (2), the stereoselectivity of the compound represented by the general formula (3), and the liquid crystallinity in the case of use for a liquid crystal material, More preferably, it is a hydrogen atom.
R21が一般式(4)で表される置換基である場合には、n41は0から2であることが好ましく、0又は1であることが好ましく、0であることが好ましい。Sp41、A41、Z41及びR41は一般式(1)におけるA11、Z11及びR11と同様な置換基が好ましいが、R41は特に炭素原子数1から8のアルキル基がより好ましい。 When R 21 is a substituent represented by General Formula (4), n 41 is preferably 0 to 2, preferably 0 or 1, and preferably 0. Sp 41 , A 41 , Z 41 and R 41 are preferably the same as A 11 , Z 11 and R 11 in the general formula (1), but R 41 is more preferably an alkyl group having 1 to 8 carbon atoms preferable.
一般式(2)における、R22は、一般式(5)で表される置換基であることが好ましい。しかし、一般式(2)で表される当該化合物の合成の容易さの観点から、一般式(5)で表される置換基におけるn51は0から2であることが好ましく、0又は1であることが好ましく、0であることが好ましい。Sp51、A51、Z51及びR51は一般式(1)におけるA11、Z11及びR11と同様な置換基が好ましいが、R51は特に炭素原子数1から8のアルキル基がより好ましい。 In General Formula (2), R 22 is preferably a substituent represented by General Formula (5). However, n 51 in the substituent represented by the general formula (5) is preferably 0 to 2, and preferably 0 or 1, from the viewpoint of the easiness of synthesis of the compound represented by the general formula (2). It is preferable that there be, and it is preferable that it is 0. Sp 51 , A 51 , Z 51 and R 51 are preferably the same as A 11 , Z 11 and R 11 in the general formula (1), but R 51 is more preferably an alkyl group having 1 to 8 carbon atoms preferable.
一般式(2)における、R23は芳香環であることが好ましいが、収率の観点から、ベンゼン環、アルキルベンゼン環、ナフタレン環、アントラセン環がより好ましい。さらに一般式(2)で表される当該化合物の合成の容易さ及び経済性の観点から、R23はフェニル基、1,4−フェニレン基であることがより好ましい。また、R23は置換基上の水素原子がハロゲン等に置換していてもよいが、反応性の観点から無置換であることが好ましい。 R 23 in the general formula (2) is preferably an aromatic ring, but from the viewpoint of yield, a benzene ring, an alkyl benzene ring, a naphthalene ring and an anthracene ring are more preferable. Furthermore, in view of the easiness of synthesis of the compound represented by the general formula (2) and the economy, it is more preferable that R 23 be a phenyl group or a 1,4-phenylene group. Further, R 23 is a hydrogen atom on a substituent may be substituted with a halogen or the like, it is preferable from the viewpoint of reactivity unsubstituted.
本明細書において、同じ意味を表しとは、両置換基が同一の化学構造を有していても有していなくてもよいが、同一の選択肢から選ばれる置換基であることを意味しており、同一の置換基を表しとは同一の化学構造を有する置換基であることを意味する。 In the present specification, “representing the same meaning” means that both substituents may or may not have the same chemical structure, but are substituents selected from the same option. The term “same substituent” means that the substituent has the same chemical structure.
塩基としては、アミン、アミド、カルバメート、イミド、スルホンアミド、グアニジン、ヒドラゾン、ヒドラジド、ヒドラジン、複素環アミン、それらの塩、炭酸塩、金属ヒドリド、金属アルコキシド又はアルキル金属類が好ましい。特に収率の観点から、金属ヒドリド、金属アルコキシド、ヒドラジド塩で、pKa15.0以上の塩基性を有し、かつ求核性の少ない塩基がより好ましい。例えば、リチウムジイソプロピルアミド、水素化ナトリウム、tert−ブトキシカリウム、カリウムヘキサメチルジシラジド、リチウムヘキサメチルジシラジド、リチウムテトラメチルピペリジン等が挙げられる。また、塩基は一種類のみを用いても、二種類以上を用いても良い。 As the base, amines, amides, carbamates, imides, sulfonamides, guanidines, hydrazones, hydrazides, hydrazines, heterocyclic amines, salts thereof, carbonates, metal hydrides, metal alkoxides or alkyl metals are preferable. In particular, from the viewpoint of yield, metal hydrides, metal alkoxides and hydrazide salts, bases having a pKa of 15.0 or more and having a low nucleophilicity are more preferable. For example, lithium diisopropylamide, sodium hydride, potassium tert-butoxide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, lithium tetramethylpiperidine and the like can be mentioned. Also, only one type of base may be used, or two or more types of bases may be used.
反応溶媒としては、反応過程において目的の化合物を与えるものであれば特に制限は無いが、具体的にはクロロホルム、四塩化炭素、ジクロロメタン、1,2−ジクロロエタン、1,2−ジクロロエチレン、1,1,2,2−テトラクロロエタン、トリクロロエチレン、1−クロロブタン、二硫化炭素、アセトン、アセトニトリル、ベンゾニトリル、N,N−ジメチルホルムアミド、N,N−ジメチルアセトアミド、ジメチルスルホキシド、ジエチルエーテル、エチレングリコールモノエチルエーテル、エチレングリコールモノエチルエーテルアセテート、エチレングリコールモノブチルエーテル、エチレングリコールモノメチルエーテル、ジエチレングリコールジエチルエーテル、o−ジクロロベンゼン、キシレン、o−キシレン、p−キシレン、m−キシレン、クロロベンゼン、酢酸イソブチル、酢酸イソプロピル、酢酸イソアミル、酢酸エチル、酢酸ブチル、酢酸プロピル、酢酸ペンチル、酢酸メチル、酢酸2−メトキシエチル、ヘキサメチルリン酸トリアミド、トリス(ジメチルアミノ)ホスフィン、シクロヘキサノン、1,4−ジオキサン、スチレン、テトラクロロエチレン、テトラヒドロフラン、ピリジン、1−メチル−2−ピロリジノン、1,1,1−トリクロロエタン、トルエン、ヘキサン、ペンタン、シクロヘキサン、シクロペンタン、ヘプタン、ベンゼン、メチルイソブチルケトン、tert−ブチルメチルエーテル、メチルエチルケトン、メチルシクロヘキサノン、メチルブチルケトン、ジエチルケトン、ガソリン、コールタールナフサ、石油エーテル、石油ナフサ、石油ベンジン、テレビン油等が挙げられる。収率の観点から、活性プロトンを持たないものが好ましく、例えば、炭化水素類、エーテル類、ホルムアミド類、スルホキシド類、ニトリル類が挙げられる。特にE/Zの観点から、添加剤を使用する際は非極性の溶媒が望ましく、具体的にはトルエン、ヘキサン、ペンタン、シクロヘキサン、シクロペンタン、ヘプタン、ベンゼン等が挙げられる。また、製造工程や精製工程の易化の観点から、テトラヒドロフラン、エチレングリコールジメチルエーテル、ジエチレングリコールジメチル、トリエチレングリコールジメチルエーテル又はテトラエチレングリコールジメチル等を用いても良い。 The reaction solvent is not particularly limited as long as it gives the target compound in the reaction process, but specifically, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,2-dichloroethylene, 1,1 2,2,2-tetrachloroethane, trichloroethylene, 1-chlorobutane, carbon disulfide, acetone, acetonitrile, benzonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, diethyl ether, ethylene glycol monoethyl ether Ethylene glycol monoethyl ether acetate, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether, diethylene glycol diethyl ether, o-dichlorobenzene, xylene, o-xylene, p-ki Ren, m-xylene, chlorobenzene, isobutyl acetate, isopropyl acetate, isopropyl acetate, isoamyl acetate, ethyl acetate, butyl acetate, propyl acetate, pentyl acetate, methyl acetate, 2-methoxyethyl acetate, hexamethyl phosphate triamide, tris (dimethylamino) phosphine , Cyclohexanone, 1,4-dioxane, styrene, tetrachloroethylene, tetrahydrofuran, pyridine, 1-methyl-2-pyrrolidinone, 1,1,1-trichloroethane, toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene, methyl isobutyl Ketone, tert-butyl methyl ether, methyl ethyl ketone, methyl cyclohexanone, methyl butyl ketone, diethyl ketone, gasoline, coal tar naphtha, petroleum ether, stone Naphtha, petroleum benzine, turpentine oil, and the like. From the viewpoint of yield, those not having an active proton are preferable, and examples thereof include hydrocarbons, ethers, formamides, sulfoxides and nitriles. In particular, from the viewpoint of E / Z, non-polar solvents are desirable when using additives, and specific examples include toluene, hexane, pentane, cyclohexane, cyclopentane, heptane, benzene and the like. Further, from the viewpoint of facilitation of the production process or the purification process, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl or the like may be used.
添加剤としては、金属カチオンの捕捉性が高いもの、具体的には、ポリアミン類、ポリエーテルアミン類、ポリエーテル類、ポリエステル類が好ましい。特に、収率とE/Zと経済性の観点から、ポリエーテル類がより好ましく、具体的にはエチレングリコールジメチルエーテル、ジエチレングリコールジメチル、トリエチレングリコールジメチルエーテル又はテトラエチレングリコールジメチル等が挙げられる。 As the additive, those having a high ability to capture metal cations, specifically, polyamines, polyether amines, polyethers and polyesters are preferable. In particular, polyethers are more preferable from the viewpoint of yield, E / Z and economy, and specific examples thereof include ethylene glycol dimethyl ether, diethylene glycol dimethyl, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl and the like.
製造温度は、−70℃から0℃が好ましく、その際の反応剤の添加順序は、塩基を作用させることで一般式(2)の化合物を活性化させ、その後基質(1)を反応させられる順序であれば他に制限は無い。しかし作業の効率性及び経済性の観点から、−60℃から0℃が好ましく、−50℃から0℃が好ましく、−40℃から0℃が好ましく、−30℃から0℃が好ましく、−20℃から0℃が好ましい。 The preparation temperature is preferably -70 ° C. to 0 ° C., and the addition order of the reaction agents in that case is that the compound of the general formula (2) is activated by reacting with a base and then the substrate (1) can be reacted. There is no other limitation if it is an order. However, from the viewpoint of work efficiency and economy, -60 ° C to 0 ° C is preferable, -50 ° C to 0 ° C is preferable, -40 ° C to 0 ° C is preferable, -30 ° C to 0 ° C is preferable, -20 C. to 0.degree. C. is preferred.
各反応剤を添加する順番は、塩基に一般式(1)及び一般式(2)で示される化合物を添加する、あるいは一般式(1)及び一般式(2)で示される化合物に塩基を添加する添加順序がより好ましい。この際にこれらを溶媒とともに使用することが好ましい。 The order of adding each reactant is to add the compound represented by the general formula (1) and the general formula (2) to the base, or add the base to the compound represented by the general formula (1) and the general formula (2) The order of addition is more preferred. At this time, it is preferable to use them together with a solvent.
さらに、−20℃から0℃のような比較的高温で製造を行う場合であって、一般式(1)で表される化合物がα位に脱プロトン化可能な水素原子を有するアルデヒドである場合は、収率の観点から、一般式(1)及び一般式(2)で示される化合物に塩基を添加する添加順序がより好ましい。 Furthermore, when the preparation is carried out at a relatively high temperature such as -20 ° C to 0 ° C and the compound represented by the general formula (1) is an aldehyde having a deprotonatable hydrogen atom at the α position The order of addition of adding a base to the compounds represented by the general formula (1) and the general formula (2) is more preferable from the viewpoint of yield.
以下、実施例を挙げて本発明を更に記述するが、本発明はこれらの実施例に限定されるものではない。以下の実施例及び比較例の組成物における「%」は『質量%』を意味する。水素圧は、大気圧を0MPaとした場合の圧力を意味する。以下に本願発明の製法及び比較例の製法によって製造した化合物について記述するが、わかりやすくするために、本願発明の製法によって製造した化合物を(3−1)のように末尾に数字のみを付記し、比較例の製法によって製造した化合物を(3−1a)のように末尾にアルファベットを付記する。 Hereinafter, the present invention will be further described by way of examples, but the present invention is not limited to these examples. “%” In the compositions of the following examples and comparative examples means “mass%”. The hydrogen pressure means the pressure when the atmospheric pressure is 0 MPa. The compounds produced by the production method of the present invention and the production methods of the comparative examples are described below, but for the sake of clarity, the compounds produced by the production method of the present invention are appended with only numerals at the end like (3-1). The compounds prepared according to the process of Comparative Example are appended with an alphabet at the end like (3-1a).
化合物の純度はGC又はUPLCによって分析した。分析条件は以下の通りである。
(GC分析条件)
カラム:Agilent Technologies,J&W Column DB−1HT,15m×0.25mm×0.10μm
温度プログラム:100℃(1分間)−(20℃/分間)−250℃−(10℃/分間)−380℃−(7℃/分間)−400℃(2.64分間)
注入口温度:350℃
検出器温度:400℃
(UPLC分析条件)
カラム:Waters ACQUITY UPLC BEH C18,2.1×100mm,1.7μm
溶出溶媒:アセトニトリル/水(90:10)
流速:0.5mL/min
検出器:UV,210nm
カラムオーブン:40℃
(実施例1) 式(3−1)で表される化合物の製造
TDA−1の製造
The purity of the compounds was analyzed by GC or UPLC. The analysis conditions are as follows.
(GC analysis conditions)
Column: Agilent Technologies, J & W Column DB-1HT, 15m × 0.25mm × 0.10μm
Temperature program: 100 ° C. (1 minute)-(20 ° C./minute)-250° C .- (10 ° C./minute)-380° C .- (7 ° C./minute)-400° C. (2.64 minutes)
Inlet temperature: 350 ° C
Detector temperature: 400 ° C
(UPLC analysis conditions)
Column: Waters ACQUITY UPLC BEH C 18 , 2.1 × 100 mm, 1.7 μm
Elution solvent: acetonitrile / water (90:10)
Flow rate: 0.5mL / min
Detector: UV, 210 nm
Column oven: 40 ° C
Example 1 Production of Compound Represented by Formula (3-1) Production of TDA-1
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(65.5mg,0.275mmol)及びトリス(2−(2−メトキシエトキシ)エチル)アミン(TDA−1)(55.0 μL,0.172mmol)をトルエン(140μL)に溶解し,撹拌しながら−70℃まで冷却した.続いてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(600μL,0.300mmol)を加えて5分間撹拌した後に,トルエン(135μL)に溶解した,4−((4−エトキシ−2,3−ジフルオロフェノキシ)メチル)シクロヘキサン−1−カルバルデヒド(1−1)(74.6mg,0.250mmol)を加え,さらに30分撹拌した.室温まで加温し,さらに2時間撹拌した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,1−エトキシ−2,3−ジフルオロ−4−((4−(プロペン−1−イル)シクロヘキシル)メトキシ)ベンゼン(3−1)(転化率87%、E/Z=97:3)の生成が確認された.
(実施例2)滴下順序及び反応温度を変更した、式(3−1)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer, under an argon atmosphere, 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) and tris (2- (2-) 2-Methoxyethoxy) ethyl) amine (TDA-1) (55.0 μL, 0.172 mmol) was dissolved in toluene (140 μL) and cooled to -70 ° C with stirring. Then, after adding potassium hexamethyl disilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) and stirring for 5 minutes, it was dissolved in toluene (135 μL), 4- ((4 -Ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (74.6 mg, 0.250 mmol) was added, and the mixture was further stirred for 30 minutes. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, after which the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4- ( The formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 87%, E / Z = 97: 3) was confirmed.
Example 2 Production of a Compound Represented by Formula (3-1) in Which the Order of Addition and the Reaction Temperature Were Changed
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,4−((4−エトキシ−2,3−ジフルオロフェノキシ)メチル)シクロヘキサン−1−カルバルデヒド(1−1)(500mg,1.68mmol),5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(438mg, 1.84mmol)及びトリス(2−(2−メトキシエトキシ)エチル)アミン(TDA−1)(370μL,1.16mmol)をトルエン(1.8mL)に溶解し,撹拌しながら−20℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(4.00mL,2.01mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,1−エトキシ−2,3−ジフルオロ−4−((4−(プロペン−1−イル)シクロヘキシル)メトキシ)ベンゼン(3−1)(転化率91%、E/Z=98:2)の生成が確認された.
(実施例3)添加剤を変更した、式(3−1)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer, 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (500 mg, 1.68 mmol) in an argon atmosphere. ), 5- (Ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (438 mg, 1.84 mmol) and tris (2- (2-methoxyethoxy) ethyl) amine (TDA-1) (370 μL, 1.16 mmol) was dissolved in toluene (1.8 mL) and cooled to −20 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (4.00 mL, 2.01 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming up to room temperature, the reaction was quenched by the addition of an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4-((4- (propene-) The formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 91%, E / Z = 98: 2) was confirmed.
Example 3 Production of a Compound Represented by Formula (3-1) in which Additives are Modified
撹拌装置及び温度計及を備えた反応容器に,アルゴン雰囲気下,4−((4−エトキシ−2,3−ジフルオロフェノキシ)メチル)シクロヘキサン−1−カルバルデヒド(1−1)(500mg,1.68mmol),5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(522mg, 2.18 mmol) 及びトリエチレングリコールジメチルエーテル(605μL,2.32mmol)をトルエン(1.8mL)に溶解し,撹拌しながら−20℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(4.40mL,2.18mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,1−エトキシ−2,3−ジフルオロ−4−((4−(プロペン−1−イル)シクロヘキシル)メトキシ)ベンゼン(3−1)(転化率94%、E/Z=98:2)の生成が確認された.有機層を分取し,これを水(10mL)、続いて飽和食塩水(10mL)にて洗浄した後、硫酸ナトリウムを用いて乾燥した.乾燥した混合物を減圧下濃縮し,カラムクロマトグラフィー(シリカゲル1g, ヘキサン10mL溶解液,ヘキサン30mL追い出し)にて精製後,濃縮し,再結晶を2回実施することで,目的物(427mg,E/Z=100:0,回収率82%)が得られた.
(実施例4)添加剤未使用、式(3−1)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer and under an argon atmosphere, 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (500 mg, 68 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (522 mg, 2.18 mmol) and triethylene glycol dimethyl ether (605 μL, 2.32 mmol) in toluene (1.8 mL) Dissolve and cool to -20 ° C while stirring. Subsequently, potassium hexamethyldisilazide (11% solution in toluene, about 0.5 mol / L) (4.40 mL, 2.18 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming up to room temperature, the reaction was quenched by the addition of an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4-((4- (propene-) The formation of 1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 94%, E / Z = 98: 2) was confirmed. The organic layer was separated, washed with water (10 mL) and then with saturated brine (10 mL), and dried over sodium sulfate. The dried mixture is concentrated under reduced pressure, purified by column chromatography (silica gel 1 g, hexane 10 mL solution, hexane 30 mL expelled), concentrated and recrystallized twice to obtain the desired product (427 mg, E /) Z = 100: 0, 82% recovery rate was obtained.
Example 4 Additive-Free, Production of Compound Represented by Formula (3-1)
撹拌装置及び温度計及を備えた反応容器に,アルゴン雰囲気下,5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(65.5mg, 0.275mmol)をトルエン(140μL)に溶解し,撹拌しながら−70℃まで冷却した.続いてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(600μL,0.300mmol)を加えて5分間撹拌した後に,トルエン(135μL)に溶解した,4−((4−エトキシ−2,3−ジフルオロフェノキシ)メチル)シクロヘキサン−1−カルバルデヒド(1−1)(74.6mg,0.250mmol)を加え,さらに30分撹拌した.室温まで加温し,さらに2時間撹拌した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,1−エトキシ−2,3−ジフルオロ−4−((4−(プロペン−1−イル)シクロヘキシル)メトキシ)ベンゼン(3−1)(転化率55%、E/Z=56:44)の生成が確認された.
(実施例5)式(3−2)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer, toluene (140 μL) of 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) (65.5 mg, 0.275 mmol) in an argon atmosphere And cooled to -70 ° C while stirring. Then, after adding potassium hexamethyl disilazide (11% toluene solution, about 0.5 mol / L) (600 μL, 0.300 mmol) and stirring for 5 minutes, it was dissolved in toluene (135 μL), 4- ((4 -Ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde (1-1) (74.6 mg, 0.250 mmol) was added, and the mixture was further stirred for 30 minutes. The reaction mixture was warmed to room temperature and stirred for a further 2 hours, after which the reaction was stopped by adding an excess amount of saturated aqueous ammonium chloride solution and analyzed by gas chromatography, 1-ethoxy-2,3-difluoro-4- ( The formation of (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1) (conversion rate 55%, E / Z = 56: 44) was confirmed.
Example 5 Production of Compound Represented by Formula (3-2)
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(1−2)(100 mg,0.285 mmol),5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(74.8 mg, 0.314 mmol)及びトリス(2−(2−メトキシエトキシ)エチル)アミン(TDA−1)(63.0 μL,0.197 mmol)をトルエン(320μL)に溶解し,撹拌しながら−40℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(628μL,0.314mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,目的物(3−2)(転化率90%、E/Z=92:8)の生成が確認された.
(実施例6)式(3−3)で表される化合物の製造
Compound (1-2) (100 mg, 0.285 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer ) (74.8 mg, 0.314 mmol) and tris (2- (2-methoxyethoxy) ethyl) amine (TDA-1) (63.0 μL, 0.197 mmol) in toluene (320 μL) It cooled to -40 degreeC, stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (628 μL, 0.314 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find that the desired product (3-2) (conversion rate 90%, E / Z = 92: The generation of 8) was confirmed.
Example 6 Production of Compound Represented by Formula (3-3)
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(1−3)(100 mg,0.476 mmol),5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(125 mg, 0.524 mmol)及びテトラエチレングリコールジメチルエーテル(115 μL,0.524 mmol)をトルエン(530μL)に溶解し,撹拌しながら−40℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(1.05mL,0.524mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,目的物(3−3)(転化率93%、E/Z=96:4)の生成が確認された.
(実施例7)式(2−1)で表される化合物の製造
Compound (1-3) (100 mg, 0.476 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer (125 mg, 0.524 mmol) and tetraethylene glycol dimethyl ether (115 μL, 0.524 mmol) were dissolved in toluene (530 μL) and cooled to −40 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (1.05 mL, 0.524 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find the desired product (3-3) (conversion rate 93%, E / Z = 96: The generation of 4) was confirmed.
Example 7 Production of Compound Represented by Formula (2-1)
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(2−1a)(14.9g,83.3mmol)と炭酸カリウム(17.3g,125mmol)をアセトン(60mL)に溶解させ,25℃下撹拌した.反応容器を氷浴に浸し,ヨウ化エチル(15.6g,100mmol)を滴下し,さらに25℃下,1時間撹拌した.反応溶液を減圧下濃縮し,トルエン(200mL)及び水(200mL)を加え,有機層と水層に分けた後,有機層を飽和食塩水(200mL)で洗浄し,硫酸ナトリウムで乾燥した.得られた溶液を減圧下濃縮すると,オイル状無色残渣(2−1b)(14.4g,純度99.8%)が得られた.
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(2−1b)(16.3g,79.2mmol)をエタノール(160mL)に溶解させ,室温下撹拌した.あらかじめ七モリブデン酸六アンモニウム四水和物(9.78g,7.92mmol)を35%過酸化水素水(78.4g)に溶解させたものを調製しておき,これを反応容器内に滴下した.滴下開始直後,発熱したために,氷浴で25℃程度に冷却しながら2時間撹拌した.10%亜硫酸ナトリウム水溶液(200mL)をゆっくり加え,20分間室温下撹拌した後,分層させ,水層から酢酸エチル(200mL)で抽出し,有機層を合わせ,飽和食塩水(200mL)で洗浄し,硫酸ナトリウムで乾燥した.得られた溶液をシリカゲル(16g)を詰めたカラムを通過させ,さらに酢酸エチル(500mL)で追い出し,溶液を減圧下濃縮すると,粗精製物(24.0g)が得られた.ヘキサン及び酢酸エチルで再結晶を行うことで,目的化合物(2−1)(17.9g,純度99.9%)が得られた.
(実施例8)式(2−2)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer, under argon atmosphere, the compound (2-1a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) are dissolved in acetone (60 mL), It stirred under 25 ° C. The reaction vessel was immersed in an ice bath, ethyl iodide (15.6 g, 100 mmol) was added dropwise, and the mixture was further stirred at 25 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, toluene (200 mL) and water (200 mL) were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with saturated brine (200 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to give an oily colorless residue (2-1b) (14.4 g, purity 99.8%).
In a reaction vessel equipped with a stirrer and a thermometer, compound (2-1b) (16.3 g, 79.2 mmol) was dissolved in ethanol (160 mL) under an argon atmosphere, and stirred at room temperature. A solution prepared by dissolving heptamolybdate hexaammonium tetrahydrate (9.78 g, 7.92 mmol) in 35% aqueous hydrogen peroxide (78.4 g) was prepared in advance, and this was dropped into the reaction vessel . Immediately after the start of the addition, the mixture was stirred for 2 hours while being cooled to about 25 ° C with an ice bath because of heat generation. Slowly add 10% aqueous sodium sulfite solution (200 mL), stir at room temperature for 20 minutes, separate layers, extract the aqueous layer with ethyl acetate (200 mL), combine the organic layers, and wash with saturated brine (200 mL) , Dried over sodium sulfate. The resulting solution was passed through a column packed with silica gel (16 g), and further chased with ethyl acetate (500 mL), and the solution was concentrated under reduced pressure to give a crude purified product (24.0 g). Recrystallization from hexane and ethyl acetate gave the target compound (2-1) (17.9 g, purity 99.9%).
Example 8 Production of Compound Represented by Formula (2-2)
(化合物2−2d)の合成
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(2−2c)(30.0g,99.9mmol)とピリジン(9.90mL,120mmol)をトルエン(120mL)に溶解させ,氷冷しながら撹拌した.これにメタンスルホニルクロリド(9.32mL,120mmol)を滴下し,常温まで昇温させ,3時間撹拌した.その後,再び氷冷し,飽和炭酸水素ナトリウム(240mL)を加え,さらに30分間撹拌した.室温まで昇温し,分層した水層からトルエン(240mL)で抽出した後,有機層を合わせ,飽和食塩水(240mL)で洗浄し,硫酸ナトリウムで乾燥した.これを減圧下濃縮したところ,目的物(2−2d)(34.8g,92.0mmol)が得られた.
(化合物2−2)の合成
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(2−2a)(14.9g,83.3mmol)と炭酸カリウム(17.3g,125mmol)をアセトン(60mL)に溶解させ,25℃下撹拌した.反応容器を氷浴に浸し,アセトン(100mL)に溶解させた化合物(2−2d)(34.8g,92.0mmol)を滴下し,さらに25℃下,5時間撹拌した.反応溶液を減圧下濃縮し,トルエン(200mL)及び水(200mL)を加え,有機層と水層に分けた後,有機層を飽和食塩水(200mL)で洗浄し,硫酸ナトリウムで乾燥した.得られた溶液を減圧下濃縮すると,無色結晶の残渣(2−2b)(37.3g,純度99.8%)が得られた.
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,化合物(2−2b)(37.3g,81.0mmol)をエタノール(400mL)に溶解させ,室温下撹拌した.あらかじめ七モリブデン酸六アンモニウム四水和物(10.0g,8.10mmol)を35%過酸化水素水(80.1g)に溶解させたものを調製しておき,これを反応容器内に滴下した.滴下開始直後,発熱したために,氷浴で25℃程度に冷却しながら2時間撹拌した.10%亜硫酸ナトリウム水溶液(200mL)をゆっくり加え,20分間室温下撹拌した後,分層させ,水層から酢酸エチル(200mL)で抽出し,有機層を合わせ,飽和食塩水(200mL)で洗浄し,硫酸ナトリウムで乾燥した.得られた溶液をシリカゲル(40g)を詰めたカラムを通過させ,さらに酢酸エチル(800mL)で追い出し,溶液を減圧下濃縮すると,粗精製物(33.0g)が得られた.ヘキサン及び酢酸エチルで再結晶を行うことで,目的化合物(2−2)(28.2g,純度99.2%)が得られた.
(実施例9)式(3−1)で表される化合物の製造
Synthesis of (Compound 2-2d) Compound (2-2c) (30.0 g, 99.9 mmol) and pyridine (9.90 mL, 120 mmol) in toluene in a reaction vessel equipped with a stirrer and a thermometer under an argon atmosphere The mixture was dissolved in (120 mL) and stirred with ice cooling. The methanesulfonyl chloride (9.32 mL, 120 mmol) was dripped at this, and it heated up to normal temperature, and stirred for 3 hours. Thereafter, the mixture was ice-cooled again, saturated sodium hydrogen carbonate (240 mL) was added, and the mixture was further stirred for 30 minutes. The temperature was raised to room temperature, and the separated aqueous layer was extracted with toluene (240 mL), then the organic layers were combined, washed with saturated brine (240 mL) and dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain the desired product (2-2d) (34.8 g, 92.0 mmol).
Synthesis of (Compound 2-2) Compound (2-2a) (14.9 g, 83.3 mmol) and potassium carbonate (17.3 g, 125 mmol) were added to a reaction vessel equipped with a stirrer and a thermometer under an argon atmosphere. It was dissolved in acetone (60 mL) and stirred at 25 ° C. The reaction vessel was immersed in an ice bath, and the compound (2-2d) (34.8 g, 92.0 mmol) dissolved in acetone (100 mL) was added dropwise, and the mixture was further stirred at 25 ° C. for 5 hours. The reaction solution was concentrated under reduced pressure, toluene (200 mL) and water (200 mL) were added, and the mixture was separated into an organic layer and an aqueous layer. The organic layer was washed with saturated brine (200 mL) and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure to give a colorless crystalline residue (2-2b) (37.3 g, purity 99.8%).
In a reaction vessel equipped with a stirrer and a thermometer, compound (2-2b) (37.3 g, 81.0 mmol) was dissolved in ethanol (400 mL) under an argon atmosphere, and stirred at room temperature. A solution prepared by dissolving heptamolybdate hexaammonium tetrahydrate (10.0 g, 8.10 mmol) in 35% aqueous hydrogen peroxide (80.1 g) was prepared beforehand, and this was dropped into the reaction vessel . Immediately after the start of the addition, the mixture was stirred for 2 hours while being cooled to about 25 ° C with an ice bath because of heat generation. Slowly add 10% aqueous sodium sulfite solution (200 mL), stir at room temperature for 20 minutes, separate layers, extract the aqueous layer with ethyl acetate (200 mL), combine the organic layers, and wash with saturated brine (200 mL) , Dried over sodium sulfate. The obtained solution was passed through a column packed with silica gel (40 g), and further chased with ethyl acetate (800 mL), and the solution was concentrated under reduced pressure to give a crudely purified product (33.0 g). Recrystallization from hexane and ethyl acetate gave the target compound (2-2) (28.2 g, purity 99.2%).
Example 9 Production of Compound Represented by Formula (3-1)
撹拌装置及び温度計を備えた反応容器に,アルゴン雰囲気下,アセトアルデヒド(21.0mg,0.476 mmol),化合物(2−2)(125 mg, 0.524 mmol)及びテトラエチレングリコールジメチルエーテル(115 μL,0.524 mmol)をトルエン(530μL)に溶解し,撹拌しながら−40℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(1.05mL,0.524mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,目的物(3−1)(転化率89%、E/Z=97:3)の生成が確認された.
(実施例10)式(3−4)で表される化合物の製造
In a reaction vessel equipped with a stirrer and a thermometer, under argon atmosphere, acetaldehyde (21.0 mg, 0.476 mmol), compound (2-2) (125 mg, 0.524 mmol) and tetraethylene glycol dimethyl ether (115) Dissolve .mu.L, 0.524 mmol) in toluene (530 .mu.L) and cool to -40.degree. C. with stirring. Subsequently, potassium hexamethyldisilazide (11% toluene solution, about 0.5 mol / L) (1.05 mL, 0.524 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming to room temperature, the reaction was quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find the desired product (3-1) (conversion rate 89%, E / Z = 97: The generation of 3) was confirmed.
Example 10 Production of Compound Represented by Formula (3-4)
撹拌装置及び温度計及を備えた反応容器に,アルゴン雰囲気下,化合物(1−4)(386mg,1.68mmol),5−(エチルスルホニル)−1−フェニル−1H−テトラゾール(2−1)(522mg, 2.18mmol) 及びトリエチレングリコールジメチルエーテル(605μL,2.32mmol)をトルエン(1.8mL)に溶解し,撹拌しながら−20℃まで冷却した.続いて同反応温度下にてカリウムヘキサメチルジシラジド(11%トルエン溶液,約0.5mol/L)(4.40mL,2.18mmol)を滴下し,さらに1時間撹拌した.室温まで加温した後に,過剰量の飽和塩化アンモニウム水溶液の加えて反応を停止し,ガスクロマトグラフィーにて分析したところ,化合物(3−4)(転化率96%、E/Z=98:2)の生成が確認された.
(比較例1)特許文献3記載の製造方法による式(3−1)で表される化合物の製造
Compound (1-4) (386 mg, 1.68 mmol) 5- (ethylsulfonyl) -1-phenyl-1H-tetrazole (2-1) in an argon atmosphere in a reaction vessel equipped with a stirrer and a thermometer (522 mg, 2.18 mmol) and triethylene glycol dimethyl ether (605 μL, 2.32 mmol) were dissolved in toluene (1.8 mL) and cooled to -20 ° C. with stirring. Subsequently, potassium hexamethyldisilazide (11% solution in toluene, about 0.5 mol / L) (4.40 mL, 2.18 mmol) was added dropwise at the same reaction temperature, and the mixture was further stirred for 1 hour. After warming up to room temperature, the reaction was quenched by the addition of an excess of saturated aqueous ammonium chloride solution and analyzed by gas chromatography to find that compound (3-4) (conversion rate 96%, E / Z = 98: 2 The generation of) was confirmed.
Comparative Example 1 Production of a Compound Represented by Formula (3-1) According to the Production Method Described in Patent Document 3
エチルトリフェニルホスホニウムブロマイド(277g,746mmol)をTHF(700mL)に溶解し,撹拌装置及び温度計及を備えた反応容器中,窒素雰囲気下−10 ℃にて撹拌した.その後,tert−ブトキシカリウム(80.3g,715mmol)を加えて,続いてTHF(700mL)に溶解した,4−((4−エトキシ−2,3−ジフルオロフェノキシ)メチル)シクロヘキサン−1−カルバルデヒド(1−1)(186g,622mmol)を滴下した.滴下後室温まで加温し,2時間撹拌した後,水を少量加え,反応溶液の色が脱色されたのを確認した.得られた混合物を減圧下濃縮し,ヘキサン/トルエン/次亜塩素酸ナトリウム/水/メタノール(350mL/80mL/45mL/250mL/520mL)にて抽出し,水/メタノール(200mL/400mL)で洗浄し,続いて水(400mL)にて洗浄後,減圧下濃縮した.得られた残渣をカラムクロマトグラフィー(シリカゲル180g,ヘキサン/トルエン(4/1))にて精製し,得られた溶液を減圧下濃縮したところ,1−エトキシ−2,3−ジフルオロ−4−((4−(プロペン−1−イル)シクロヘキシル)メトキシ)ベンゼン(3−1a)(174g,収率89%,E/Z=9:91)が得られた.
撹拌装置及び温度計及を備えた反応容器中,窒素雰囲気下,得られた化合物(3−1a)(174g, 559mmol)及びベンゼンスルフィン酸ナトリウム(4.60g,28.0mmol)及び10% 塩酸(21.1g,55.9mmol)をトルエン(680mL)に溶解し,85℃で2時間撹拌した.反応溶液をガスクロマトグラフィーにて分析したところ,化合物(3−1)(E/Z=82:18)が生成していることが確認された.これに飽和炭酸水素ナトリウム水溶液(500mL)を加え,さらに1時間撹拌した後,有機層を分取し,これを水(500mL)にて洗浄した.得られた混合物を減圧下濃縮し,カラムクロマトグラフィー(シリカゲル200g, ヘキサン600mL溶解液,ヘキサン1500mL追い出し)にて精製後,濃縮し,再結晶を12回実施することで,化合物(3−1)(68.3g,E/Z=99.85:0.15,回収率42%)が得られた.
この製造方法では、反応終了後の立体選択性が低いため、E体の純度を高めるためには再結晶を繰り返す必要があり、回収率が大きく低下した。
Ethyl triphenylphosphonium bromide (277 g, 746 mmol) was dissolved in THF (700 mL) and stirred at -10 ° C. under a nitrogen atmosphere in a reaction vessel equipped with a stirrer and thermometer. Then 4-((4-ethoxy-2,3-difluorophenoxy) methyl) cyclohexane-1-carbaldehyde in the presence of potassium tert-butoxide (80.3 g, 715 mmol) and then dissolved in THF (700 mL) (1-1) (186 g, 622 mmol) was dropped. After dropping, the mixture was warmed to room temperature and stirred for 2 hours, then a small amount of water was added, and it was confirmed that the color of the reaction solution was decolorized. The resulting mixture was concentrated under reduced pressure, extracted with hexane / toluene / sodium hypochlorite / water / methanol (350 mL / 80 mL / 45 mL / 250 mL / 520 mL), and washed with water / methanol (200 mL / 400 mL). Then, it was washed with water (400 mL) and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 180 g, hexane / toluene (4/1)), and the obtained solution was concentrated under reduced pressure to give 1-ethoxy-2,3-difluoro-4- (4). (4- (propen-1-yl) cyclohexyl) methoxy) benzene (3-1a) (174 g, yield 89%, E / Z = 9: 91) was obtained.
The resulting compound (3-1a) (174 g, 559 mmol), sodium benzenesulfinate (4.60 g, 28.0 mmol) and 10% hydrochloric acid (in a reaction vessel equipped with a stirrer and a thermometer and under a nitrogen atmosphere) 21.1 g (55.9 mmol) was dissolved in toluene (680 mL) and stirred at 85 ° C. for 2 hours. The reaction solution was analyzed by gas chromatography to confirm that compound (3-1) (E / Z = 82: 18) was formed. Saturated sodium hydrogencarbonate aqueous solution (500 mL) was added to this, and after stirring for further 1 hour, the organic layer was separated, and this was washed with water (500 mL). The resulting mixture is concentrated under reduced pressure, purified by column chromatography (silica gel 200 g, hexane 600 mL solution, hexane 1500 mL expelled), concentrated, and recrystallized 12 times, compound (3-1) (68.3 g, E / Z = 99.85: 0.15, recovery rate 42%) was obtained.
In this production method, since the stereoselectivity after completion of the reaction is low, it is necessary to repeat recrystallization to increase the purity of the E form, and the recovery rate is greatly reduced.
Claims (7)
A11は、(a) シクロヘキサン−1,4−ジイル基(この基中に存在する1個の−CH2−又は隣接していない2個以上の−CH2−は−O−に置き換えられてもよい。)
(b) 1,4−フェニレン基(この基中に存在する1個の−CH=又は隣接していない2個以上の−CH=は−N=に置き換えられてもよい。)
(c) 1,4−シクロヘキセニレン基、1,4−ビシクロ(2.2.2)オクチレン基、ピペリジン−1,4−ジイル基、ナフタレン−2,6−ジイル基、デカヒドロナフタレン−2,6−ジイル基及び1,2,3,4−テトラヒドロナフタレン−2,6−ジイル基からなる群より選ばれる基を表し、上記の基(a)、基(b)又は基(c)中の水素原子はそれぞれ独立してハロゲンで置換されていても良く、
Z11は単結合、−CH2CH2−、−(CH2)4−、−OCH2−、−CH2O−、−COO−、−OCO−、−OCF2−、−CF2O−、−CH=CH−、−CF=CF−又は−C≡C−を表し、
n11は0〜10の自然数を表すが、n11が2〜10を表す場合に複数存在するA11は同一であっても異なっていてもよく、n11が2〜10を表す場合に複数存在するZ11は同一であっても異なっていてもよく、n11が0を表す場合にR11は水素原子を表すことはなく、
Sp11は単結合又は炭素原子数1〜20のアルキレン基を表し、基中の−CH2−又は隣接していない2個以上の−CH2−はそれぞれ独立的に−O−に置換されても良く、また、基中に存在する1個又は2個以上の水素原子はそれぞれ独立的にハロゲンに置換されても良く、
一般式(2)における、R21は水素原子又は一般式(4)で表される置換基を表し、R22は一般式(5)で表される置換基を表し、
R23は芳香環を表し、
一般式(3)における、R11は、一般式(1)におけるR11と同一の置換基を表し、A11は、一般式(1)におけるA11と同一の置換基を表し、Z11は、一般式(1)におけるZ11と同一の置換基を表し、n11は、一般式(1)におけるn11と同一の自然数を表し、Sp11は、一般式(1)におけるSp11と同一の自然数を表し、R21は、一般式(2)におけるR21と同一の置換基を表し、R22は、一般式(2)におけるR22と同一の置換基を表す。) Polyamines, as an additive , using one or more compounds represented by general formula (1), one or more compounds represented by general formula (2), a base and an additive , and The manufacturing method of the compound represented by General formula (3) which uses polyetheramines, polyethers, or polyesters .
A 11 is (a) a cyclohexane-1,4-diyl group (one —CH 2 — present in this group or two or more non-adjacent —CH 2 — is replaced by —O— Also good.)
(B) 1,4-phenylene group (one -CH = present in this group or two or more non-adjacent -CH = may be replaced by -N =)
(C) 1,4-cyclohexenylene group, 1,4-bicyclo (2.2.2) octyrene group, piperidine-1,4-diyl group, naphthalene-2,6-diyl group, decahydronaphthalene-2 And a group selected from the group consisting of 6, 6-diyl group and 1, 2, 3, 4-tetrahydronaphthalene-2, 6-diyl group, and in the above group (a), group (b) or group (c) Each hydrogen atom may be independently substituted with halogen,
Z 11 is a single bond, -CH 2 CH 2 -, - (CH 2) 4 -, - OCH 2 -, - CH 2 O -, - COO -, - OCO -, - OCF 2 -, - CF 2 O- , -CH = CH-, -CF = CF- or -C≡C-,
n 11 represents a natural number of 0 to 10. However, when n 11 represents 2 to 10, a plurality of A 11 may be the same or different, and a plurality of n 11 represents 2 to 10 Z 11 present may be the same or different, and when n 11 represents 0, R 11 does not represent a hydrogen atom,
Sp 11 represents a single bond or an alkylene group of carbon atoms 1 to 20, -CH in group 2 - or nonadjacent two or more -CH 2 - may be replaced each independently -O- Also, one or more hydrogen atoms present in the group may be independently substituted with halogen, respectively.
In the general formula (2), R 21 represents a hydrogen atom or a substituent represented by the general formula (4), and R 22 represents a substituent represented by the general formula (5),
R 23 represents an aromatic ring,
In the general formula (3), R 11 has the general formula (1) represent the same substituent as R 11 in, A 11 represents the same substituent as A 11 in the general formula (1), Z 11 is represents a Z 11 and identical substituents in the general formula (1), n 11 represents an integer of same n 11 in the general formula (1), Sp 11 is identical to the Sp 11 in the general formula (1) It represents a natural number, R 21 represents the same substituent as R 21 in the general formula (2), R 22 represents the same substituent as R 22 in the general formula (2). )
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