JP5514522B2 - Method for producing chromanone compound and intermediate thereof - Google Patents

Description

  The present invention relates to a method for producing a chromanone compound useful as a synthetic intermediate for a novel serotonin reuptake inhibitor and an intermediate thereof.

  Depression is a chronic illness that affects people of all ages. Among the various antidepressants currently used, the most successful is a selective serotonin reuptake inhibitor (hereinafter sometimes abbreviated as SSRI). SSRI has a serotonin reuptake inhibitory action higher than the dopamine and noradrenaline reuptake inhibitory action. The first drug marketed as SSRI was zimelidine. Other SSRIs subsequently marketed or under development include, for example, fluoxetine, fluvoxamine, citalopram, sertraline and paroxetine.

  Although such SSRI is widely used as a therapeutic agent for depression, it has been pointed out that it still has some problems. For refractory patients that account for about 1/3 of all depression patients, SSRIs cannot achieve a sufficient therapeutic effect, and a long period of 3 to 8 weeks before sufficient antidepressant action appears The need for this is a typical problem. Thus, while the onset of the antidepressant action of SSRI is slow, its side effects can occur immediately. That is, there arises a problem in that the patient experiences a vulnerable period in which only the side effects are experienced without obtaining the therapeutic effect of the drug. Therefore, persuading the patient to continue taking the same medication during this period is often a heavy burden on the treating physician. In addition, for patients who are at risk of committing suicide, the onset of antidepressant action is slow, so that they recover their initiative before experiencing sufficient improvement in depressive symptoms. The need for frequent hospitalizations arises. Therefore, it is desired to develop an antidepressant that exhibits an antidepressant action quickly.

The reason why SSRI requires a long period of several weeks until it exhibits an antidepressant action is considered as follows.
SSRIs inhibit acute serotonin reuptake of serotonin turnover. When this inhibitory action occurs at the nerve endings of serotonin neurons, neurotransmission by serotonin is enhanced and antidepressant action is expressed. However, since this inhibitory action also occurs in serotonin neuron cell bodies and dendrites present in the raphe nucleus, the raphe nucleus enhances the suppression of serotonin neuron self-ignition (negative feedback reaction) via the serotonin 1A autoreceptor. End up. As a result, in the initial stage after administration of SSRI, neurotransmission in serotonin neurons is not enhanced as expected as a whole. On the other hand, while continuing to take SSRI for several weeks, serotonin neuron cell bodies in raphe nuclei and serotonin 1A autoreceptors on dendrites are desensitized and the negative feedback reaction disappears. As a result, the increased activity of serotonin neurons and the inhibition of serotonin uptake at nerve endings work in concert, and serotonin neurotransmission is strengthened, and sufficient antidepressant action is expressed.

  Therefore, serotonin 1A receptor antagonists are used in combination to block serotonin 1A autoreceptors to stop serotonin's negative feedback reaction, or serotonin 1A receptor agonists are used in combination to actively stimulate serotonin 1A autoreceptors and desensitize them. By shortening the period until the cropping, it is possible to shorten the period until the action of SSRI appears and to enhance the antidepressant action. In fact, when pindolol, which has a high affinity for the serotonin 1A receptor, is used in combination with SSRIs, it enhances the action of serotonin reuptake inhibitors in depressed patients and shortens the time to onset of action. Have been reported (Arch, Gen. Psychiatry, (1994), 51,248-251).

  When a patient takes a drug, it is desirable that the number and type of the drug be smaller. Therefore, based on the above findings, a compound having both serotonin reuptake inhibitory activity and affinity for serotonin 1A receptor is a single agent without using in combination with other drugs, has a strong antidepressant effect, and has a period until the onset of action. It is thought that it can become a shortened new antidepressant, and development of such a compound as a drug is desired.

  In addition, many antidepressants such as tricyclic antidepressants (TCA) and SSRI are enzymes involved in drug metabolism and have strong inhibitory action on CYP2D6, which is one of the human cytochrome P450 molecular species. It is known. On the other hand, it is also known that many psychiatric disease therapeutic agents that can be used in combination with TCA and SSRI in the treatment of depression and anxiety symptoms are metabolized by CYP2D6. Therefore, in the combined use of these drugs, the blood concentration of the latter drug increases due to inhibition of the metabolism of the other drug based on the inhibitory action of CYP2D6 by one drug, resulting in serious side effects. May develop. Therefore, the weaker the antidepressant CYP2D6 inhibitory action, the smaller the drug interaction with the combined psychiatric disorder metabolized by CYP2D6, and thus such antidepressants are more safe It is expected to be a drug and its development is desired.

  Furthermore, CYP2D6 is known to have large interindividual variation in enzyme activity due to genetic polymorphism. Drugs that are highly metabolized by CYP2D6 cause large individual differences in the drug concentration in the body, and blood in patients with metabolic defects (Poor Metabolizer, PM) compared to those in normal metabolizers (Extensive Metabolizer, EM). There is a high risk that medium drug concentration will rise significantly. In addition, there is a risk that such a drug has a stronger drug interaction with a drug that inhibits CYP2D6 or that is metabolized by CYP2D6. Therefore, the lower the contribution rate of CYP2D6 in drug metabolism, the smaller the pharmacokinetic effects of CYP2D6 genetic polymorphisms. Therefore, it is expected that such drugs can be safer and their development. Is also desired.

  There is no document that specifically discloses or suggests a serotonin reuptake inhibitor synthesized from an intermediate compound of a chromanone compound according to the present invention. However, there are literature examples disclosing compounds partially having a common chemical structure (see Patent Documents 1 to 4).

  There is no document that specifically discloses the chromanone compound synthesized from the intermediate compound of the chromanone compound according to the present invention. However, there are literature examples disclosing compounds having a partially common chemical structure (see Patent Literature 5, Patent Literature 6 and Non-Patent Literature 1).

  There is no document specifically disclosing the intermediate of the chromanone compound according to the present invention [compound represented by the following formula (1)]. However, ethyl 3- [4- (2-hydroxyethyl) phenoxy] propionate is disclosed as a raw material for 2-amino-1- (4-hydroxy-2-methylphenyl) propanol derivatives that have a completely different chemical structure from the chromanone compound. There is a literature example (see Patent Literature 7). Further, there is a literature example disclosing 3- [4- (2-methoxyethyl) phenoxy] propionic acid as a raw material of a 2-acylaminopropanol derivative having a completely different chemical structure from that of a chromanone compound (see Patent Documents 8 to 10). .

US Pat. No. 6,787,560 International Publication No. 88/02365 Pamphlet International Publication No. 97/23216 Pamphlet International Publication No. 2005/108389 Pamphlet JP 58-135877 A French Patent Application No. 2672601 International Publication No. 98/013333 Pamphlet International Publication No. 2008/150486 Pamphlet International Publication No. 2009/045503 Pamphlet International Publication No. 2009/117150 Pamphlet

Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1979), 17B (2), 155-7

  The problem to be solved by the present invention is a novel that enables production of a chromanone compound useful as an intermediate on an industrial scale in the synthesis of a novel serotonin reuptake inhibitor expected as a therapeutic agent for depression and the like. It is to provide a novel intermediate compound and to provide a novel method for producing a chromanone compound using the compound.

  As a result of intensive studies to create a novel serotonin reuptake inhibitor, the present inventors have found that a compound represented by the following formula (3) or a pharmaceutically acceptable salt thereof has a high human serotonin reuptake inhibitory action. It has been found that the compound or the salt not only has a binding affinity for the human 5-HT1A receptor but also has a weak CYP2D6 inhibition and a small contribution of CYP2D6 in metabolism.

［式中、Ｒ³は、水素原子またはメチル基を表し、Ｒ⁴は、メチレン基に対してｐ位またはｍ位に結合した基であって、ｐ位に結合した塩素原子、ｐ位に結合した臭素原子、ｐ位に結合したメチル基、ｍ位に結合した塩素原子またはｍ位に結合した臭素原子を表す。］

[In the formula, R ³ represents a hydrogen atom or a methyl group, and R ⁴ is a group bonded to the p-position or m-position to the methylene group, and is a chlorine atom bonded to the p-position, bonded to the p-position Represents a bromine atom, a methyl group bonded to the p-position, a chlorine atom bonded to the m-position, or a bromine atom bonded to the m-position. ]

  The compound represented by the above formula (3) is expected to be a new antidepressant, and can be produced from a novel chromanone compound represented by the following formula (2).

  That is, the problem to be solved by the present invention is to enable the production of a compound represented by the above formula (3) expected as a therapeutic agent for depression and anxiety (anxiety disorder) on an industrial scale, The object is to provide a novel production method of a novel chromanone compound represented by the above formula (2) [a synthetic intermediate of a compound represented by the above formula (3)] and a novel intermediate thereof.

The present invention provides a novel intermediate of the chromanone compound (2) represented by the following [1] to [11].
[1] Compound represented by formula (1):

［式中、破線は単結合または二重結合を表し、
（ｉ）破線が二重結合であるとき、
Ｒ¹は水素原子、メチル基、エチル基または置換もしくは無置換のベンゼンスルホニル基を表し、
Ｒ²はメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表し；
（ｉｉ）破線が単結合であるとき、
Ｒ¹は水素原子を表し、
Ｒ²はメチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；
Ｒ¹はメチル基を表し、
Ｒ²はメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；
Ｒ¹はエチル基またはベンゼンスルホニル基を表し、
Ｒ²は水素原子、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；あるいは
Ｒ¹は置換ベンゼンスルホニル基を表し、
Ｒ²は水素原子、メチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表す。］；

[In the formula, a broken line represents a single bond or a double bond,
(I) when the broken line is a double bond,
R ¹ represents a hydrogen atom, a methyl group, an ethyl group or a substituted or unsubstituted benzenesulfonyl group,
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
(Ii) when the broken line is a single bond,
R ¹ represents a hydrogen atom,
R ² represents a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents a methyl group,
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents an ethyl group or a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a substituted or unsubstituted benzyl group; or R ¹ represents a substituted group Represents a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group. ];

[2] Compound represented by formula (1):

［式中、破線は単結合または二重結合を表し、
（ｉ）破線が二重結合であるとき、
Ｒ¹は水素原子、エチル基または置換もしくは無置換のベンゼンスルホニル基を表し、
Ｒ²はメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；
あるいは
Ｒ¹はメチル基を表し、
Ｒ²はメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基または置換もしくは無置換のベンジル基を表し；
（ｉｉ）破線が単結合であるとき、
Ｒ¹は水素原子を表し、
Ｒ²はメチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；
Ｒ¹はメチル基を表し、
Ｒ²はプロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；
Ｒ¹はエチル基またはベンゼンスルホニル基を表し、
Ｒ²は水素原子、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；あるいは
Ｒ¹は置換ベンゼンスルホニル基を表し、
Ｒ²は水素原子、メチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表す。］；

[In the formula, a broken line represents a single bond or a double bond,
(I) when the broken line is a double bond,
R ¹ represents a hydrogen atom, an ethyl group or a substituted or unsubstituted benzenesulfonyl group,
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
Or R ¹ represents a methyl group;
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a substituted or unsubstituted benzyl group;
(Ii) when the broken line is a single bond,
R ¹ represents a hydrogen atom,
R ² represents a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents a methyl group,
R ² represents a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents an ethyl group or a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a substituted or unsubstituted benzyl group; or R ¹ represents a substituted group Represents a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group. ];

[3] The compound according to [1] or [2], wherein R ² is a hydrogen atom, a tert-butyl group or a benzyl group;

[4] The compound according to [3], wherein R ² is a hydrogen atom;

[5] The compound according to [3], wherein R ² is a tert-butyl group;

[6] The compound according to [3], wherein R ² is a benzyl group;

[7] The compound according to any one of [1] to [6], wherein R ¹ is a hydrogen atom, a benzenesulfonyl group or a p-toluenesulfonyl group;

[8] The compound according to [7], wherein R ¹ is a hydrogen atom;

[9] The compound according to [7], wherein R ¹ is a benzenesulfonyl group;

[10] The compound according to [7], wherein R ¹ is a p-toluenesulfonyl group;

[11] The compound represented by the formula (1) is:
Tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate,
3- [4- (2-hydroxyethyl) phenoxy] ethyl acrylate,
Tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate,
3- [4- (2-hydroxyethyl) phenoxy] benzyl acrylate,
3- [4- (2-benzenesulfonyloxyethyl) phenoxy] acrylic acid benzyl, or 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] propionic acid,
The compound according to [1] or [2].
Moreover, this invention relates to the manufacturing method of a chromanone compound represented by the following [12]-[14].

[12] From the compound according to any one of [1] to [11] by the method shown by the following (a), (b), (c) or (d):

［式中、Ｒ¹は水素原子、メチル基、エチル基または置換もしくは無置換のベンゼンスルホニル基である。］
で表される化合物を製造する方法：
（ａ）式（１）で表される化合物において、破線が単結合であり、Ｒ²がｔｅｒｔ−ブチル基である化合物を、無水トリフルオロ酢酸（ＴＦＡＡ）と反応させる方法；
（ｂ）式（１）で表される化合物において、破線が単結合であり、Ｒ²がメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基または置換もしくは無置換のベンジル基である化合物を、Ｒ²が水素原子である化合物に変換した後、ＴＦＡＡと反応させる方法；
（ｃ）式（１）で表される化合物において、破線が二重結合であり、Ｒ²がｔｅｒｔ−ブチル基である化合物を、破線が単結合である化合物に変換した後、ＴＦＡＡと反応させる方法；
（ｄ）式（１）で表される化合物において、破線が二重結合であり、Ｒ²がメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基または置換もしくは無置換のベンジル基である化合物を、破線が単結合でありＲ²が水素原子である化合物に変換した後、ＴＦＡＡと反応させる方法。

[Wherein, R ¹ represents a hydrogen atom, a methyl group, an ethyl group, or a substituted or unsubstituted benzenesulfonyl group. ]
A method for producing a compound represented by:
(A) A method of reacting a compound represented by formula (1), wherein the broken line is a single bond and R ² is a tert-butyl group, with trifluoroacetic anhydride (TFAA);
(B) In the compound represented by formula (1), the broken line is a single bond, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a substituted or non-substituted group. A method in which a compound having a substituted benzyl group is converted to a compound in which R ² is a hydrogen atom, and then reacted with TFAA;
(C) In the compound represented by formula (1), a compound in which the broken line is a double bond and R ² is a tert-butyl group is converted to a compound in which the broken line is a single bond, and then reacted with TFAA. Method;
(D) In the compound represented by the formula (1), the broken line is a double bond, and R ² is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group or substituted or A method in which a compound that is an unsubstituted benzyl group is converted to a compound in which the broken line is a single bond and R ² is a hydrogen atom, and then reacted with TFAA.

[13] The production method according to [12], wherein the reaction with TFAA is performed in the presence of an acid (for example, an inorganic acid such as phosphoric acid or sulfuric acid).

[14] The method of converting the compound of the formula (1) in which the broken line is a double bond into the compound of the formula (1) in which the broken line is a single bond is a catalytic reduction method, and R ² is a methyl group, ethyl group, propyl The method of converting a compound of formula (1) which is a group, isopropyl group, butyl group, isobutyl group or sec-butyl group into a compound of formula (1) wherein R ² is a hydrogen atom is a hydrolysis method, and R ² The method of converting the compound of the formula (1) in which is a substituted or unsubstituted benzyl group into the compound of the formula (1) in which R ² is a hydrogen atom is a hydrolysis method or a catalytic reduction method [12] or [13 ] The manufacturing method of description.

  With the intermediate of the present invention and a novel production method using the same, a novel serotonin reuptake inhibitor useful as an antidepressant can be produced on an industrial scale.

The present invention will be described more specifically below.
“Substituted or unsubstituted benzyl group” means a halogen atom (including a fluorine atom, a chlorine atom, a bromine atom and an iodine atom), an alkyl group (a linear or branched alkyl having 1 to 6 carbon atoms). Group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like. A fluoromethyl group, a cyano group, a nitro group, or an alkoxy group (representing a linear or branched alkoxy group having 1 to 6 carbon atoms; specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) Group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, etc.). It means a good benzyl group.

  “Substituted or unsubstituted benzenesulfonyl group” means a halogen atom (including a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom), an alkyl group (a linear or branched chain having 1 to 6 carbon atoms). Represents an alkyl group, and specific examples include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group. Or an alkoxy group (representing a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec- And a benzenesulfonyl group optionally substituted by a butoxy group, a tert-butoxy group, a pentyloxy group, a hexyloxy group, etc.) That. Preferred examples of the group include a benzenesulfonyl group and a p-toluenesulfonyl group.

In the compound represented by the formula (1) (sometimes referred to as “the compound of the present invention”), when the broken line represents a double bond, a geometric isomer may be formed. The compound represented by Formula (1) may have an asymmetric carbon atom depending on the case. These stereoisomers, mixtures thereof and racemates are included in the compounds of the present invention.
Since the compound represented by the formula (1) may exist in the form of hydrate and / or solvate, these hydrate and / or solvate are also included in the compound of the present invention. The

The compound represented by the formula (1) of the present invention is appropriately combined with known methods from methods shown in the following production methods 1 to 3, methods similar to the following production methods, or synthesis methods well known to those skilled in the art. Can be manufactured. Some of the starting compounds (12) are novel, but may be prepared by appropriately combining the methods described in the examples below, methods similar to the examples, or synthetic methods well known to those skilled in the art. it can.
In this specification, the following abbreviations may be used for the sake of simplicity.
Boc: tert-butoxycarbonyl group,
Piv: tert-butylcarbonyl group,
Me: methyl group,
Et: ethyl group,
Ph: phenyl group,
Bn: benzyl group,
Ms: methanesulfonyl group,
Bs: benzenesulfonyl group,
Ts: p-toluenesulfonyl group.

[Production Method 1]
Of the compounds represented by formula (1), formula (11):

［式中、Ｒ^1aは水素原子を表し、Ｒ^2aはメチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表すか；あるいは、Ｒ^1aはメチル基またはエチル基を表し、Ｒ^2aはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表す。］
で表される化合物は、例えば下記の方法によって製造できる。

[In the formula, R ^1a represents a hydrogen atom, and R ^2a represents a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group. Or R ^1a represents a methyl group or an ethyl group, and R ^2a represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted group. Represents a benzyl group. ]
Can be produced by, for example, the following method.

［式中、Ｒ^1aおよびＲ^2aは、前記と同義である。］
化合物（１２）は、市販の２−（４−ヒドロキシフェニル）エタノールであるか、２−（４−ヒドロキシフェニル）エタノールから公知の方法で合成できる化合物である。アクリル酸エステル（１３）は、市販もしくは公知の方法を適宜組み合わせることにより合成可能な化合物である。
原料化合物（１２）と化合物（１３）を必要に応じ塩基の存在下、適当な不活性溶媒中で反応させることにより、化合物（１１）を得ることができる。反応温度は約−２０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜５日間である。
塩基の具体例としては、例えばトリエチルアミン、Ｎ−メチルモルホリン、ピリジン等の有機塩基、炭酸カリウム、水酸化カリウム、水素化ナトリウム等の無機塩基、ナトリウムメトキシド、カリウムｔｅｒｔ−ブトキシド等の金属アルコキシド等があげられる。不活性溶媒の具体例としては、例えばアセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒もしくはこれらの混合溶媒が挙げられる。

[Wherein, R ^1a and R ^2a are as defined above. ]
Compound (12) is commercially available 2- (4-hydroxyphenyl) ethanol or a compound that can be synthesized from 2- (4-hydroxyphenyl) ethanol by a known method. The acrylic ester (13) is a compound that can be synthesized by appropriately combining commercially available or known methods.
Compound (11) can be obtained by reacting starting compound (12) and compound (13) in a suitable inert solvent in the presence of a base, if necessary. The reaction temperature ranges from about −20 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 5 days.
Specific examples of the base include organic bases such as triethylamine, N-methylmorpholine and pyridine, inorganic bases such as potassium carbonate, potassium hydroxide and sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, and the like. can give. Specific examples of the inert solvent include acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Solvents, lower alcohols such as methanol, ethanol and isopropanol, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof may be mentioned.

[Production Method 2]
The compound represented by the formula (11) can also be produced by the following method.

［式中、Ｒ^1aおよびＲ^2aは、前記と同義であり、ＬＧ¹は脱離基（例えば、塩素原子、臭素原子、ヨウ素原子などのハロゲン原子や、ｐ−トルエンスルホニルオキシ基、メタンスルホニルオキシ基などの置換スルホニルオキシ基が挙げられる。）を表す。］
化合物（１４）は市販もしくは公知の方法を適宜組み合わせることにより合成可能な化合物である。
化合物（１２）と化合物（１４）を必要に応じ塩基の存在下、適当な不活性溶媒中で反応させることにより、化合物（１１）を得ることができる。反応温度は約−２０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜５日間である。
塩基との具体例としては、製造方法１に記載のものと同様のものが挙げられる。不活性溶媒の具体例としては、例えばアセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、アセトン、メチルエチルケトン等のケトン、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒もしくはこれらの混合溶媒が挙げられる。

[Wherein, R ^1a and R ^2a are as defined above, and LG ¹ represents a leaving group (for example, a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, a p-toluenesulfonyloxy group, a methanesulfonyloxy group). A substituted sulfonyloxy group such as a group). ]
Compound (14) is a compound that can be synthesized by appropriately combining commercially available or known methods.
Compound (11) can be obtained by reacting compound (12) and compound (14) in the presence of a base, if necessary, in a suitable inert solvent. The reaction temperature ranges from about −20 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 5 days.
Specific examples of the base include those described in Production Method 1. Specific examples of the inert solvent include acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Solvents, lower alcohols such as methanol, ethanol and isopropanol, ketones such as acetone and methyl ethyl ketone, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof.

[Production Method 3]
Of the compounds represented by formula (1), formula (15):

［式中、Ｒ^1aは水素原子、メチル基またはエチル基を表し、Ｒ^2bはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表す。］
で表される化合物は、例えば下記の方法によって製造できる。

[Wherein, R ^1a represents a hydrogen atom, a methyl group or an ethyl group, and R ^2b represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a substituted group. Alternatively, it represents an unsubstituted benzyl group. ]
Can be produced by, for example, the following method.

［式中、Ｒ^1aおよびＲ^2bは、前記と同義である。］
プロピオル酸エステル（１６）は、市販もしくは公知の方法を適宜組み合わせることにより合成可能な化合物である。
Ｒ^2bが置換もしくは無置換のベンジル基であるプロピオル酸エステル（１６）は、ｐ−トルエンスルホン酸触媒を用いたベンジルアルコールのエステル化（例えば、特公昭４６−３５６９号公報、特開昭５４−７３７９０号公報を参照）、DCC-DMAP（ジシクロヘキシルカルボジイミド−４‐ジメチルアミノピリジン）を用いたベンジルアルコールの縮合（Tetrahedron Letters (1989), Vol.30, No.34, 4525-6.、国際公開第２００７／８５１３６パンフレット、Synthetic Communications (1990), 20(15), 2259-65.参照）、炭酸カリウムやＤＢＵ（1,8‐ジアザビシクロ[5.4.0]ウンデセ−7−エン）などの塩基存在下でのベンジルハロゲン化物によるアルキル化（米国特許第５１２８４４８号明細書、特開平０１−２４２５５０号公報を参照）などの公知の方法により、合成することが出来る。
化合物（１２）と化合物（１６）を必要に応じ塩基の存在下、適当な不活性溶媒中で反応させることにより、化合物（１５）を得ることができる。反応温度は約−２０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜２日間である。

[Wherein, R ^1a and R ^2b are as defined above. ]
Propiolic acid ester (16) is a compound that can be synthesized by appropriately combining commercially available or known methods.
Propiolic acid ester (16) in which R ^2b is a substituted or unsubstituted benzyl group is obtained by esterification of benzyl alcohol using a p-toluenesulfonic acid catalyst (for example, Japanese Examined Patent Publication No. 46-3568, Japanese Patent Laid-Open Publication No. 54- No. 73790), condensation of benzyl alcohol using DCC-DMAP (dicyclohexylcarbodiimide-4-dimethylaminopyridine) (Tetrahedron Letters (1989), Vol. 30, No. 34, 4525-6., International Publication No. 2007/85136 pamphlet, Synthetic Communications (1990), 20 (15), 2259-65.), In the presence of bases such as potassium carbonate and DBU (1,8-diazabicyclo [5.4.0] undec-7-ene). Can be synthesized by a known method such as alkylation of benzene with a benzyl halide (see US Pat. No. 5,128,448, JP-A-01-242550). I can do it.
Compound (15) can be obtained by reacting compound (12) and compound (16) in a suitable inert solvent in the presence of a base as necessary. The reaction temperature ranges from about −20 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 2 days.

  Specific examples of the base and the inert solvent are the same as those described in Production Method 1.

  Manufacture of the compound represented by Formula (2) from the compound represented by Formula (1) of this invention can be performed by the method shown to the manufacturing methods 4-6 shown below.

[Production Method 4]

［式中、Ｒ¹は、前記と同義である。］
化合物（１７）を必要に応じ酸の存在下、適当な不活性溶媒中で無水トリフルオロ酢酸と反応させることにより化合物（２）を得ることができる。反応温度は約−２０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜７日間である。
酸の具体例としては、例えば無機酸（リン酸、硫酸など）等があげられる。不活性溶媒の具体例としては、例えばアセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒もしくはこれらの混合溶媒が挙げられる。
Ｒ¹が置換もしくは無置換のベンゼンスルホニル基である化合物（１７）は、Ｒ¹が水素原子である化合物（１７）から、常法や、後記実施例１０、参考例１などに記載の方法、あるいはこれらに準じる方法で製造することができる。

[Wherein, R ¹ has the same meaning as described above. ]
Compound (2) can be obtained by reacting compound (17) with trifluoroacetic anhydride in a suitable inert solvent, if necessary, in the presence of an acid. The reaction temperature ranges from about −20 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 7 days.
Specific examples of the acid include inorganic acids (phosphoric acid, sulfuric acid, etc.). Specific examples of the inert solvent include acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Solvents, lower alcohols such as methanol, ethanol and isopropanol, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof may be mentioned.
The compound (17) in which R ¹ is a substituted or unsubstituted benzenesulfonyl group can be obtained from the compound (17) in which R ¹ is a hydrogen atom by a conventional method, the method described in Example 10 and Reference Example 1 below, Or it can manufacture by the method according to these.

[Production Method 5]

［式中、Ｒ^1bは水素原子、メチル基、エチル基を表し、Ｒ^2cはメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基または置換もしくは無置換のベンジル基を表す。
化合物（１１）を必要に応じ酸または塩基の存在下、適当な不活性溶媒中で加水分解することにより、化合物（１８）を得ることができる。
反応温度は約０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜２日間である。酸の具体例としては、例えば塩酸、硫酸等の無機酸、塩基としては、例えばトリエチルアミン、Ｎ−メチルモルホリン、ピリジン等の有機塩基、炭酸カリウム、水酸化カリウム、水素化ナトリウム等の無機塩基等が挙げられる。不活性溶媒の具体例としては、例えば、アセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒、水もしくはこれらの混合溶媒が挙げられる。
Ｒ^2cが置換もしくは無置換のベンジル基である場合、化合物（１１）を触媒存在下、適当な不活性溶媒中で接触還元を行うことにより、化合物（１８）を得ることができる。
反応温度は約０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜2日間反応である。
触媒の具体例としては、例えばパラジウム／炭素、水酸化パラジウム等があげられる。不活性溶媒としては、例えば、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、酢酸エチル、酢酸プロピル等の酢酸エステル、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒、酢酸、水もしくはこれらの混合溶媒が挙げられる。
化合物（１８）から化合物（１９）を製造する方法は、製造方法４に記載の方法と同様である。

[Wherein, R ^1b represents a hydrogen atom, a methyl group, or an ethyl group, and R ^2c represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted group. Alternatively, it represents an unsubstituted benzyl group.
Compound (18) can be obtained by hydrolyzing compound (11) in an appropriate inert solvent, if necessary, in the presence of an acid or a base.
The reaction temperature ranges from about 0 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 2 days. Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and bases include organic bases such as triethylamine, N-methylmorpholine and pyridine, and inorganic bases such as potassium carbonate, potassium hydroxide and sodium hydride. Can be mentioned. Specific examples of the inert solvent include, for example, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Examples thereof include system solvents, lower alcohols such as methanol, ethanol, and isopropanol, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, water, or a mixed solvent thereof.
When R ^2c is a substituted or unsubstituted benzyl group, compound (18) can be obtained by catalytic reduction of compound (11) in a suitable inert solvent in the presence of a catalyst.
The reaction temperature ranges from about 0 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 2 days.
Specific examples of the catalyst include palladium / carbon and palladium hydroxide. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, ethyl acetate, Examples include acetic acid esters such as propyl acetate, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, acetic acid, water, and mixed solvents thereof.
The method for producing compound (19) from compound (18) is the same as the method described in production method 4.

[Production Method 6]

［式中、Ｒ¹およびＲ^2bは、前記と同義であり、Ｒ^2dは、メチル基、エチル基、プロピル基イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基またはｔｅｒｔ−ブチル基である。］
Ｒ^2bがメチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ−ブチル基またはｔｅｒｔ−ブチル基である場合、化合物（２０）を触媒存在下、適当な不活性溶媒中で接触還元を行うことにより、化合物（２２）を得ることができる。
Ｒ^2bが置換もしくは無置換のベンジル基である場合、化合物（２０）を触媒存在下、適当な不活性溶媒中で接触還元を行うことにより、化合物（２１）を得ることができる。
反応温度は約０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜2日間反応である。
触媒の具体例としては、例えばパラジウム／炭素、水酸化パラジウム等があげられる。不活性溶媒としては、例えば、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、酢酸エチル、酢酸プロピル等の酢酸エステル、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒、酢酸、水もしくはこれらの混合溶媒が挙げられる。
化合物（２２）から化合物（２１）を製造する方法は、製造方法５に記載の方法と同様である。
化合物（２１）から化合物（２）を製造する方法は、製造方法４に記載の方法と同様である。
Ｒ¹が置換もしくは無置換のベンゼンスルホニル基である化合物（２０）は、Ｒ¹が水素原子である化合物（２０）から、常法や、後記実施例１０、参考例１などに記載の方法、あるいはこれらに準じる方法で製造することができる。

[Wherein, R ¹ and R ^2b are as defined above, and R ^2d is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a tert-butyl group. ]
When R ^2b is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, the compound (20) is prepared in a suitable inert solvent in the presence of a catalyst. Compound (22) can be obtained by performing catalytic reduction.
When R ^2b is a substituted or unsubstituted benzyl group, compound (21) can be obtained by catalytic reduction of compound (20) in a suitable inert solvent in the presence of a catalyst.
The reaction temperature ranges from about 0 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 2 days.
Specific examples of the catalyst include palladium / carbon and palladium hydroxide. Examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene, ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, ethyl acetate, Examples include acetic acid esters such as propyl acetate, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone, and dimethyl sulfoxide, acetic acid, water, and mixed solvents thereof.
The method for producing compound (21) from compound (22) is the same as the method described in production method 5.
The method for producing compound (2) from compound (21) is the same as the method described in production method 4.
The compound (20) in which R ¹ is a substituted or unsubstituted benzenesulfonyl group can be obtained from the compound (20) in which R ¹ is a hydrogen atom by a conventional method, the method described in Example 10, Reference Example 1 or the like, Or it can manufacture by the method according to these.

The compound of the present invention represented by the formula (1) can be used as a useful intermediate in the synthesis of a compound having an antidepressant activity represented by the formula (3), for example.
The compound represented by formula (3) or a salt thereof can be produced, for example, by the following method.

［式中、Ｒ³、Ｒ⁴およびＬＧ¹は、前記と同義である。］
化合物（３）またはその塩は、化合物（４）またはその塩を必要に応じ塩基の存在下、また、必要に応じ相間移動触媒の存在下、適当な不活性溶媒中で化合物（５）と反応させることにより得ることができる。反応温度は、約−２０℃から用いた溶媒の沸点までの範囲であり、反応時間は１０分間〜４８時間である。
塩基の具体例としては、例えばトリエチルアミン、ピリジン等の有機塩基、炭酸カリウム、水酸化カリウム、水素化ナトリウム等の無機塩基、ナトリウムメトキシド、カリウムtert-ブトキシド等の金属アルコキシド等が挙げられる。
相間移動触媒の具体例としては、例えば硫酸水素テトラブチルアンモニウムなどが挙げられる。
不活性溶媒の具体例としては、例えばアセトニトリルや、クロロホルム、ジクロロメタン等のハロゲン化炭化水素、ベンゼン、トルエン等の芳香族炭化水素、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，４−ジオキサン等のエーテル系溶媒、メタノール、エタノール、イソプロパノール等の低級アルコール、ジメチルホルムアミド、Ｎ−メチルピロリドン、ジメチルスルホキシド等の非プロトン性極性溶媒もしくはこれらの混合溶媒が挙げられる。より好ましい溶媒としてはアセトニトリルが挙げられる。

[Wherein R ³ , R ⁴ and LG ¹ are as defined above. ]
Compound (3) or a salt thereof is reacted with compound (5) in a suitable inert solvent in the presence of a base, and optionally in the presence of a phase transfer catalyst. Can be obtained. The reaction temperature ranges from about −20 ° C. to the boiling point of the solvent used, and the reaction time is 10 minutes to 48 hours.
Specific examples of the base include organic bases such as triethylamine and pyridine, inorganic bases such as potassium carbonate, potassium hydroxide and sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, and the like.
Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate.
Specific examples of the inert solvent include acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane. Solvents, lower alcohols such as methanol, ethanol and isopropanol, aprotic polar solvents such as dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof may be mentioned. A more preferred solvent is acetonitrile.

Preferably sulfonyloxy groups substituted Specific examples of the leaving group LG ^1, p-toluenesulfonyloxy group and benzenesulfonyl group is more preferable.
In addition, the conversion of the OR ¹ group of the compound of the present invention represented by the formula (2) in which R ¹ is a hydrogen atom, a methyl group or an ethyl group into the leaving group LG ¹ is, for example, a conventional method described in the literature (PROTECTIVE GROUP IN ORGANIC SYNTHESIS Second Edition, Theodora W. Greene and Peter GM Wuts, JOHN WILEY & SONS, INC., 1990). For example, a compound of the formula (2) in which R ¹ is a methyl group is reacted with pivaloyl chloride and sodium iodide to convert to a compound of the formula (2) in which R ¹ is a hydrogen atom. It can be produced by the method described in Example 10 and Reference Example 1 described later, or a method analogous thereto.

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples, but the present invention is not limited to these examples. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature.
For the identification of the compound, a hydrogen nuclear magnetic resonance absorption spectrum ( ¹ H-NMR spectrum) or the like was used. For some compounds, ¹ H-NMR spectrum data and melting points were shown. The purity and the like were also confirmed by liquid chromatography analysis. SUMPAX ODS C-212 (5 μm, 6 mmφ × 15 cm) was used for the column, the measurement wavelength was set to 220 nm, and the moving bed flow rate was set to 1.0 ml / min for analysis. As the moving layer, a mixed solvent of 0.05% trifluoroacetic acid-acetonitrile (liquid A) and 0.05% trifluoroacetic acid-water (liquid B) was used. In condition 1, the mixing ratio of liquid A and liquid B (liquid A: liquid B) is 10:90 at the start of measurement (0 minutes), and the ratio of liquid A is 90:10 40 minutes after the start of measurement. Was increased by 2.0% per minute for a measurement time of 50 minutes. The retention time (condition 1) in which the compound was detected when the mixing ratio of liquid A and liquid B was the present condition was also shown for some compounds.

３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル
２−（４−ヒドロキシルフェニル）エタノール（５００ｍｇ，３．６２ｍｍｏｌ）のアセトニトリル（５ｍＬ）溶液またはＮ−メチルピロリドン（５ｍＬ）溶液にアクリル酸ｔｅｒｔ−ブチル（５１０ｍｇ，３．９８ｍｍｏｌ）、塩基［トリエチルアミン（４０３ｍｇ，３．９８ｍｍｏｌ）、Ｎ−メチルモルホリン（４０３ｍｇ，３．９８ｍｍｏｌ）または炭酸カリウム（５５０ｍｇ，３．９８ｍｍｏｌ）］を加え、室温で５時間撹拌後、５０℃で９時間加熱撹拌した。反応液をＨＰＬＣ分析し、目的物が８％から１７％生成していることを確認した。
保持時間（条件１）：２７．８５分

To a solution of tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate 2- (4-hydroxylphenyl) ethanol (500 mg, 3.62 mmol) in acetonitrile (5 mL) or N-methylpyrrolidone (5 mL) Add tert-butyl acrylate (510 mg, 3.98 mmol), base [triethylamine (403 mg, 3.98 mmol), N-methylmorpholine (403 mg, 3.98 mmol) or potassium carbonate (550 mg, 3.98 mmol)] at room temperature. And stirred at 50 ° C. for 9 hours. The reaction solution was subjected to HPLC analysis, and it was confirmed that the target product was produced from 8% to 17%.
Holding time (condition 1): 27.85 minutes

３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル
２−（４−ヒドロキシルフェニル）エタノール（５００ｍｇ，３．６２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液またはＮ−メチルピロリドン（１０ｍＬ）溶液にブロモプロピオン酸ｔｅｒｔ−ブチル（９０８ｍｇ，４．３４ｍｍｏｌ）、塩基［カリウムｔｅｒｔ−ブトキシド（６０９ｍｇ，５．４３ｍｍｏｌ）または炭酸カリウム（７５０ｍｇ，５．４３ｍｍｏｌ）］を加え３０℃で８時間撹拌した。反応液をＨＰＬＣ分析し、目的物が６％から１８％生成していることを確認した。
保持時間（条件１）：２７．８５分

To a solution of tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate 2- (4-hydroxylphenyl) ethanol (500 mg, 3.62 mmol) in acetone (10 mL) or N-methylpyrrolidone (10 mL) Tert-butyl bromopropionate (908 mg, 4.34 mmol), base [potassium tert-butoxide (609 mg, 5.43 mmol) or potassium carbonate (750 mg, 5.43 mmol)] were added, and the mixture was stirred at 30 ° C. for 8 hours. The reaction solution was subjected to HPLC analysis, and it was confirmed that the target product was produced from 6% to 18%.
Holding time (condition 1): 27.85 minutes

３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ｔｅｒｔ−ブチル
２−（４−ヒドロキシルフェニル）エタノール（１０．０ｇ，７２．４ｍｍｏｌ）のアセトニトリル（１００ｍＬ）溶液にプロピオル酸ｔｅｒｔ−ブチル（９．１ｇ，７２．４ｍｍｏｌ）、Ｎ−メチルモルホリン（０．７３ｇ，７．２４ｍｍｏｌ）を加え室温で３時間撹拌した。反応液を減圧濃縮後、トルエン（１００ｍＬ）、水（５０ｍＬ）を加えて分液し、有機層を水（５０ｍＬ）で洗浄し、溶媒を減圧濃縮することで、標記化合物（１９．６ｇ，定量的）を無色油状物として得た。
Ｅ体（Trans体）
1H-NMR（400 MHz，CDCl₃）δ：1.48（9H，s），2.84-2.88（2H，m），3.83-3.88（2H，m），5.44（1H，d，J=12.4 Hz），7.00-7.07（2H，m），7.20-7.26（2H，m），7.67（1H，d，J=12.4 Hz）
Ｚ体（Cis体）
1H-NMR（400 MHz，CDCl₃）δ：1.51（9H，s），2.84-2.88（2H，m），3.83-3.88（2H，m），5.07（1H，d，J=7.2 Hz），7.00-7.07（2H，m），7.20-7.26（2H，m），6.78（1H，d，J=6.8 Hz）

Tert-Butyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate 2- (4-hydroxylphenyl) ethanol (10.0 g, 72.4 mmol) in acetonitrile (100 mL) in tert-butyl propiolate (9 0.1 g, 72.4 mmol) and N-methylmorpholine (0.73 g, 7.24 mmol) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture is concentrated under reduced pressure, toluene (100 mL) and water (50 mL) are added and the layers are separated, the organic layer is washed with water (50 mL), and the solvent is concentrated under reduced pressure to give the title compound (19.6 g, quantitative). Was obtained as a colorless oil.
E body (Trans body)
1H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (9H, s), 2.84-2.88 (2H, m), 3.83-3.88 (2H, m), 5.44 (1H, d, J = 12.4 Hz), 7.00 -7.07 (2H, m), 7.20-7.26 (2H, m), 7.67 (1H, d, J = 12.4 Hz)
Z body (Cis body)
1H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (9H, s), 2.84-2.88 (2H, m), 3.83-3.88 (2H, m), 5.07 (1H, d, J = 7.2 Hz), 7.00 -7.07 (2H, m), 7.20-7.26 (2H, m), 6.78 (1H, d, J = 6.8 Hz)

３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル
実施例３で得た３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ｔｅｒｔ−ブチル（１９．０ｇ，７１．９ｍｍｏｌ）を酢酸エチル（１９０ｍＬ）中で１０％パラジウム炭素（５０％ｗｅｔ）（３．８ｇ）を用いて室温で５時間常圧水素添加反応を行った。触媒をセライトでろ去し、ろ液を減圧濃縮することで、標記化合物（１８．７ｍｇ，９７％）を無色油状物として得た。
1H-NMR（400 MHz，CDCl₃）δ：1.47（9H，s），2.71（2H，t，J=6.5Hz），2.82（2H，t，J=6.5Hz），3.84（2H，t，J=6.5 Hz），4.21（2H，t，J=6.5 Hz），6.87（2H，t，J=8.6 Hz），7.15（2H，t，J=8.7 Hz）
保持時間（条件１）：２７．８５分

Tert-Butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate tert-Butyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate obtained in Example 3 (19.0 g, 71.9 mmol) ) Was subjected to a hydrogenation reaction at room temperature for 5 hours using 10% palladium carbon (50% wet) (3.8 g) in ethyl acetate (190 mL). The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (18.7 mg, 97%) as a colorless oil.
1H-NMR (400 MHz, CDCl ₃ ) δ: 1.47 (9H, s), 2.71 (2H, t, J = 6.5Hz), 2.82 (2H, t, J = 6.5Hz), 3.84 (2H, t, J = 6.5 Hz), 4.21 (2H, t, J = 6.5 Hz), 6.87 (2H, t, J = 8.6 Hz), 7.15 (2H, t, J = 8.7 Hz)
Holding time (condition 1): 27.85 minutes

３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル
実施例３で得た３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ｔｅｒｔ−ブチル（２９０ｍｇ，１．１０ｍｍｏｌ）を酢酸（５０ｍｇ，０．８３ｍｍｏｌ）、メタノール（１０ｍＬ）中で１０％パラジウム炭素（５８ｍｇ）を用いて室温で３時間常圧水素添加反応を行った。触媒をセライトでろ去し、ろ液を減圧濃縮後、標記化合物（４５０ｍｇ，定量的）を無色油状物として得た。
保持時間（条件１）：２７．８５分

Tert-Butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate 3- [4- (2-hydroxyethyl) phenoxy] tert-butyl acrylate (290 mg, 1.10 mmol) obtained in Example 3 was used. A normal pressure hydrogenation reaction was performed at room temperature for 3 hours using 10% palladium carbon (58 mg) in acetic acid (50 mg, 0.83 mmol) and methanol (10 mL). The catalyst was filtered off through celite, and the filtrate was concentrated under reduced pressure to give the title compound (450 mg, quantitative) as a colorless oil.
Holding time (condition 1): 27.85 minutes

３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸エチル
２−（４−ヒドロキシルフェニル）エタノール（２００ｍｇ，１．４５ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液にプロピオル酸エチル（１５６ｍｇ，１．５９ｍｍｏｌ）、Ｎ−メチルモルホリン（７ｍｇ，０．０７ｍｍｏｌ）を加え３０℃で３時間撹拌した。反応液を減圧濃縮した。濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘプタン：アセトン＝４０：１→１０：１）で精製することで、標記化合物（２８０ｍｇ，８２％）を無色油状物として得た。
1H-NMR（400 MHz，CDCl₃）δ：1.28（3H，t，J=7.2Hz），2.86（2H，t，J=6.6Hz），3.86（2H，t，J=6.6Hz），4.19（2H，q，J=7.2 Hz），5.53（1H，d，J=12.0 Hz），7.00-7.04（2H，m），7.22-7.25（2H，m），7.78（1H，d，J=12.0Hz）

Ethyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate 2- (4-hydroxylphenyl) ethanol (200 mg, 1.45 mmol) in acetonitrile (2 mL) in ethyl propiolate (156 mg, 1.59 mmol), N-methylmorpholine (7 mg, 0.07 mmol) was added and stirred at 30 ° C. for 3 hours. The reaction solution was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (heptane: acetone = 40: 1 → 10: 1) to obtain the title compound (280 mg, 82%) as a colorless oil.
1H-NMR (400 MHz, CDCl ₃ ) δ: 1.28 (3H, t, J = 7.2 Hz), 2.86 (2H, t, J = 6.6 Hz), 3.86 (2H, t, J = 6.6 Hz), 4.19 ( 2H, q, J = 7.2 Hz), 5.53 (1H, d, J = 12.0 Hz), 7.00-7.04 (2H, m), 7.22-7.25 (2H, m), 7.78 (1H, d, J = 12.0 Hz) )

６−（２−ヒドロキシエチル）−２，３−ジヒドロ−４Ｈ−クロメン−４−オン
無水トリフルオロ酢酸（３．１５ｇ，１５．０ｍｍｏｌ）のアセトニトリル（２０ｍＬ）に氷冷下、３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル（１．０ｇ，３．７５ｍｍｏｌ）を滴下し、室温で７日間撹拌した（1日後の原料残存率は３５．９％（ＬＣ分析値）であった。）。反応液を減圧濃縮し、濃縮残渣にトルエン（１０ｍＬ）、水（５ｍＬ）を加え分液し、有機層を飽和炭酸水素ナトリウム水溶液（５ｍＬ）、水（５ｍＬ）で洗浄し、溶媒を減圧濃縮し、標記化合物と標記化合物のトリフルオロアセチルエステルとの混合物を濃縮残渣として得た。濃縮残渣にメタノール（１０ｍL）、炭酸カリウム（０．５２ｇ，３．７５ｍｍｏｌ）を加え室温で２時間撹拌した。反応液を減圧濃縮し、濃縮残渣に酢酸エチル（１０ｍＬ）、水（１０ｍＬ）を加え分液し、有機層を減圧濃縮することで、標記化合物（０．５１ｇ，７０．１％）を褐色油状物として得た。
保持時間（条件１）：１４．８１分

6- (2-Hydroxyethyl) -2,3-dihydro-4H-chromen-4-one Trifluoroacetic anhydride (3.15 g, 15.0 mmol) in acetonitrile (20 mL) under ice-cooling, 3- [4- (2-Hydroxyethyl) phenoxy] tert-butyl propionate (1.0 g, 3.75 mmol) was added dropwise, and the mixture was stirred at room temperature for 7 days (the raw material residual rate after 1 day was 35.9% (LC analysis value)). there were.). The reaction mixture is concentrated under reduced pressure, toluene (10 mL) and water (5 mL) are added to the concentrated residue, and the mixture is separated. The organic layer is washed with a saturated aqueous sodium bicarbonate solution (5 mL) and water (5 mL), and the solvent is concentrated under reduced pressure. A mixture of the title compound and the trifluoroacetyl ester of the title compound was obtained as a concentrated residue. Methanol (10 mL) and potassium carbonate (0.52 g, 3.75 mmol) were added to the concentrated residue, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added to the concentrated residue, and the mixture was partitioned. The organic layer was concentrated under reduced pressure to give the title compound (0.51 g, 70.1%) as a brown oil. Obtained as a thing.
Holding time (condition 1): 14.81 minutes

６−（２−ヒドロキシエチル）−２，３−ジヒドロ−４Ｈ−クロメン−４−オン
無水トリフルオロ酢酸（１７．６ｇ，８４．０ｍｍｏｌ）のアセトニトリル（１００ｍＬ）に氷冷下、リン酸（１．０３ｇ，１０．５ｍｍｏｌ）、３−［４−（２−ヒドロキシエチル）フェノキシ］プロピオン酸ｔｅｒｔ−ブチル（５．０ｇ，２０．１ｍｍｏｌ）を滴下し、室温で２時間撹拌した。反応液を減圧濃縮し、濃縮残渣にトルエン（１００ｍＬ）、水（５０ｍＬ）を分液し、有機層を飽和炭酸水素ナトリウム水溶液（５０ｍＬ）、水（５０ｍＬ）で洗浄し、溶媒を減圧濃縮し、標記化合物と標記化合物のトリフルオロアセチルエステルとの混合物を濃縮残渣として得た。濃縮残渣にメタノール（５５ｍL）、炭酸カリウム（２．６１ｇ，１８．９ｍｍｏｌ）を加え室温で３時間撹拌した。反応液を減圧濃縮し、濃縮残渣に酢酸エチル（６０ｍＬ）、水（６０ｍＬ）を加え分液し、有機層を減圧濃縮することで、標記化合物（２．９５ｇ，７６％）を褐色油状物として得た。
保持時間（条件１）：１４．８１分

6- (2-Hydroxyethyl) -2,3-dihydro-4H-chromen-4-one Trifluoroacetic anhydride (17.6 g, 84.0 mmol) in acetonitrile (100 mL) under ice cooling with phosphoric acid (1. 03 g, 10.5 mmol) and tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate (5.0 g, 20.1 mmol) were added dropwise and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, toluene (100 mL) and water (50 mL) were separated into the concentrated residue, the organic layer was washed with saturated aqueous sodium hydrogencarbonate (50 mL) and water (50 mL), and the solvent was concentrated under reduced pressure. A mixture of the title compound and the trifluoroacetyl ester of the title compound was obtained as a concentrated residue. Methanol (55 mL) and potassium carbonate (2.61 g, 18.9 mmol) were added to the concentrated residue, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (60 mL) and water (60 mL) were added to the concentrated residue, and the mixture was partitioned. The organic layer was concentrated under reduced pressure to give the title compound (2.95 g, 76%) as a brown oil. Obtained.
Holding time (condition 1): 14.81 minutes

３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ベンジル
２−（４−ヒドロキシルフェニル）エタノール（１８１ｍｇ，１．３１ｍｍｏｌ）のアセトニトリル（２ｍＬ）溶液にプロピオル酸ベンジル（２００ｍｇ，１．２５ｍｍｏｌ）、Ｎ−メチルモルホリン（１２．６ｍｇ，０．１２５ｍｍｏｌ）を加え室温で６時間撹拌した。反応液にトルエン（５ｍＬ）、水（５ｍＬ）を加えて分液し、有機層を５％炭酸カリウム水溶液（５ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧濃縮することで、標記化合物（３６６ｍｇ，９８．１％）を無色油状物として得た。
保持時間（条件１）：Ｚ体（Ｃｉｓ体）２８．４８分、Ｅ体（Ｔｒａｎｓ体）３１．０１分

Benzyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate 2- (4-hydroxylphenyl) ethanol (181 mg, 1.31 mmol) in acetonitrile (2 mL) in benzyl propiolate (200 mg, 1.25 mmol), N-methylmorpholine (12.6 mg, 0.125 mmol) was added and stirred at room temperature for 6 hours. Toluene (5 mL) and water (5 mL) were added to the reaction solution, and the mixture was separated. The organic layer was washed with 5% aqueous potassium carbonate solution (5 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title. The compound (366 mg, 98.1%) was obtained as a colorless oil.
Retention time (condition 1): Z form (Cis form) 28.48 minutes, E form (Trans form) 31.01 minutes

３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］アクリル酸ベンジル
３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ベンジル（９３９ｍｇ、３．１５ｍｍｏｌ）のアセトニトリル（１５ｍＬ）溶液に、トリメチルアミン塩酸塩（８２．６ｍｇ，０．３２ｍｍｏｌ）およびトリエチルアミン（８７３ｍＬ，６．３０ｍｍｏｌ）を加え、氷浴で冷却して内温５℃以下でベンゼンスルホニルクロライド（６６７ｍｇ, ３．７８ｍｍｏｌ）を少しずつ加え、反応混合物を内温５℃以下で４時間攪拌した。内温10℃以下で５％重曹水（７．５ｍＬ）を加え、室温に昇温してからトルエン(７．５ｍＬ)を加えて分液し、水層をトルエン(７．５ｍＬ)で再抽出した。全有機層を１％硫酸水素カリウム水溶液（３．８ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去することで標記化合物（１．６４ｇ，定量的）を無色油状物として得た。
保持時間（条件１）：Ｚ体（Ｃｉｓ体）３７．１６分、Ｅ体（Ｔｒａｎｓ体）３９．３０分

3- [4- (2-Benzenesulfonyloxyethyl) phenoxy] benzyl acrylate 3- [4- (2-hydroxyethyl) phenoxy] benzyl acrylate (939 mg, 3.15 mmol) was added to a solution of trimethylamine in acetonitrile (15 mL). Hydrochloride (82.6 mg, 0.32 mmol) and triethylamine (873 mL, 6.30 mmol) were added, cooled in an ice bath and benzenesulfonyl chloride (667 mg, 3.78 mmol) was added little by little at an internal temperature of 5 ° C. or less. The reaction mixture was stirred at an internal temperature of 5 ° C. or lower for 4 hours. Add 5% sodium bicarbonate water (7.5 mL) at an internal temperature of 10 ° C or lower, raise the temperature to room temperature, add toluene (7.5 mL) to separate, and re-extract the aqueous layer with toluene (7.5 mL). did. The whole organic layer was washed with 1% aqueous potassium hydrogen sulfate solution (3.8 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.64 g, quantitative) as a colorless oil. It was.
Retention time (condition 1): Z form (Cis form) 37.16 minutes, E form (Trans form) 39.30 minutes

３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］プロピオン酸
３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］アクリル酸ベンジル（７１８ｍｇ，１．６４ｍｍｏｌ）の酢酸エチル（７．２ｍＬ）溶液中、１０%パラジウム炭素（１４４ｍｇ）を用いて室温で３時間常圧水素添加反応を行った。触媒をろ去し、ろ液を減圧濃縮することで濃縮残渣（７２０ｍｇ）を得た。トルエン（７．２ｍＬ）を加えて室温で１時間攪拌し、析出物をろ取し、トルエン（３ｍＬ）で洗浄し、減圧乾燥することで、標記化合物（４４４ｍｇ，７８．７％）を無色粉末として得た。
保持時間（条件１）：２７．７３分

3- [4- (2-Benzenesulfonyloxyethyl) phenoxy] propionic acid 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] benzyl acrylate (718 mg, 1.64 mmol) in ethyl acetate (7.2 mL) Atmospheric pressure hydrogenation reaction was performed at room temperature for 3 hours using 10% palladium carbon (144 mg) in the solution. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a concentrated residue (720 mg). Toluene (7.2 mL) was added and stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with toluene (3 mL), and dried under reduced pressure to give the title compound (444 mg, 78.7%) as a colorless powder. Got as.
Holding time (condition 1): 27.73 minutes

６−（２−ベンゼンスルホニルオキシエチル）−２，３−ジヒドロ−４Ｈ−クロメン−４−オン
無水トリフルオロ酢酸（４８０ｍｇ，２．２８ｍｍｏｌ）のアセトニトリル（１ｍＬ）に氷冷下、リン酸（６５．８ｍｇ，０．５７１ｍｍｏｌ）、３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］プロピオン酸（２００ｍｇ，０，５７１ｍｍｏｌ）を滴下し、室温で２時間撹拌した。反応液にトルエン（５ｍＬ）、水（２．５ｍＬ）を加えて分液し、水層をトルエン（５ｍＬ）で再抽出した。全有機層を５％炭酸カリウム水溶液（５ｍＬ）、水（５ｍＬ）で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧濃縮し、標記化合物（１９１ｍｇ，定量的）を無色粉末として得た。
保持時間（条件１）：２９．２７分
［参考例１］

6- (2-Benzenesulfonyloxyethyl) -2,3-dihydro-4H-chromen-4-one Trifluoroacetic anhydride (480 mg, 2.28 mmol) in acetonitrile (1 mL) under ice cooling with phosphoric acid (65. 8 mg, 0.571 mmol) and 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] propionic acid (200 mg, 0,571 mmol) were added dropwise and stirred at room temperature for 2 hours. Toluene (5 mL) and water (2.5 mL) were added to the reaction solution for liquid separation, and the aqueous layer was re-extracted with toluene (5 mL). The whole organic layer was washed with 5% aqueous potassium carbonate solution (5 mL) and water (5 mL), dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (191 mg, quantitative) as a colorless powder.
Retention time (condition 1): 29.27 minutes [Reference Example 1]

２−（４−オキソ−３,４−ジヒドロ−２Ｈ−クロメン−６−イル）エチル ４−メチルベンゼンスルホネート
６−（２−ヒドロキシエチル）−２，３−ジヒドロ−４Ｈ−クロメン−４−オン（10.0g、52mmol）のアセトニトリル（150 mL）溶液に、トリメチルアミン塩酸塩（497mg，5.20mmol）およびトリエチルアミン（14.4 mL, 104 mmol）を加え、氷浴で冷却して内温15℃以下でp-トルエンスルホニルクロライド（11.9 g, 62.4 mmol）を少しずつ加え、反応混合物を内温5℃以下で1.5時間攪拌した。内温10℃以下で5%重曹水（75 mL）を加え、室温に昇温してからトルエン(75 mL)を加えて分液し、水層をトルエン(75 mL)で再抽出した。全有機層を1%硫酸水素カリウム水溶液（38 mL×2）で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去することで濃縮残渣（16.61 g）を得た。トルエン（50 mL）を加えて50℃で1.5時間攪拌し、引き続き30分間で室温（20〜25℃）まで冷却した。水冷し内温20〜25℃で1時間攪拌後、析出物をろ取し、トルエン（10 mL×2）で洗浄し、減圧乾燥することで、標記化合物（10.65 g）を淡黄色粉末として得た。
融点：121−122℃
［参考例２］

2- (4-Oxo-3,4-dihydro-2H-chromen-6-yl) ethyl 4-methylbenzenesulfonate 6- (2-hydroxyethyl) -2,3-dihydro-4H-chromen-4-one ( To a solution of 10.0 g, 52 mmol) in acetonitrile (150 mL), add trimethylamine hydrochloride (497 mg, 5.20 mmol) and triethylamine (14.4 mL, 104 mmol), cool in an ice bath and p-toluene at an internal temperature of 15 ° C or lower. Sulfonyl chloride (11.9 g, 62.4 mmol) was added little by little, and the reaction mixture was stirred at an internal temperature of 5 ° C. or lower for 1.5 hours. 5% aqueous sodium hydrogen carbonate (75 mL) was added at an internal temperature of 10 ° C. or lower, the temperature was raised to room temperature, toluene (75 mL) was added to separate the solution, and the aqueous layer was re-extracted with toluene (75 mL). All organic layers were washed with 1% aqueous potassium hydrogen sulfate solution (38 mL × 2), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a concentrated residue (16.61 g). Toluene (50 mL) was added and stirred at 50 ° C. for 1.5 hours, and then cooled to room temperature (20-25 ° C.) over 30 minutes. After cooling with water and stirring at an internal temperature of 20 to 25 ° C. for 1 hour, the precipitate is collected by filtration, washed with toluene (10 mL × 2), and dried under reduced pressure to give the title compound (10.65 g) as a pale yellow powder. It was.
Melting point: 121-122 ° C
[Reference Example 2]

６−（２−{４−[４−ブロモ−３−（２−メトキシエトキシ）ベンジル]ピペリジン−１−イル}エチル）−２,３−ジヒドロ−４Ｈ−クロメン−４−オン
１）4-ブロモ-3-フルオロトルエン（25.0 g, 132 mmol）、５，５−ジメチル−１，３−ジブロモヒダントイン(18.9 g, 66.1 mmol)、アゾビスイソブチロニトリル（1.09 g, 6.64 mmol）のクロロベンゼン（400 mL）溶液を内温80-90℃で1時間攪拌した。反応混合物を氷浴で冷却後、水（200 mL）とチオ硫酸ナトリウム（33 g, 132 mmol）を加えて攪拌した。分液し、有機層を水（200 mL）で洗浄し、無水硫酸ナトリウムで乾燥後、全体が100 mL程度の体積になるまで濃縮した。そこへトリフェニルホスフィン（34.69 g, 132 mmol）とクロロベンゼン（30 mL）を加えて3時間加熱還流した。反応混合物を室温まで冷却後、析出物をろ取し、ろ上物をトルエンで洗浄後、減圧乾燥することで、（４−ブロモ−3−フルオロベンジル）(トリフェニル)ホスホニウム ブロマイド（47.0 g）を得た。

6- (2- {4- [4-Bromo-3- (2-methoxyethoxy) benzyl] piperidin-1-yl} ethyl) -2,3-dihydro-4H-chromen-4-one 1) 4-bromo -3-fluorotoluene (25.0 g, 132 mmol), 5,5-dimethyl-1,3-dibromohydantoin (18.9 g, 66.1 mmol), azobisisobutyronitrile (1.09 g, 6.64 mmol) in chlorobenzene (400 mL) The solution was stirred at an internal temperature of 80-90 ° C. for 1 hour. The reaction mixture was cooled in an ice bath, water (200 mL) and sodium thiosulfate (33 g, 132 mmol) were added and stirred. The organic layer was washed with water (200 mL), dried over anhydrous sodium sulfate, and concentrated to a total volume of about 100 mL. Triphenylphosphine (34.69 g, 132 mmol) and chlorobenzene (30 mL) were added thereto, and the mixture was heated to reflux for 3 hours. After cooling the reaction mixture to room temperature, the precipitate is collected by filtration, and the filtered product is washed with toluene and dried under reduced pressure to give (4-bromo-3-fluorobenzyl) (triphenyl) phosphonium bromide (47.0 g). Got.

2) (4-Bromo-3-fluorobenzyl) (triphenyl) phosphonium bromide (15.0 g, 28.3 mmol), 1-tert-butoxycarbonyl-4-piperidone (3.76 g, 18.9 mmol) and potassium carbonate (5.21 g, 37,7 mmol) in 2-propanol (28 mL) was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature, the salt was filtered off, toluene (300 mL) was added to the filtrate, and the mixture was washed with water (100 mL) and saturated brine (100 mL). After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. N-Hexane (107 mL) was added to the concentrated residue, heated under reflux for 1 hour, cooled to room temperature, stirred for 1 hour, and then stirred for 1 hour while cooling in an ice bath. The precipitated triphenylphosphine oxide was filtered off, washed with n-hexane, and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-[(4-bromo-3-fluorophenyl) methylidene] piperidine-1-carboxyl. The rate (8.08 g) was obtained as a yellow solid.

3) tert-butyl 4-[(4-bromo-3-fluorophenyl) methylidene] piperidine-1-carboxylate (8.08 g) with 5% platinum carbon (800 mg) in ethyl acetate (57 mL) A normal pressure hydrogenation reaction was carried out for a time. The catalyst was filtered off through Celite filtration, and the filtrate was concentrated to obtain tert-butyl 4- (4-bromo-3-fluorobenzyl) piperidine-1-carboxylate (8.61 g) as a pale yellow solid.

4) N-methyl-2-tert-butyl 4- (4-bromo-3-fluorobenzyl) piperidine-1-carboxylate (8.61 g, equivalent to 18.9 mmol), 2-methoxyethanol (2.98 mL, 37.7 mmol) Potassium t-butoxide (4.23 g, 37.7 mmol) was added to the piperidone (38 mL) solution at room temperature, and the reaction mixture was stirred at an internal temperature of 90 ° C. for 2.5 hours, and then potassium t-butoxide (1.06 g, 9.43 mmol) was added. The mixture was stirred for 30 minutes at 90 ° C., potassium t-butoxide (1.06 g, 9.43 mmol) was further added, and the mixture was stirred for 30 minutes at 90 ° C. The reaction mixture was cooled in an ice bath, saturated aqueous ammonium chloride solution (80 mL) was added, and the mixture was extracted with toluene (80 mL × 3). The whole organic layer was washed with water (40 mL × 2) and saturated brine (40 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Add n-hexane (162 mL) to the concentrated residue, heat to 60 ° C. and confirm dissolution, then slowly cool to room temperature, stir at room temperature overnight, cool in ice bath and stir for 1 hour, precipitate The product was collected by filtration, and the filtered product was washed with n-hexane and then dried under reduced pressure to give tert-butyl 4- [4-bromo-3- (2-methoxyethoxy) benzyl] piperidine-1-carboxylate ( 6.34 g) was obtained as a light brown powder.

5) 10% hydrochloric acid-methanol at room temperature in a solution of tert-butyl 4- [4-bromo-3- (2-methoxyethoxy) benzyl] piperidine-1-carboxylate (6.00 g, 14.0 mmol) in methanol (24 mL) Solution (24 mL) was added and the reaction mixture was stirred at 50 ° C. for 5 h. After cooling to room temperature, the solvent was distilled off under reduced pressure, acetonitrile (6 mL) was added to the concentrated residue, and vacuum concentration was repeated 4 times. Acetonitrile (38 mL) is added to the concentrated residue and heated in an oil bath at 80 ° C. After confirming dissolution of the solid, it is cooled to room temperature in 1 hour, cooled in a water bath and then at 20 ° C for 1 hour in an ice bath. After stirring for 1 hour, the precipitate was collected by filtration, and the filtered product was washed with cold acetonitrile (30 mL) and dried under reduced pressure to give 4- [4-bromo-3- (2-methoxyethoxy) benzyl]. Piperidine hydrochloride (4.56 g, 89%) was obtained as a white powder.

6) 4- [4-Bromo-3- (2-methoxyethoxy) benzyl] piperidine hydrochloride (52.0 g, 143 mmol) was added to 5% aqueous potassium carbonate solution (350 mL), and toluene (700 mL × 3) was added. Extracted. All organic layers were dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 4- [4-bromo-3- (2-methoxyethoxy) benzyl] piperidine (48.1 g). Next, 4- [4-bromo-3- (2-methoxyethoxy) benzyl] piperidine (2.00 g, 6.1 mmol), 2- (4-oxo-3,4-dihydro-2H-chromene-6- Yl) ethyl A solution of 4-methylbenzenesulfonate (2.01 g, 5.8 mmol) and potassium carbonate (1.66 g, 12 mmol) in acetonitrile (20 mL) was stirred at 70-80 ° C. for 7 hours. After cooling to room temperature, water (100 mL) was added, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the resulting concentrated residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → chloroform: methanol = 20: 1) to give the title compound (3.07 g, Quantitative).
¹ H-NMR (300 MHz, CDCl ₃ ) δ: 1.24-1.39 (2H, m), 1.40-1.73 (3H, m), 1.93 (2H, t, J = 10.6 Hz), 2.40-2.61 (2H, m ), 2.48 (2H, d, J = 7.2 Hz), 2.66-2.87 (2H, m), 2.79 (2H, t, J = 6.4 Hz), 2.95 (2H, d, J = 11.7 Hz), 3.49 (3H , s), 3.81 (2H, t, J = 4.9 Hz), 4.17 (2H, t, J = 4.9 Hz), 4.51 (2H, t, J = 6.4 Hz), 6.64 (1H, dd, J = 8.1, 1.8 Hz), 6.71 (1H, d, J = 1.8 Hz), 6.89 (1H, d, J = 8.4 Hz), 7.32 (1H, dd, J = 8.4, 2.2 Hz), 7.41 (1H, d, J = 8.1 Hz), 7.70 (1H, d, J = 2.2 Hz).
[Reference Example 3]

6- (2- {4- [4-Bromo-3- (2-methoxyethoxy) benzyl] piperidin-1-yl} ethyl) -2,3-dihydro-4H-chromen-4-one hydrochloride

参考例２で得た化合物（３．０７g , ５．８ mmol)の２−プロパノール（２０mL）溶液に室温で濃塩酸水溶液（３６%, ７６０μL, ８．５ mmol）を加え、溶液を室温で１５．５時間攪拌した。析出物をろ取し、ろ上物を２−プロパノール（２mＬ×２）で洗浄し、減圧乾燥することで、標記化合物（２．２６ｇ, ７２％）を白色粉末として得た。
融点：156-157℃
［参考例４］

To a solution of the compound obtained in Reference Example 2 (3.07 g, 5.8 mmol) in 2-propanol (20 mL) was added concentrated aqueous hydrochloric acid (36%, 760 μL, 8.5 mmol) at room temperature, and the solution was stirred at room temperature for 15 Stir for 5 hours. The precipitate was collected by filtration, and the filtered product was washed with 2-propanol (2 mL × 2) and dried under reduced pressure to obtain the title compound (2.26 g, 72%) as a white powder.
Melting point: 156-157 ° C
[Reference Example 4]

[2-Bromo-5-({1- [2- (4-oxo-3,4-dihydro-2H-chromen-6-yl) ethyl] piperidin-4-yl} methyl) phenoxy] acetic acid hydrochloride 1) A solution of 4- [4-bromo-3- (2-methoxyethoxy) benzyl] piperidine hydrochloride (5.00 g, 13.8 mmol) in dichloromethane (100 mL) was ice-cooled, and boron tribromide ( 1.0 M-dichloromethane solution, 55 mL, 55 mmol) was added dropwise over 35 minutes, and the reaction mixture was stirred for 1 day while slowly warming up. The reaction solution was ice-cooled, methanol (20 mL) was added dropwise over 20 minutes, and the solvent was evaporated under reduced pressure. 10% aqueous potassium carbonate solution (100 mL) and 1,4-dioxane (100 mL) were added to the resulting concentrated residue without purification, and di-tert-butyl dicarbonate (3.00 g, 13 mL) was added to the mixed solution at room temperature. .8 mmol) in 1,4-dioxane (20 mL) was added dropwise over 30 minutes. After stirring the reaction mixture at room temperature for 21 hours, 1,4-dioxane was distilled off under reduced pressure, and the concentrated residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the resulting concentrated residue was added a mixed solution (20 mL) of n-hexane-ethyl acetate (2: 1), and the resulting precipitate was collected by filtration, and mixed solution (5: 1) of n-hexane-ethyl acetate (2: 1). After washing with mL × 2) and drying under reduced pressure, tert-butyl 4- (4-bromo-3-hydroxybenzyl) piperidine-1-carboxylate (4.25 g, 83%) was obtained.

2) A solution of tert-butyl 4- (4-bromo-3-hydroxybenzyl) piperidine-1-carboxylate (3.50 g, 9.49 mmol) and potassium carbonate (2.62 g, 19 mmol) in acetonitrile (70 mL) To the mixture was added bromoacetic acid t-butyl ester (1.35 mL, 9.96 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. Water (200 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The obtained concentrated residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give tert-butyl 4- [4-bromo-3- (2-tert-butoxy-2-oxoethoxy). )] Benzyl] piperidine-1-carboxylate (4.24 g, 92%) was obtained as a white powder.

3) tert-butyl 4- [4-bromo-3- (2-tert-butoxy-2-oxoethoxy) benzyl] piperidine-1-carboxylate (4.20 g, 8.96 mmol) of 1,4-dioxane ( To the solution was added 4N-hydrochloric acid-1,4-dioxane solution (40 mL) at room temperature while cooling with water, and the reaction mixture was stirred at room temperature for 20 minutes. The solution was poured little by little into a solution of sodium hydrogen carbonate (20 g) in water (200 mL) and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain tert-butyl [2-bromo-5- (piperidin-4-ylmethyl) phenoxy] acetate (2.34 g, 70%) as a white solid. Obtained.

4) tert-butyl [2-bromo-5- (piperidin-4-ylmethyl) phenoxy] acetate (2.30 g, 6.0 mmol), 2- (4-oxo-3,4-dihydro-2H-chromene-6 -Il) ethyl A solution of 4-methylbenzenesulfonate (1.97 g, 5.7 mmol) and potassium carbonate (1.57 g, 11 mmol) in acetonitrile (25 mL) was stirred at 55-60 ° C for 19.5 hours. After cooling to room temperature, water (100 mL) was added, extracted with chloroform, and the chloroform layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the resulting concentrated residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → chloroform: methanol = 20: 1), whereby tert-butyl [2-bromo -5-({1- [2- (4-oxo-3,4-dihydro-2H-chromen-6-yl) ethyl] piperidin-4-yl} methyl) phenoxy] acetate (3.51 g, quantitative) Got.

5) tert-butyl [2-bromo-5-({1- [2- (4-oxo-3,4-dihydro-2H-chromen-6-yl) ethyl] piperidin-4-yl} methyl) phenoxy] To acetate (3.50 g, 6.8 mmol) was added 4N-hydrochloric acid-1,4-dioxane solution (35 mL), and the reaction mixture was stirred at 50 ° C. for 1.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, acetone (35 mL) was added to the concentrated residue, and the resulting precipitate was collected by filtration and washed with acetone (5 mL × 2) to give a crude product of the title compound (2. 34 g) was obtained. The crude product was added to acetone (50 mL), heated under reflux for 1 hour, cooled to room temperature in 1.5 hours, stirred at 20 ° C. for 1 hour, the precipitate was collected by filtration, and washed with acetone (5 mL × 2). This gave the title compound (2.20 g, 60%) as a white powder.
Melting point: 163-166 ° C
[Reference Example 5]

プロピオル酸ベンジル
炭酸カリウム（18.59 g, 134.48 mmol）にジメチルホルムアミド（80.00 g）を加えて懸濁液とし、さらにプロピオル酸（9.42 g, 134.48 mmol）のジメチルホルムアミド（5.00 g）溶液を氷冷下にて加えた。10分撹拌後、ベンジルブロミド（20.00 g, 116.94 mmol）のジメチルホルムアミド（5.00 g）溶液を加え、30℃で加熱攪拌を行った。4時間後、氷冷下で水を加え、再び30℃に昇温し、酢酸エチル（100 g）で抽出を行った。有機層を分離後、5% 食塩水、続いて8% 食塩水で洗浄し、濃縮することで黄色油状物として標記化合物（18.73g, 116.94 mmol）を得た。
¹H-NMR (400MHz，CDCl₃) δ：7.42-7.35 (5H, m), 5.24 (2H, s), 2.91 (1H, s).

Benzyl propiolate Potassium carbonate (18.59 g, 134.48 mmol) was added with dimethylformamide (80.00 g) to make a suspension, and a solution of propiolic acid (9.42 g, 134.48 mmol) in dimethylformamide (5.00 g) was cooled with ice. Added. After stirring for 10 minutes, a solution of benzyl bromide (20.00 g, 116.94 mmol) in dimethylformamide (5.00 g) was added, and the mixture was heated and stirred at 30 ° C. After 4 hours, water was added under ice cooling, the temperature was raised again to 30 ° C., and extraction was performed with ethyl acetate (100 g). The organic layer was separated, washed with 5% brine, then 8% brine, and concentrated to give the title compound (18.73 g, 116.94 mmol) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.42-7.35 (5H, m), 5.24 (2H, s), 2.91 (1H, s).

３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ベンジル
２−（４−ヒドロキシルフェニル）エタノール（19.39 g, 140.33 mmol）に酢酸エチル（112.38 g）を加え、さらにＮ−メチルモルホリン（1.18 g, 11.69 mmol）および水（4.78 g）を加えた。プロピオル酸ベンジル（18.73g, 116.94 mmol）の酢酸エチル（100.00 g）溶液を加え、30℃で過熱攪拌を行った。2時間後、8%食塩水（187.30 g）を加え、攪拌後水層を分離した。有機層を濃縮後、トルエン（74.92 g）を加え、水洗（187.30 g）を３回行った。有機層を濃縮することで、淡黄色液体として標記化合物（34.89 g, 116.94 mmol）を得た。
¹H-NMR (400MHz，CDCl₃) δ：7.83 (1H, d, J = 12.2 Hz), 7.44-7.33 (5H, m), 7.25 (2H, d, J = 8.6 Hz), 7.03 (2H, d, J = 8.6 Hz), 5.59 (1H, d, J = 12.2 Hz), 3.89-3.85 (2H, m), 2.87 (2H, t, J = 6.5 Hz).

Ethyl acetate (112.38 g) was added to 2- [4- (2-hydroxyethyl) phenoxy] acrylic acid benzyl 2- (4-hydroxylphenyl) ethanol (19.39 g, 140.33 mmol), and N-methylmorpholine (1.18 g) was added. 11.69 mmol) and water (4.78 g) were added. A solution of benzyl propiolate (18.73 g, 116.94 mmol) in ethyl acetate (100.00 g) was added, and the mixture was stirred with heating at 30 ° C. After 2 hours, 8% brine (187.30 g) was added, and the aqueous layer was separated after stirring. After concentrating the organic layer, toluene (74.92 g) was added, followed by washing with water (187.30 g) three times. The organic layer was concentrated to obtain the title compound (34.89 g, 116.94 mmol) as a pale yellow liquid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.83 (1H, d, J = 12.2 Hz), 7.44-7.33 (5H, m), 7.25 (2H, d, J = 8.6 Hz), 7.03 (2H, d , J = 8.6 Hz), 5.59 (1H, d, J = 12.2 Hz), 3.89-3.85 (2H, m), 2.87 (2H, t, J = 6.5 Hz).

３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］アクリル酸ベンジル
３−［４−（２−ヒドロキシエチル）フェノキシ］アクリル酸ベンジル（34.89 g, 116.94 mmol）にトルエン（296.53 g）、トリエチルアミン (17.75 g, 175.41 mmol)、N-メチルイミダゾール（0.96 g, 11.69 mmol）、N,N,N',N'-テトラメチルエチレンジアミン（1.36 g, 11.69 mmol）を加え、5℃に冷却した。ベンゼンスルホニルクロライド（24.78 g, 140.33 mmol）のトルエン（17.44 g）溶液を滴下し、15℃で攪拌を行った。3時間後、水（348.86 g）を加え、40℃で4時間加熱攪拌を行った。水層を分離後、25℃に冷却し、1.0%硫酸水素カリウム水溶液（348.86 g）、及び水（348.86 g）で洗浄し、濃縮することで、無色油状物として標記化合物（51.28 g, 116.94 mmol）を得た。
¹H-NMR (400MHz，CDCl₃) δ：7.82 (2H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, d, J = 12.2 Hz), 7.62 (1H, tt, J = 1.2, 7.5 Hz), 7.50 (2H, dd, J = 7.5, 8.1 Hz), 7.39-7.32 (5H, m), 7.12 (2H, d, J = 8.6 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.58 (1H, d, J = 12.2 Hz), 5.20 (2H, s), 4.24 (2H, t, J = 6.8 Hz), 2.96 (2H, t, J = 6.8 Hz).

Benzyl 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] acrylate 3- [4- (2-hydroxyethyl) phenoxy] benzyl acrylate (34.89 g, 116.94 mmol) and toluene (296.53 g), triethylamine ( 17.75 g, 175.41 mmol), N-methylimidazole (0.96 g, 11.69 mmol), N, N, N ′, N′-tetramethylethylenediamine (1.36 g, 11.69 mmol) were added, and the mixture was cooled to 5 ° C. A toluene (17.44 g) solution of benzenesulfonyl chloride (24.78 g, 140.33 mmol) was added dropwise, and the mixture was stirred at 15 ° C. Three hours later, water (348.86 g) was added, and the mixture was heated and stirred at 40 ° C. for 4 hours. The aqueous layer was separated, cooled to 25 ° C., washed with 1.0% aqueous potassium hydrogen sulfate solution (348.86 g) and water (348.86 g), and concentrated to give the title compound (51.28 g, 116.94 mmol) as a colorless oil. )
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.82 (2H, dd, J = 1.2, 8.1 Hz), 7.79 (1H, d, J = 12.2 Hz), 7.62 (1H, tt, J = 1.2, 7.5 Hz ), 7.50 (2H, dd, J = 7.5, 8.1 Hz), 7.39-7.32 (5H, m), 7.12 (2H, d, J = 8.6 Hz), 6.95 (2H, d, J = 8.6 Hz), 5.58 (1H, d, J = 12.2 Hz), 5.20 (2H, s), 4.24 (2H, t, J = 6.8 Hz), 2.96 (2H, t, J = 6.8 Hz).

３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］プロピオン酸
３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］アクリル酸ベンジル（51.28 g, 116.94 mmol）にテトラヒドロフラン（333.29 g）、10%パラジウム炭素（50 wet% w/w）（15.38 g）を加え、水素雰囲気下、室温で激しく攪拌を行った。反応溶液を濾過して10%パラジウム炭素を除去後、濃縮を行った。残渣にトルエン（615.31 g）、テトラヒドロフラン（66.66 g）を加え、70℃で加熱攪拌を行った。30分後から徐々に冷却し、0℃で1時間保温後、濾過することで白色固体として標記化合物（31.5 g, 89.90 mmol）を得た。
¹H-NMR (400MHz，CDCl₃) δ：7.82 (2H, dd, J = 1.2, 8.1 Hz), 7.63 (1H, tt, J = 1.2, 7.5 Hz), 7.50 (2H, dd, J = 7.5, 8.1 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 4.23 (2H, t, J = 6.2 Hz), 4.20 (2H, t, J = 7.0 Hz), 2.91 (2H, t, J = 7.0 Hz), 2.84 (2H, t, J = 6.2 Hz).

3- [4- (2-Benzenesulfonyloxyethyl) phenoxy] propionic acid 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] benzyl acrylate (51.28 g, 116.94 mmol) in tetrahydrofuran (333.29 g), 10 % Palladium on carbon (50 wet% w / w) (15.38 g) was added, and the mixture was vigorously stirred at room temperature in a hydrogen atmosphere. The reaction solution was filtered to remove 10% palladium on carbon and then concentrated. Toluene (615.31 g) and tetrahydrofuran (66.66 g) were added to the residue, and the mixture was heated and stirred at 70 ° C. After 30 minutes, the mixture was gradually cooled, kept at 0 ° C. for 1 hour, and filtered to obtain the title compound (31.5 g, 89.90 mmol) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.82 (2H, dd, J = 1.2, 8.1 Hz), 7.63 (1H, tt, J = 1.2, 7.5 Hz), 7.50 (2H, dd, J = 7.5, 8.1 Hz), 7.06 (2H, d, J = 8.6 Hz), 6.80 (2H, d, J = 8.6 Hz), 4.23 (2H, t, J = 6.2 Hz), 4.20 (2H, t, J = 7.0 Hz) ), 2.91 (2H, t, J = 7.0 Hz), 2.84 (2H, t, J = 6.2 Hz).

６−（２−ベンゼンスルホニルオキシエチル）−２，３−ジヒドロ−４Ｈ−クロメン−４−オン
３−［４−（２−ベンゼンスルホニルオキシエチル）フェノキシ］プロピオン酸（30.00 g, 85.62 mmol）をトルエン（300.00g）に溶解し、室温で無水トリフルオロ酢酸（26.97g）を室温にて加えた。30分撹拌後、リン酸（0.84 g, 8.56mmol）を加えさらに3時間撹拌した。水（150.00 g）を加えた後、有機層を５％炭酸水素ナトリウム水、続いて水で洗浄した。有機層を濃縮し、濃縮残渣をイソプロパノール（216 g）および、水（54 g）の混合液に45℃で溶解した。25℃まで冷却した後、水（600 g）を加え、さらに5℃まで冷却した。析出した固体をろ取・乾燥することで標記化合物（27.78 g, 97.6%）を得た。
¹H-NMR (400MHz，CDCl₃) δ：7.83 (2H, dd, J = 1.2 Hz, 7.4 Hz), 7.64 (1H, tt, J = 1.2 Hz, 7.4 Hz), 7.61 (1H, d, J = 2.3 Hz), 7.53 (2H, t, J = 7.4Hz), 7.27 (1H, dd, J = 2.3 Hz, 8.5 Hz), 6.90 (1H, d, J = 8.5 Hz), 4.53 (2H, t, J = 6.5 Hz), 4.22 (2H, t, J = 6.8 Hz), 2.93 (2H, t, J = 6.8 Hz), 2.80 (2H, t, J = 6.5 Hz).

6- (2-Benzenesulfonyloxyethyl) -2,3-dihydro-4H-chromen-4-one 3- [4- (2-Benzenesulfonyloxyethyl) phenoxy] propionic acid (30.00 g, 85.62 mmol) in toluene (300.00 g) and trifluoroacetic anhydride (26.97 g) was added at room temperature at room temperature. After stirring for 30 minutes, phosphoric acid (0.84 g, 8.56 mmol) was added, and the mixture was further stirred for 3 hours. After adding water (150.00 g), the organic layer was washed with 5% aqueous sodium bicarbonate followed by water. The organic layer was concentrated, and the concentrated residue was dissolved in a mixture of isopropanol (216 g) and water (54 g) at 45 ° C. After cooling to 25 ° C., water (600 g) was added and further cooled to 5 ° C. The precipitated solid was collected by filtration and dried to obtain the title compound (27.78 g, 97.6%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.83 (2H, dd, J = 1.2 Hz, 7.4 Hz), 7.64 (1H, tt, J = 1.2 Hz, 7.4 Hz), 7.61 (1H, d, J = 2.3 Hz), 7.53 (2H, t, J = 7.4 Hz), 7.27 (1H, dd, J = 2.3 Hz, 8.5 Hz), 6.90 (1H, d, J = 8.5 Hz), 4.53 (2H, t, J = 6.5 Hz), 4.22 (2H, t, J = 6.8 Hz), 2.93 (2H, t, J = 6.8 Hz), 2.80 (2H, t, J = 6.5 Hz).

Test Example 1: in order to assess the inhibitory action Human serotonin reuptake ^{[3 H] citalopram binding ([} 3 H] citalopram binding) Screening Test 1-1 using cells and membrane preparation Human serotonin preparation experiments using CHO cells (h-SERT / CHO) in which a transporter (h-SERT) was expressed were used. Cells are cultured in F12 (all made by Sigma Aldrich) containing 10% FCS, 500 μg / ml Geneticin and 100 U / ml penicillin (penicillin) -100 μg / ml streptmycin (all from Sigma Aldrich) in a 5% CO ₂ incubator. (SERT buffer) (50 mM Tris-HCl (pH = 7.4) containing 120 mM NaCl and 5 mM KCl) The cells detached and collected were homogenized with a Teflon (registered trademark) homogenizer, and then centrifuged (50,000 × g, 30 min, 4 ° C.). The sediment was resuspended in an appropriate amount of SERT buffer and stored at −80 ° C. until use. The amount of protein in the membrane preparation was quantified by Dye Reagent Concentrate (manufactured by BIO-RAD) using bovine serum albumin (manufactured by Sigma Aldrich) as a standard substance.
1-2 Receptor binding experiment
[ ³ H] citalopram binding was measured according to the method of Owens et al. [Owens MJ et al., J. Pharm. Exp. Ther., 283, 1305-1322 (1997)]. That is, add 50 μl of [ ³ H] citalopram (final concentration about 2 nM) diluted with SERT buffer, 149 μl of h-SERT / CHO membrane preparation (40 μg / well as the amount of protein), and 1 μl of the test drug solution dissolved in dimethylsulfoxide The total volume was 200 μl. This solution was allowed to react at room temperature for 60 minutes, and then quickly subjected to low-pressure suction filtration using glass fiber filter paper coated with 0.05% polyethyleneimine aqueous solution. The glass fiber filter paper was washed twice with 250 μl of SERT buffer, then transferred to a glass vial containing 4 ml of ACS-II (Amersham), and the radioactivity remaining on the filter paper was measured using a liquid scintillation counter. Nonspecific binding of [ ³ H] citalopram was defined as the amount of binding in the presence of 1 μM clomipramine.
IC ₅₀ value was calculated by Hill analysis [see Hill AV, J. Physiol., 40, 190-200 (1910)], and h-SERT binding inhibition constant (Ki) was calculated using the formula:
h-SERT binding inhibition constant (Ki) = IC ₅₀ / (1 + S / Kd)
[S represents the added [ ³ H] citalopram concentration. The Kd value is the binding dissociation constant of [ ³ H] citalopram, and a value (2.16 nM) calculated from a saturation binding experiment separately performed using the same cell membrane was used. ]
Calculated by A smaller h-SERT binding inhibition constant Ki value means a higher human serotonin reuptake inhibitory action.

Test Example 2: [ ³ H] 8-OH-DPAT binding test 2-1 for evaluating affinity for human serotonin 1A receptor Preparation of cells and membrane preparation Human serotonin 1A receptor (h- CHO cells (h-5-HT _1A / CHO) in which 5-HT _1A was expressed were used. Cells were cultured in F12 (all from Sigma Aldrich) containing 10% FCS, 500 μg / ml Geneticin and 100 U / ml penicillin-100 μg / ml streptmycin in a 5% CO ₂ incubator, and the membrane preparation was the method of Yabuuchi et al. [Yabuuchi K. et al., Biogenic Amines, 18, 319-328 (2004)]. That is, the cells detached and collected with 50 mM Tris-HCl (pH = 7.4) were homogenized with a Teflon (registered trademark) homogenizer, and then centrifuged (48,000 × g, 20 min, 4 ° C.). The sediment was resuspended in an appropriate amount of 50 mM Tris-HCl (pH = 7.4) and stored at −80 ° C. until use. The amount of protein in the membrane preparation was quantified by Dye Reagent Concentrate (manufactured by BIO-RAD) using bovine serum albumin (manufactured by Sigma Aldrich) as a standard substance.
2-2 Receptor binding experiment The experiment was performed according to the method of Yabuuchi et al. [Yabuuchi K. et al., Biogenic Amines, 18, 319-328 (2004)]. In a buffer containing 50 mM Tris-HCl (pH = 7.4) and 4 mM CaCl ₂ , [ ³ H] 8-OH-DPAT (final concentration 0.5 nM) 50 μl, test drug solution 1 μl, h-5-HT 149 μl of _1A / CHO membrane preparation (25 μg / well as protein mass) was added, and the total amount was measured using a 200 μl reaction solution. The reaction solution was reacted at room temperature for 30 minutes, and then quickly filtered under low pressure with suction onto a glass fiber filter paper. The glass fiber filter paper was washed twice with 250 μl of 50 mM Tris-HCl (pH = 7.4), and then added to a counting vial containing 4 ml of ACS-II (Amersham), and the receptor-bound radioactivity remaining on the filter paper was observed. Measured with a liquid scintillation counter. Nonspecific binding was defined as the amount of binding in the presence of 10 μM 8-OH-DPAT.
IC ₅₀ value was calculated by Hill analysis [see Hill AV, J. Physiol., 40, 190-200 (1910)], and h-5-HT _1A binding inhibition constant (Ki) was calculated using the formula:
h-5-HT _1A binding inhibition constant (Ki) = IC ₅₀ / (1 + S / Kd)
[S represents the concentration of [ ³ H] 8-OH-DPAT added. The Kd value is the binding dissociation constant of [ ³ H] 8-OH-DPAT, and a value (1.28 nM) calculated from a saturation binding experiment conducted separately using the same cell membrane was used. ]
Calculated by The smaller the value of the h-5-HT _1A binding inhibition constant Ki value, the higher the affinity for the human serotonin 1A receptor.

When the test of the above Test Examples 1 and 2 was performed on the compound of Reference Example 2, the h-SERT binding inhibition constant (Ki) and h-5-HT _1A binding inhibition constant (Ki) of the compound of Reference Example 2 were They were 0.79 nM and 4.2 nM, respectively. From these test results, it was revealed that the compound of Reference Example 2 has not only a human serotonin reuptake inhibitory action and a binding affinity for human 5-HT1A receptor, but also a high human serotonin reuptake inhibitory action. .

Test Example 3: CYP2D6 Inhibition Screening Test 3-1 Materials Bufuralol hydrochloride was purchased from Toronto Research Chemicals Inc. and Pooled of Human Liver Microsomes was purchased from Xenotech, LLC.
3-2-1 Preparation of 0.5 M potassium phosphate buffer (pH 7.4)
The mixture was adjusted to pH 7.4 by mixing 150 mL of 0.5 M monopotassium phosphate solution and 700 mL of 0.5 M dipotassium phosphate solution.
3-2-2 Preparation of 165 mM Magnesium Chloride Solution Magnesium chloride hexahydrate (MgCl ₂ · 6H ₂ O) was dissolved in pure water to give 3.35 g / 100 mL.
3-2-3 Preparation of human liver microsome solution
It was prepared by mixing 150 μL of Pooled of Human Liver Microsomes (20 mg / ml), 12 mL of 0.5 M potassium phosphate buffer, 1.2 mL of 165 mM magnesium chloride solution and 34.65 mL of pure water.
3-2-4 Preparation of 13 mM β-NADPH solution β-NADPH was dissolved in pure water to 11.75 mg / mL.
3-2-5 Preparation of Substrate Solution Bufulalol was dissolved in DMSO to 1.0 mM, and then diluted 20 times with pure water.
3-3 Experimental method A 10 mM DMSO solution of a test drug was diluted four times with DMSO four times to prepare 10, 2, 0.4, and 0.08 mM DMSO solutions.
2. The test drug solution of 1. and DMSO were diluted 160-fold with a human liver microsome solution and dispensed into microplates in 80 μL aliquots.
3. 10 μL of substrate solution and 10 μL of β-NADPH solution were added to 2. and incubated at 37 ° C. for 10 min.
4). 300 μL of methanol was added to stop the reaction.
5. The reaction mixture was filtered and analyzed by LC-MSMS.
3-4 Determination and calculation
The amount of 1′-hydroxybufuralol produced was quantified by LC-MSMS, and this was defined as the activity value of CYP2D6 in each well. Compared with the activity of wells using DMSO as a test drug, the residual activity of each sample addition group was determined, and the IC ₅₀ value of CYP2D6 inhibition was determined from the test drug concentration. IC ₅₀ value was calculated from a straight line connecting two points sandwiching 50% of the residual activity. The larger the value of an IC ₅₀ value of CYP2D6 inhibition means CYP2D6 inhibition is weak.

Test example 4: CYP2D6 contribution screening test in human liver microsome metabolism Final concentration of 3 mM NADPH (manufactured by Oriental Yeast Co., Ltd.), 1 mg / mL human liver microsome (manufactured by XENOTECH, LLC), and 0.2 mL containing 1 μM test substance The metabolic reaction was carried out by heating 50 mM potassium phosphate buffer (pH 7.4) on a 37 ° C. water bath. After reacting for 15 or 30 minutes, the reaction was stopped by adding 3 volumes of methanol to the reaction solution and stirring. The reaction solution was centrifuged to precipitate the protein, and the supernatant was collected and subjected to LC-MS / MS analysis. The results were analyzed as follows.
The test substance was quantified, the time course of the residual amount was logarithmically plotted, and the metabolic rate was calculated from the slope.
The ratio of the metabolic rate when added to the metabolic rate when the final concentration of 4 μM quinidine was not added to the reaction solution was defined as the contribution rate of enzymes other than CYP2D6, and the remainder was defined as the contribution rate of CYP2D6. That is, the formula:
Contribution rate (%) = {1- (metabolic rate [with quinidine added] / metabolic rate [without quinidine added])} × 100
Calculated by The smaller the numerical value of the contribution rate of CYP2D6, the smaller the contribution of CYP2D6.

When the compounds of Reference Example 2 were tested in Test Examples 3 and 4, the CYP2D6 inhibition (IC ₅₀ ) and CYP2D6 contribution ratio of the compound of Reference Example 2 were 22.9 μM and 0%, respectively. From these test results, it was clarified that the compound of Reference Example 2 has weak CYP2D6 inhibition and a small contribution of CYP2D6 in metabolism.

  The compound represented by the formula (3) and pharmaceutically acceptable salts thereof are novel compounds, have an affinity for the serotonin 1A receptor, improve human serotonin reuptake inhibitory activity, and human cytochrome P450 molecular species Is a new serotonin reuptake inhibitor that has a weak inhibitory effect on CYP2D6, or a small contribution of CYP2D6 in human drug metabolism. For example, for diseases such as depression and anxiety (anxiety disorder), It can be used as a novel therapeutic or prophylactic agent with high therapeutic effect and high safety. Therefore, the compound represented by the formula (1) is a compound useful as an intermediate of the novel therapeutic agent represented by the formula (3).

Claims (6)

Compound represented by formula (1):

[In the formula, a broken line represents a single bond or a double bond,
(I) when the broken line is a double bond,
R ¹ represents a hydrogen atom, an ethyl group or a substituted or unsubstituted benzenesulfonyl group,
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a substituted or unsubstituted benzyl group; or R ¹ represents a methyl group ,
R ² represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a substituted or unsubstituted benzyl group;
(Ii) when the broken line is a single bond,
R ¹ represents a hydrogen atom,
R ² represents a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents a methyl group,
R ² represents a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group;
R ¹ represents an ethyl group or a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or a substituted or unsubstituted benzyl group; or R ¹ represents a substituted group Represents a benzenesulfonyl group,
R ² represents a hydrogen atom, a methyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, or a substituted or unsubstituted benzyl group. ]. The compound according to claim 1, wherein R ² is a hydrogen atom, a tert-butyl group or a benzyl group. The compound according to claim 1, wherein R ¹ is a hydrogen atom, a benzenesulfonyl group or a p-toluenesulfonyl group. The compound represented by the formula (1) is
Tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] propionate,
3- [4- (2-hydroxyethyl) phenoxy] ethyl acrylate,
Tert-butyl 3- [4- (2-hydroxyethyl) phenoxy] acrylate,
3- [4- (2-hydroxyethyl) phenoxy] benzyl acrylate,
3- [4- (2-benzenesulfonyloxyethyl) phenoxy] benzyl acrylate,
Or 3- [4- (2-benzenesulfonyloxyethyl) phenoxy] propionic acid,
The compound of claim 1, wherein From the compound according to claim 1, by the method represented by the following (a), (b), (c) or (d), formula (2):

[Wherein, R ¹ represents a hydrogen atom, a methyl group, an ethyl group, or a substituted or unsubstituted benzenesulfonyl group. ]
A method for producing a compound represented by:
(A) A method of reacting a compound represented by formula (1), wherein the broken line is a single bond and R ² is a tert-butyl group, with trifluoroacetic anhydride;
(B) In the compound represented by formula (1), the broken line is a single bond, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, or a substituted or non-substituted group. A method in which a compound having a substituted benzyl group is converted to a compound in which R ² is a hydrogen atom, and then reacted with trifluoroacetic anhydride;
(C) In the compound represented by the formula (1), a compound in which the broken line is a double bond and R ² is a tert-butyl group is converted into a compound in which the broken line is a single bond, and then trifluoroacetic anhydride A method of reacting with
(D) In the compound represented by the formula (1), the broken line is a double bond, and R ² is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group or substituted or A method in which a compound having an unsubstituted benzyl group is converted to a compound in which a broken line is a single bond and R ² is a hydrogen atom, and then reacted with trifluoroacetic anhydride.   The production method according to claim 5, wherein the reaction with trifluoroacetic anhydride is carried out in the presence of an acid.