Vitamin D3-like compounds

Abstract

Provided is a novel vitamin D3-like compound.　A compound according to the present invention is represented by formula (1). In the formula, m and n are independently 0 or 1, p is an integer of 0-4, and s is an integer of 0-4. Y represents an oxygen atom, a sulfur atom, or a divalent group represented by -NR6-. R1 represents a predetermined monovalent aliphatic hydrocarbon group. R2 represents a predetermined alkyl group, a hydroxyl group, a predetermined alkoxy group, or a halogen atom. R3 represents a predetermined divalent aliphatic hydrocarbon group which may have a substituent and may contain a heteroatom in a carbon chain. R4 represents a predetermined monovalent aliphatic hydrocarbon group. R5 represents a hydrogen atom, a hydroxyl group, a predetermined alkoxy group which may have a substituent, or a predetermined monovalent aliphatic hydrocarbon group which may have a substituent. R6 represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. R7 and R8 both represent a hydrogen atom, or are integrated to represent a methylidene group.

Description

[Technical Field]

[0001] This invention relates to a novel vitamin D3-like compound. [Background technology]

[0002] Active vitamin D3 derivatives have the effect of promoting calcium absorption in the small intestine and regulating bone resorption and bone formation in the bones, and are used as a treatment for osteoporosis. They also have an inhibitory effect on the secretion of parathyroid hormone (PTH) and are used to treat secondary hyperparathyroidism characterized by elevated PTH levels. Furthermore, in addition to these effects, immunomodulatory, cell proliferation inhibitory, and cell differentiation-inducing effects have been found, and their application as a treatment for diseases such as cancer, psoriasis, rheumatoid arthritis, diabetes mellitus, hypertension, acne, eczema, and dermatitis is being investigated.

[0003] Thus, active vitamin D3 derivatives are useful in treating various diseases, and various forms of derivatives have been produced over time (see, for example, Non-Patent Documents 1 and 2).

[0004] Incidentally, a known method for producing vitamin D3 derivatives involves using vitamin D2, which has the structure shown in formula (A) below, as a starting material, cleaving the wavy-lined portion to obtain the common natural-type C and D rings, and then derivatizing the lower ring and side chains to these.

[0005] [ka] [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Maestro et al.,J.Med.Chem.,2019,62,6854-6875 [Non-Patent Document 2] Gogoi et al.,J.Med.Chem.,2018,61,4928-4937 [Overview of the project] [Problems that the invention aims to solve]

[0007] Since the C and D rings in formula (A) above are difficult to synthesize chemically, a common method involves obtaining vitamin D2 through cell expression and then synthesizing it from that. However, cell-based synthesis is more time-consuming, costly, and labor-intensive than chemical synthesis. Therefore, cell-based synthesis presents the challenge of not being able to easily supply large quantities of a wide variety of vitamin D3 derivatives.

[0008] This invention was proposed in view of these circumstances, and aims to provide a novel vitamin D3-like compound. [Means for solving the problem]

[0009] The inventors of this invention, after diligent research to solve the above-mentioned problems, discovered that a compound represented by the following formula (1) exhibits agonist activity on the active vitamin D3 receptor, and thus completed the present invention. More specifically, the present invention provides the following.

[0010] <1> A compound represented by the following formula (1). [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4represents a linear or branched monovalent saturated or unsaturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. R 5 represents a hydrogen atom, a hydroxyl group, an optionally substituted alkoxy group having 1 to 6 carbon atoms, or an optionally substituted linear or branched monovalent saturated or unsaturated aliphatic hydrocarbon group having 1 to 6 carbon atoms. R 6 represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. R 7 and R 8 simultaneously represent hydrogen atoms, or together form a methylidene group.]

[0011] <2> A prophylactic or therapeutic agent for a disease for which an action of active vitamin D3 is effective, comprising the compound according to <1> as an active ingredient.

[0012] <3> The prophylactic or therapeutic agent according to <2>, wherein the disease for which an action of active vitamin D3 is effective is osteoporosis, rickets, chronic hypocalcemia, renal osteodystrophy, secondary hyperparathyroidism, psoriasis, or cancer.

[0013] <4> A compound represented by the following formula (2).

Chemical Formula

[0014] <5> The compound represented by the following formula (4). [ka] [In the formula, m is 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. Z indicates a halogen atom or a group represented by the following formula (3). R 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 9 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 19 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 10 This represents an alkyl group with 1 to 8 carbon atoms. [ka] [In the formula, * indicates a bond.]

[0015] <6> A compound represented by the following formula (5). [ka] [In the formula, p is an integer from 0 to 4, and s is an integer from 0 to 6. Z represents a halogen atom or a group represented by the following formula (3). R 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 4 This represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. [ka] [In the formula, * indicates a bond.]

[0016] <7> A compound represented by the following formula (6). [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. W indicates a protecting group. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 6 This represents a hydrogen atom or a monovalent aliphatic hydrocarbon group.

[0017] <8> A method for producing a compound represented by the following formula (1), A step of reacting a compound represented by the following formula (7) with a compound represented by the following formula (8) to obtain a compound represented by the following formula (9), A step of removing the group represented by W from the compound represented by the following formula (9) to obtain the compound represented by the following formula (1), A manufacturing method that includes this. [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 5 R represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have substituents, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituents. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 7 and R 8 This simultaneously represents a hydrogen atom, or, when combined, represents a methylidene group. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 As stated above, W indicates a protecting group. 1 This represents a halogen atom or a group represented by the following formula (3). [ka] [In the formula, * indicates a bond.] [ka] [In the formula, R 5 , R 7 , R 8 , and W are as described above. Z 2represents a halogen atom or a group represented by formula (3) above. However, Z in formula (7) above 1 If it is a halogen atom, then Z 2 is a group represented by the above formula (3), and Z 1 If is a group represented by the above formula (3), then Z 2 It is a halogen atom. [ka] [In the formula, m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 This is as stated above.

[0018] <9> A method for producing a compound represented by the following formula (13): A step of reacting a compound represented by the following formula (10) with a compound represented by the following formula (8) to obtain a compound represented by the following formula (11), A step of obtaining a compound represented by formula (12) from a compound represented by formula (11) below, A step of removing the group represented by W from the compound represented by the following formula (12) to obtain the compound represented by the following formula (13), A manufacturing method that includes this. [ka] [In the formula, m is 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 5R represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have substituents, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituents. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 7 and R 8 R simultaneously represents a hydrogen atom, or it is integrated to represent a methylidene group. 9 This represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 19 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. [ka] [In the formula, m, p, s, Y, R 1 , R 2 , R 4 , R 6 , R 9 , and R 10 The above is true. R 10 Z represents an alkyl group with 1 to 8 carbon atoms. 1 This represents a halogen atom or a group represented by the following formula (3). [ka] [In the formula, * indicates a bond.] [ka] [In the formula, R 5 , R 7 , and R 8 As stated above, W indicates a protecting group. 2 represents a halogen atom or a group represented by formula (3) above. However, Z in formula (10) above 1 If it is a halogen atom, then Z 2 is a group represented by the above formula (3), and Z 1 If is a group represented by the above formula (3), then Z 2 It is a halogen atom. [ka] [In the formula, m, p, s, W, Y, R1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are as defined above.]

Chem.

[0019] <10> A method for producing a compound represented by the following formula (16), a step of reacting a compound represented by the following formula (14) with a compound represented by the following formula (8) to obtain a compound represented by the following formula (15), and a step of eliminating the group represented by W from the compound represented by the following formula (15) to obtain a compound represented by the following formula (16), and A production method comprising:

Chem.

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0020] <11> A method for producing a compound represented by the following formula (19), comprising a step of reacting a compound represented by the following formula (6) with a compound represented by the following formula (17) to obtain a compound represented by the following formula (18), and a step of eliminating the group represented by W from the compound represented by the following formula (18) to obtain the compound represented by the following formula (19), the production method comprising the above steps. [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 5 R represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have substituents, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituents. 6 This represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 As stated above, W indicates a protecting group. [ka] [In the formula, R 5 And W is as described above. R 11 and R 12 These independently represent monovalent hydrocarbon groups with 1 to 20 carbon atoms. [ka] [In the formula, m, n, p, s, W, Y, R 1 , R 2 , R3 , R 4 , R 5 , and R 6 This is as stated above.

[0021] <12> A method for producing a compound represented by the following formula (23): A step of reacting a compound represented by formula (7) below with a compound represented by formula (20) below to obtain a compound represented by formula (21) below, A step of obtaining a compound represented by the following formula (22) from a compound represented by the following formula (21), A step of removing the group represented by W from the compound represented by the following formula (22) to obtain the compound represented by the following formula (23), A manufacturing method that includes this. [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 7 and R 8 R simultaneously represents a hydrogen atom, or it is integrated to represent a methylidene group. 13 This represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 4 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 are as defined above. W represents a protecting group. Z 1 represents a halogen atom or a group represented by the following formula (3).]

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0022] <13> A method for producing a compound represented by the following formula (27): A step of reacting a compound represented by the following formula (6) with a compound represented by the following formula (24) to obtain a compound represented by the following formula (25), A step of removing the group represented by W from the compound represented by the following formula (25) to obtain the compound represented by the following formula (26), A step of obtaining a compound represented by the following formula (27) from a compound represented by the following formula (26), A manufacturing method that includes this. [ka] [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR] 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 7 and R 8 This simultaneously represents a hydrogen atom, or, when combined, represents a methylidene group. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 As stated above, W indicates a protecting group. [ka] [In the formula, W is as described above. R 14 and R 15 These independently represent monovalent hydrocarbon groups with 1 to 20 carbon atoms. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and W are as described above. [ka] [In the formula, m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 This is as stated above. [Effects of the Invention]

[0023] According to the present invention, a novel vitamin D3-like compound can be provided. [Brief explanation of the drawing]

[0024] [Figure 1] This figure shows the concentration-activity curve obtained from the time-resolved fluorescence resonance energy transfer (TR-FRET) vitamin D receptor (VDR) coactivator assay performed as Test Example 1. [Figure 2] This figure shows the concentration-activity curve obtained from the vitamin D receptor (NR1I1, VDR) reporter assay performed as Test Example 2. [Modes for carrying out the invention]

[0025] The following describes specific embodiments of the present invention in detail. However, the present invention is not limited to the following embodiments, and various modifications are possible without altering the essence of the invention. In this specification, the notation "X~Y" (where X and Y are arbitrary numerical values) means "X or greater and Y or less".

[0026] <Compound> The compound according to this embodiment is a compound represented by the following formula (1).

[0027] [ka]

[0028] In formula (1) above, m and n are independently 0 or 1. m and n may be the same or different, but it is preferable that m and n are 1, m is 0 and n is 1, or m and n are 0, and it is more preferable that m and n are 1, or m is 0 and n is 1.

[0029] In equation (1) above, p is an integer from 0 to 4, and s is an integer from 0 to 4. If p is an integer greater than or equal to 2, R 2 They may be different from each other, or they may be the same. Also, if s is an integer greater than or equal to 2, R 4 They may be different from each other or the same. p and s are preferably integers between 0 and 3, more preferably integers between 0 and 2, even more preferably 0 or 1, and particularly preferably 0.

[0030] In formula (1) above, Y is an oxygen atom, a sulfur atom, or -NR 6 This represents a divalent group represented by -. Among these, Y is preferably an oxygen atom or a sulfur atom, and more preferably an oxygen atom.

[0031] In the above equation (1), R 1 This represents a linear or branched, saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms.

[0032] Examples of monovalent monovalent aliphatic hydrocarbon groups having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated, include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, isopentyl, and tert-butyl; alkenyl groups such as vinyl, allyl, and butenyl; alkynyl groups such as ethynyl, propynyl, and butynyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and cycloalkenyl groups such as cyclopentenyl and cyclohexenyl.

[0033] Among these, from the perspective of three-dimensional structure, R 1 The group is preferably an alkyl group, more preferably a methyl group, an ethyl group, or a propyl group, and even more preferably a methyl group or an ethyl group.

[0034] In the above equation (1), R 2 This represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom.

[0035] Examples of alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups. Examples of alkoxy groups having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy, and heptoxy groups. Examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms.

[0036] Among these, R 2 It is preferable that it is an alkyl group having 1 to 8 carbon atoms.

[0037] In the above equation (1), R 3 This represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain.

[0038] Substituents include halogen atoms, epoxy groups, hydroxyl groups, and amino groups. Heteroatoms include oxygen atoms, sulfur atoms, and nitrogen atoms. Linear or branched saturated or unsaturated divalent aliphatic hydrocarbon groups having 1 to 20 carbon atoms include methylene groups, ethylene groups, propylene groups, tetramethylene groups, ethylethylene groups, pentamethylene groups, and hexamethylene groups.

[0039] Among these, R 3 This is -(CH2)2-, -(CH2)3-, -(CH2)4-, -CH2-C(CH3)2-, -(CH2)2-C(CH3)2-, -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -CH2-C(CH2CH3)2-, -(CH2)2-C(CH2CH3)2-, -(CH2)3-C(CH2CH3)2-, -(CH2)4-C(CH2CH3)2-, -C≡C-CH2-C(CH3)2-, -C≡C-CH2-C(CH2CH3)2-, or -C≡C-CH2-C(CH2CH2CH3)2- It is preferable that -CH2-C(CH3)2-, -(CH2)2-C(CH3)2-, -(CH2)3-C(CH3)2-, -(CH2)4-C(CH3)2-, -C≡C-CH2-C(CH2CH3)2-, or -C≡C-CH2-C(CH2CH2CH3)2-, and even more preferably that -CH2-C(CH3)2-, -(CH2)2-C(CH3)2-, -(CH2)3-C(CH3)2-, -C≡C-CH2-C(CH2CH3)2-, or -C≡C-CH2-C(CH2CH2CH3)2-.

[0040] In the above equation (1), R 4 This represents a linear or branched, saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms.

[0041] Examples of monovalent monovalent aliphatic hydrocarbon groups having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated, include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, isopentyl, and tert-butyl; alkenyl groups such as vinyl, allyl, and butenyl; alkynyl groups such as ethynyl, propynyl, and butynyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; and cycloalkenyl groups such as cyclopentenyl and cyclohexenyl.

[0042] Among these, R 4 It is preferably an alkyl group, and more preferably an isopropyl group.

[0043] In the above equation (1), R 5 This represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have substituents, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituents.

[0044] Substituents include halogen atoms, epoxy groups, hydroxyl groups, amino groups, etc. Alkoxy groups with 1 to 6 carbon atoms include methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, pentoxy groups, hexoxy groups, etc. Linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon groups with 1 to 6 carbon atoms include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, isopentyl, and tert-butyl groups; alkenyl groups such as vinyl, allyl, and butenyl groups; alkynyl groups such as ethynyl, propynyl, and butynyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; and cycloalkenyl groups such as cyclopentenyl and cyclohexenyl groups.

[0045] Among these, R 5It is preferably a hydrogen atom or an alkoxy group having 1 to 6 carbon atoms, which may have substituents, and more preferably a hydrogen atom.

[0046] In the above equation (1), R 6 This represents a hydrogen atom or a monovalent aliphatic hydrocarbon group.

[0047] Examples of monovalent aliphatic hydrocarbon groups include linear or branched saturated or unsaturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms. Specifically, examples include alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, isopentyl, and tert-butyl groups; alkenyl groups such as vinyl, allyl, and butenyl groups; alkynyl groups such as ethynyl, propynyl, and butynyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups; and cycloalkenyl groups such as cyclopentenyl and cyclohexenyl groups.

[0048] Among these, R 6 Preferably, it is a hydrogen atom or an alkyl group.

[0049] In the above equation (1), R 7 and R 8 This simultaneously represents a hydrogen atom, or it is integrated to represent a methylidene group.

[0050] Specific examples of compounds represented by formula (1) above are listed below. However, compounds represented by formula (1) above are not limited to these specific examples.

[0051] [ka]

[0052] [ka]

[0053] If the compound represented by formula (1) has an acidic or basic functional group, the compound may be in the form of a pharmaceutically acceptable salt. For example, if the compound represented by formula (1) has an acidic functional group, the compound may be in the form of an alkali metal salt (sodium salt, potassium salt, etc.), an alkaline earth metal salt (calcium salt, magnesium salt, etc.), an ammonium salt, etc. Also, if the compound represented by formula (1) has a basic functional group, the compound may be in the form of a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, or phosphoric acid, or in the form of a salt with an organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid.

[0054] <Preventive or therapeutic agent> The preventive or therapeutic agent contains the compound represented by formula (1) above as an active ingredient and is effective against diseases for which the action of active vitamin D3 is effective. As described above, the compound represented by formula (1) is as follows, so a detailed explanation is omitted. Note that "prevention" includes not only preventing the onset of the disease but also delaying the onset. Furthermore, "treatment" includes not only eliminating or reducing the symptoms of the disease but also suppressing the degree of progression of the symptoms.

[0055] Diseases for which active vitamin D3 is effective include, for example, osteoporosis, rickets, chronic hypocalcemia, renal osteodystrophy, secondary hyperparathyroidism, psoriasis, and cancer.

[0056] Preventive or therapeutic agents can be manufactured by any method used in the field of pharmaceuticals, or by a method with appropriate modifications.

[0057] The preventive or therapeutic agent may contain components other than the compound represented by formula (1) above. For example, the preventive or therapeutic agent may contain conventional organic or inorganic carriers as formulation materials. In solid formulations, these carriers are incorporated as excipients, lubricants, binders, disintegrants, etc., and in liquid formulations, as solvents, solubilizers, suspending agents, isotonic agents, buffers, etc. The preventive or therapeutic agent may also contain formulation additives such as preservatives, antioxidants, colorants, and sweeteners.

[0058] There are no particular restrictions on the dosage form of preventive or therapeutic agents. Examples of dosage forms for preventive or therapeutic agents include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, suspensions, and films; and parenteral preparations such as injections, intravenous infusions, topical preparations, suppositories, pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops.

[0059] The target population for preventive or therapeutic agents is not particularly limited, but mammals are preferred. Mammals may include humans and non-human animals (such as mice, rats, hamsters, rabbits, cats, dogs, cattle, sheep, and monkeys).

[0060] The dosage of preventive or therapeutic agents is determined appropriately according to the target recipient, route of administration, target disease, symptoms, etc.

[0061] Furthermore, preventive or therapeutic agents may be administered in combination with other drugs, depending on the purpose of administration. The type and amount of drugs used in combination with preventive or therapeutic agents should be appropriately selected based on the desired effect, and they may be administered together with the preventive or therapeutic agents or separately.

[0062] <Intermediate compounds> As an intermediate compound of the compound represented by formula (1) above, the compound represented by formula (2) below can be given.

[0063] [ka]

[0064] In the above formula (2), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 The above is true.

[0065] In formula (2) above, V represents a hydrogen atom or W, and W represents a protecting group. Examples of protecting groups include silyl ether protecting groups such as TMS (trimethylsilyl), TES (triethylsilyl), and TBS (tert-butyldimethylsilyl).

[0066] In formula (2) above, Z represents a halogen atom or a group represented by formula (3) below. Examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms.

[0067] [ka]

[0068] In equation (3) above, * indicates a bond.

[0069] As an intermediate compound of the compound represented by formula (1) above, the compound represented by formula (4) below can be given.

[0070] [ka]

[0071] In equation (4) above, m, p, s, Y, Z, R 1 , R 2 , R 4 , R 6 The above is true.

[0072] In the above equation (4), R 9 This represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 19 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain.

[0073] Examples of heteroatoms include oxygen atoms, sulfur atoms, and nitrogen atoms. Examples of linear or branched saturated or unsaturated divalent aliphatic hydrocarbon groups having 1 to 19 carbon atoms include methylene groups, ethylene groups, propylene groups, tetramethylene groups, ethylethylene groups, pentamethylene groups, and hexamethylene groups.

[0074] In the above equation (4), R 10 This represents an alkyl group having 1 to 8 carbon atoms. Examples of alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl groups.

[0075] As an intermediate compound of the compound represented by formula (1) above, the compound represented by formula (5) below can be given.

[0076] [ka]

[0077] In equation (5) above, p, s, Z, R 1 , R 2 , and R 4 The above is true.

[0078] As an intermediate compound of the compound represented by formula (1) above, the compound represented by formula (6) below can be given.

[0079] [ka]

[0080] In the above formula (6), m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , R 6 The above is true.

[0081] <Method for producing intermediate compounds> The methods for producing the intermediate compounds represented by the above formulas (2), (4), (5), and (6) will be described in order according to the following scheme (Scheme 1). In this specification, "OMOM" represents a methoxymethoxy group, "i-Bu" represents an isobutyl group, and "Tf" represents a trifluoromethylsulfonyl group.

[0082] [ka]

[0083] Compound 1 and Compound 2 are reacted to obtain compounds 3a to 3c.

[0084] Compounds 3a to 3c are reacted in a tetrahydrofuran solution containing, for example, (S)-α,α-diphenylprolinol, trimethylborate, and N,N-diethylanilineborane to obtain compounds 4a to 4c.

[0085] Z A -W(Z A Z is a halogen atom, and examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms. Among these, Z A It is preferable that is a chlorine atom. The protective agent W is as described above.) is reacted with compounds 4a to 4c to obtain compounds 5a to 5c.

[0086] Compounds 5a to 5c are reacted under a hydrogen atmosphere to obtain compounds 6a to 6c. This reaction may be carried out using palladium or the like as a catalyst.

[0087] The protecting group W is removed from compounds 6a to 6c to obtain compounds 7a to 7c.

[0088] Compounds 7a to 7c are reacted with an oxidizing agent to obtain compounds 8a to 8c. Examples of oxidizing agents include pyridinium chlorochromate.

[0089] Compounds 8a to 8c are isomerized to obtain compounds 9a to 9c.

[0090] Compounds 9a to 9c are reacted with a halogenating agent to obtain compounds 10a to 10c. Examples of halogenating agents include (bromomethyl)triphenylphosphonium bromide.

[0091] Compounds 11a to 11c are obtained by reacting compounds 10a to 10c with an acid. Examples of suitable acids include hydrochloric acid.

[0092] Compounds 11a-11c are reacted with compound 13 to obtain compounds 12aA-12cC. Compound 13 contains m, n, W, Y, and R. 3 As stated above, in compound 13, Z B These are halogen atoms, and examples of halogen atoms include chlorine atoms, bromine atoms, iodine atoms, and fluorine atoms.

[0093] Compounds 11a to 11c are reacted with the compound represented by the following formula (B) to obtain compounds 14a to 14c. Note that in the following formula (B), Z C These are halogen atoms, and examples of halogen atoms include chlorine atoms, bromine atoms, iodine atoms, and fluorine atoms.

[0094] [ka]

[0095] Compounds 9a-9c are reacted with an acid to obtain compounds 15a-15c. Examples of suitable acids include hydrochloric acid.

[0096] Compounds 15a to 15c are reacted with trifluoromethanesulfonic acid anhydride to obtain compounds 16a to 16c.

[0097] Compounds 16a to 16c are reacted with 2-methylpenta-4-in-2-ol to obtain compounds 17a to 17c.

[0098] Compounds 17a to 17c are reacted under a hydrogen atmosphere to obtain compounds 18a to 18c. This reaction may be carried out using palladium or the like as a catalyst.

[0099] Z D -W(Z D Z is a halogen atom, and examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms. Among these, Z D It is preferable that is a chlorine atom. The protective agent W is as described above.) is reacted with compounds 18a to 18c to obtain compounds 19a to 19c.

[0100] Compounds 19a to 19c are reacted with a halogenating agent to obtain compounds 20a to 20c. Examples of halogenating agents include (bromomethyl)triphenylphosphonium bromide.

[0101] Compounds 15a-15c are reacted with compound 13 to obtain compounds 21aA-21cC. Compound 13 contains m, n, W, Y, and Z. B , R 3 The above is true.

[0102] Next, we will explain the process step by step according to the following scheme (Scheme2).

[0103] [ka]

[0104] Compound C1 and compound 2 are reacted to obtain compounds C2a to C2c.

[0105] Compounds C2a to C2c are reacted with an oxidizing agent to obtain compounds C3a to C3c. Examples of oxidizing agents include pyridinium chlorochromate.

[0106] Compounds C3a to C3c are reacted under a hydrogen atmosphere to obtain compounds C8a to C8c. This reaction may be carried out using palladium or the like as a catalyst.

[0107] Compounds C8a to C8c are isomerized to obtain compounds C9a to C9c.

[0108] Compounds C9a to C9c are reacted with a halogenating agent to obtain compounds C10a to C10c. Examples of halogenating agents include (bromomethyl)triphenylphosphonium bromide.

[0109] Compounds C11a to C11c are obtained by reacting compounds C10a to C10c with an acid. Hydrochloric acid is an example of such an acid.

[0110] Compounds C11a to C11c are reacted with compound 13 to obtain compounds C12aA to C12cC. Compound 13 contains m, n, Y, W, and Z. B , R 3 The above is true.

[0111] <Method for producing the final compound> A method for producing the compound represented by formula (1) above includes the steps of reacting a compound represented by formula (7) below with a compound represented by formula (8) below to obtain a compound represented by formula (9) below, and removing a group represented by W from the compound represented by formula (9) below to obtain a compound represented by formula (1) below.

[0112] [ka]

[0113] In the above equation (7), m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , and R 6 The above is true. Z 1 This represents a halogen atom or a group represented by the following formula (3). Examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms.

[0114] [ka]

[0115] In equation (3) above, * indicates a bond.

[0116] [ka]

[0117] In the above equation (8), R 5 , R 7 , R 8 , and W are as described above.

[0118] In the above equation (8), Z 2 represents a halogen atom or a group represented by formula (3) above. Examples of halogen atoms include chlorine, bromine, iodine, and fluorine atoms. However, Z in formula (7) above 1 If it is a halogen atom, then Z 2 is a group represented by the above formula (3), and Z 1 If is a group represented by the above formula (3), then Z 2 It is a halogen atom.

[0119] [ka]

[0120] In the above formula (9), m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 The above is true.

[0121] A method for producing the compound represented by the following formula (13) includes the steps of: reacting the compound represented by the following formula (10) with the compound represented by the following formula (8) to obtain the compound represented by the following formula (11); obtaining the compound represented by the following formula (12) from the compound represented by the following formula (11); and removing the group represented by W from the compound represented by the following formula (12) to obtain the compound represented by the following formula (13).

[0122] [ka]

[0123] In the above formula (13), m, p, s, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The above is true.

[0124] [ka]

[0125] In the above formula (10), m, p, s, Y, R 1 , R 2 , R 4 , R 6 , R 9 , R 10 , and Z 1 The above is true.

[0126] [ka]

[0127] In equation (8) above, W, Z 2 , R 5 , R 7 , and R 8 The above is true.

[0128] [ka]

[0129] In the above formula (11), m, p, s, W, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10The above is true.

[0130] [ka]

[0131] In the above formula (12), m, p, s, W, Y, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 The above is true.

[0132] A method for producing the compound represented by formula (16) below includes the steps of reacting a compound represented by formula (14) below with a compound represented by formula (8) below to obtain a compound represented by formula (15) below, and removing a group represented by W from the compound represented by formula (15) below to obtain a compound represented by formula (16) below.

[0133] [ka]

[0134] In the above formula (16), p, s, R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 The above is true.

[0135] [ka]

[0136] In equation (14) above, p, s, Z 1 , R 1 , R 2 , and R 4 The above is true.

[0137] [ka]

[0138] In equation (8) above, W, Z 2 , R 5 , R 7 , and R 8 The above is true.

[0139] [ka]

[0140] In the above formula (15), p, s, W, R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 The above is true.

[0141] A method for producing the compound represented by the following formula (19) includes the steps of reacting the compound represented by the following formula (6) with the compound represented by the following formula (17) to obtain the compound represented by the following formula (18), and removing the group represented by W from the compound represented by the following formula (18) to obtain the compound represented by the following formula (19).

[0142] [ka]

[0143] In the above formula (19), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 The above is true.

[0144] [ka]

[0145] In the above formula (6), m, n, p, s, W, Y, R 1 , R2 , R 3 , R 4 , and R 6 The above is true.

[0146] [ka]

[0147] In the above equation (17), R 5 And W is as described above. R 11 and R 12 These independently represent monovalent hydrocarbon groups having 1 to 20 carbon atoms. Examples of monovalent hydrocarbon groups having 1 to 20 carbon atoms include phenyl groups, naphthyl groups, and aryl groups having 6 to 20 carbon atoms.

[0148] [ka]

[0149] In the above formula (18), m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 The above is true.

[0150] A method for producing the compound represented by the following formula (23) includes the steps of: reacting the compound represented by the following formula (7) with the compound represented by the following formula (20) to obtain the compound represented by the following formula (21); obtaining the compound represented by the following formula (22) from the compound represented by the following formula (21); and removing the group represented by W from the compound represented by the following formula (22) to obtain the compound represented by the following formula (23).

[0151] [ka]

[0152] In the above formula (23), m, n, p, s, Y, R 1 , R 2, R 3 , R 4 , R 6 , R 7 , R 8 , and R 13 This is as stated above.

[0153] [ka]

[0154] In equation (7) above, m, n, p, s, W, Y, Z 1 , R 1 , R 2 , R 3 , R 4 , and R 6 The above is true.

[0155] [ka]

[0156] In equation (3) above, * indicates a bond.

[0157] [ka] In the above equation (20), Z 2 , R 7 , R 8 , and R 13 The above is true.

[0158] [ka] In the above formula (21), m, n, p, s, W, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and R 13 The above is true.

[0159] [ka] In the above formula (22), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 13 , and W are as described above.

[0160] A method for producing the compound represented by formula (27) below includes the steps of: reacting the compound represented by formula (6) below with the compound represented by formula (24) below to obtain the compound represented by formula (25); removing the group represented by W from the compound represented by formula (25) below to obtain the compound represented by formula (26); and obtaining the compound represented by formula (27) below from the compound represented by formula (26).

[0161] [ka]

[0162] In formula (27) above, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR 6 - indicates a divalent group. 1 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 2 R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. 3 R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. 4 R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. 6 R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. 7 and R 8 This simultaneously represents a hydrogen atom, or it is integrated to represent a methylidene group.

[0163] [ka]

[0164] In the above formula (6), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , and R 6 As stated above, W indicates a protecting group.

[0165] [ka]

[0166] In equation (24) above, W is as described above. R 14 and R 15 These independently represent monovalent hydrocarbon groups with 1 to 20 carbon atoms.

[0167] [ka]

[0168] In the above formula (25), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , and W are as described above.

[0169] [ka]

[0170] In the above formula (26), m, n, p, s, Y, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , and R 8 The above is true. [Examples]

[0171] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0172] [Synthesis of Compounds] <Synthesis Example 1> [ka]

[0173] 3-Isobutoxy-2-methylcyclohex-2-en-1-one was prepared from commercially available 2-methylcyclohexane-1,3-dione according to the method described in the literature (Levine, et al., Organic Letters, 2009, 11, 289-292).

[0174] <Synthesis Example 2> [ka]

[0175] <Synthesis Example 2-1> [ka]

[0176] Under an argon atmosphere, a solution of 1-iodo-2-(methoxymethoxy)benzene (16.9 g, 64.0 mmol, 1.3 equivalents) in tetrahydrofuran (128 mL) was added dropwise to a solution of n-butyllithium in hexane (1.55 M hexane solution, 43.4 mL, 67.2 mmol, 1.4 equivalents) at -78°C. After stirring at 0°C for 30 minutes, the mixture was cooled to -78°C, and 3-isobutoxy-2-methylcyclohexa-2-en-1-none (9.0 g, 49.2 mmol, 1.0 equivalent) was added, followed by stirring for 1.5 hours. The reaction mixture was stopped by adding 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, followed by saturated brine, dried over anhydrous magnesium sulfate, filtered by Celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 3a (9.3 g) in 58% yield.

[0177] 1 H NMR (600 MHz, CDCl3) δ 7.25-7.28 (m, 1H, Ar), 7.15 (d, J = 8.4 Hz, 1H, Ar), 7.01-7.03 (m, 2H, Ar), 5.15 (s, 2H, OCH2O), 3.44 (s, 3H, CH3O), 2.42-2.68 (m, 4H, CH2), 2.04-2.12 (m, 2H, CH2C H 2CH2), 1.61 (t, J = 1.8 Hz, 3H, CH3C=C). 13 C NMR (150 MHz, CDCl3) δ 200.0, 155.1, 152.9, 132.8, 131.1, 129.0, 128.3, 121.8, 114.8, 94.5, 56.1, 38.0, 32.3, 22.9, 12.7. IR (ATR) 2948, 2825, 1664, 1625, 1487, 1450, 1440, 1353, 1239, 1195, 1153, 1117, 1102, 1079, 1041, 995, 973, 923, 756 cm -1 . HR-MS m / z = calcd for C 15 H18 NaO3[M+Na] + : 269.11536, found 269.11431.

[0178] <Synthesis Example 2-2> [ka]

[0179] Under an argon atmosphere, 1-bromo-3-(methoxymethoxy)benzene (12.7 g, 58.7 mmol, 1.3 equivalents) was added dropwise to a mixture of magnesium shavings (2.1 g, 88 mmol, 3.0 equivalents) and tetrahydrofuran (58.7 mL). After stirring for 30 minutes, 3-isobutoxy-2-methylcyclohexa-2-en-1-none (8.2 g, 45.1 mmol, 1.0 equivalent) was added to the Grignard reaction solution at 0°C, and the mixture was stirred for 1.5 hours. The reaction was stopped by adding 1 M hydrochloric acid, and then extracted with ethyl acetate. The resulting organic layer was washed with saturated sodium bicarbonate solution, followed by saturated brine, dried over anhydrous magnesium sulfate, filtered by Celite, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound 3b (8.5 g) in 76% yield.

[0180] 1 H NMR (600 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 1H, Ar), 7.00 (dd, J = 3.0, 7.8 Hz, 1H, Ar), 6.87 (dd, 1H, J = 1.2, 3.0 Hz, Ar), 6.83 (dd, J = 1.2, 7.8 Hz, 1H, Ar), 5.19 (s, 2H, OCH2O), 3.50 (s, 3H, CH3O), 2.63-2.61 (m, 2H, CH2), 2.52 (t, J = 6.0 Hz, 2H, CH2), 2.09 (quint, J = 6.5 Hz, 2H, CH2), 1.73 (t, J = 1.8 Hz, 3H, CH3C=C). 13C NMR (150 MHz, CDCl3) δ 200.0, 157.2, 156.2, 142.8, 131.9, 129.5, 120.6, 115.5, 115.1, 94.5, 56.1, 37.8, 32.8, 22.8, 12.9. IR (ATR) 2948, 2825, 1662, 1598, 1576, 1483, 1432, 1352, 1306, 1262, 1149, 1107, 1078, 1017, 979, 921, 875, 787, 701 cm -1 . HR-MS m / z = calcd for C 15 H 18 NaO3[M+Na] + : 269.11536, found 269.11526.

[0181] <Synthesis Example 2-3> [ka]

[0182] Compound 3c (10.9 g) was obtained in 76% yield from compound 1 (10.6 g, 58.1 mmol) in the same manner as the synthesis of compound 3b.

[0183] 1 H NMR (600 MHz, CDCl3) δ 7.15 (d, J = 9.0 Hz, 2H, Ar), 7.06 (d, J = 9.0 Hz, 2H, Ar), 5.20 (s, 2H, OCH2O), 3.50 (s, 3H, CH3O), 2.63-2.59 (m, 2H, CH2), 2.51 (t, J = 6 Hz, 2H, CH2), 2.08 (quint, J = 6.3 Hz, 2H, CH2), 1.75 (t, J = 1.8 Hz, 3H, CH3C=C). 13¹³C NMR (150 MHz, CDCl₃) δ 200.1, 156.9, 156.1, 134.7, 131.7, 128.7, 115.9, 94.4, 56.1, 37.8, 32.9, 22.7, 13.0. IR (ATR) 2948, 2826, 1660, 1606, 1508, 1439, 1353, 1234, 1197, 1176, 1151, 1104, 1078, 996, 974, 922, 835 cm -1 . HR-MS m / z = calcd for C 15 H 18 NaO₃[M+Na] + : 269.11536, found 269.11711.

[0184] <Synthesis Example 3>

Chemical Formula

[0185] <Synthesis Example 3-1>

Chemical Formula

[0186] Under an argon atmosphere, (S)-α,α-diphenylprolinol (0.76 g, 3.0 mmol, 10.0 mol%) and trimethylborate (0.4 mL, 3.6 mmol, 12.0 mol%) were dissolved in tetrahydrofuran (50 mL) and stirred at room temperature for 1 hour. Then, N,N-diethylanilineborane (5.6 mL, 31.5 mmol, 1.05 equivalents) was added. This was cooled to -10°C, and a tetrahydrofuran solution (50 mL) of compound 3a (7.4 g, 30.0 mmol, 1.0 equivalent) was added dropwise over 45 minutes, followed by stirring at -5°C for 12 hours. 1 M hydrochloric acid was added to the reaction mixture to stop it, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound (R)-4a (6.8g) in 91% yield.

[0187] 1 H NMR (600 MHz, CDCl3) δ 7.19 (t, J = 8.4 Hz, 1H, Ar), 7.09 (d, J = 8.4 Hz, 1H, Ar), 7.09-6.96 (m, 2H, Ar), 5.12 (s, 1H, OCH2O), 4.18-4.06 (m, 1H, OCH), 3.45 (s, 3H, CH3O), 2.39-1.62 (m, 6H, OH and CH2), 1.59 (t, J = 1.8 Hz, 3H, CH3C=C), 1.55-1.47 (m, 1H, CH2). 13 C NMR (150 MHz, CDCl3) δ 154.2 and 153.9 (rotamers), 134.0, 133.2, 131.2, 130.2 and 127.8 (rotamers), 127.6, 121.9, 115.5 and 115.4 (rotamers), 94.9, 69.5 and 69.3 (rotamers), 55.9, 32.3 and 32.1 (rotamers), 31.4, 18.9 and 18.4 (rotamers), 17.5. IR (ATR) 3393, 2933, 2860, 1597, 1578, 1487, 1440, 1240, 1193, 1151, 1114, 1076, 1046, 1002, 957, 922, 753 cm -1 . HR-MS m / z = calcd for C 15 H 20 NaO3[M+Na] + : 271.13101, found 271.13283.

[0188] <Synthesis Example 3-2> [ka]

[0189] Compound (R)-4b (4.6g) was obtained in 93% of the yield of compound 3b (4.9g, 19.9 mmol) in the same manner as the synthesis of compound (R)-4 from compound 3a.

[0190] 1 H NMR (600 MHz, CDCl3) δ 7.24 (t, J = 7.8 Hz, 1H, Ar), 6.91 (dd, J = 2.4, 8.4 Hz, 1H, Ar), 6.82 (t, J = 1.8 Hz, 1H, Ar), 6.78 (d, J = 7.8 Hz, 1H, Ar), 5.17 (s, 2H, OCH2O), 4.12 (brs, 1H, CHO), 3.49 (s, 3H, OCH3), 2.31-2.17 (m, 2H, CH2), 1.87-1.77 (m, 3H, CH2), 1.72-1.67 (m, 1H, CH2), 1.70 (t, J = 1.8 Hz, 3H, CH3C=C), 1.53 (brs, 1H, OH). 13C NMR (150 MHz, CDCl3) δ 157.1, 144.8, 136.5, 130.5, 129.1, 121.8, 116.1, 114.2, 94.5, 69.4, 56.0, 32.2, 32.0, 18.6, 17.7. IR (ATR) 3362, 2931, 2861, 2827, 1598, 1577, 1483, 1434, 1275, 1150, 1077, 1013, 983, 963, 922, 787, 703 cm -1 . HR-MS m / z = calcd for C 15 H 20 NaO3[M+Na] + : 271.13101, found 271.13326.

[0191] <Synthesis Example 3-3> [ka]

[0192] Compound (R)-4c (10.7g) was obtained in 93% of the yield of compound 3c (10.9g, 44.3 mmol) in the same manner as the synthesis of compound (R)-4 from compound 3a.

[0193] 1 H NMR (600 MHz, CDCl3) δ 7.06 (d, J = 9.0 Hz, 2H, Ar), 6.99 (d, J = 9.0 Hz, 2H, Ar), 5.18 (s, 2H, OCH2O), 4.12 (brs, 1H, CHO), 3.50 (s, 3H, OCH3), 2.27-2.18 (m, 2H, CH2), 1.87-1.77 (m, 3H, CH2), 1.74-1.67 (m, 1H, CH2), 1.70 (t, J = 1.8 Hz, 3H, C H 3), 1.53 (brs, 1H, OH). 13C NMR (150 MHz, CDCl3) δ 155.7, 136.9, 136.2, 130.3, 129.2, 115.8, 94.5, 69.5, 56.0, 32.3, 32.0, 18.7, 17.7. IR (ATR) 3389, 2932, 2861, 2827, 1606, 1508, 1442, 1230, 1198, 1151, 1077, 1004, 958, 922, 834 cm -1 . HR-MS m / z = calcd for C 15 H 20 NaO3[M+Na] + : 271.13101, found 271.13371.

[0194] <Synthesis Example 4> [ka]

[0195] <Synthesis Example 4-1> [ka]

[0196] To a solution of compound 4a (3.4 g, 13.6 mmol, 1.0 equivalent) and imidazole (2.0 g, 29.9 mmol, 2.2 equivalents) in N,N-dimethylformamide (27.2 mL), chlorotriethylsilane (3.4 mL, 20.4 mmol, 1.5 equivalents) was added at 0°C. After stirring at room temperature for 3 hours, saturated sodium bicarbonate solution was added at 0°C, and the mixture was extracted with hexane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 5a.

[0197] To a methanol solution (68 mL) of the crude product of compound 5a obtained, 10% by mass of palladium (charcoal-supported, 0.25 g) was added. The mixture was stirred at room temperature (or 40°C) for 12 hours under a hydrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product of compound 6a.

[0198] To a solution of the crude product of compound 6a obtained in tetrahydrofuran (13.6 mL), tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 20.4 mL, 20.4 mmol, 1.5 equivalents) was added at 0°C. After stirring at room temperature for 3 hours, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 7a (dr92:8) (2.7 g) in 80% yield.

[0199] 1 H NMR (600 MHz, CDCl3) δ 7.14 (t, J = 7.8 Hz, 1H, Ar), 7.11 (d, J = 7.2 Hz, 1H, Ar), 7.07 (d, J = 8.4 Hz, 1H, Ar), 6.96 (t, J = 7.8 Hz, 1H, Ar), 5.20 (d, J = 6.0 Hz, 1H, OCH2O), 5.18 (d, J = 6.0 Hz, 1H, OCH2O), 3.96 (dt, J = 11.4, 4.2 Hz, 1H, CHO), 3.49 (s, 3H, OCH3), 3.22 (dt, J = 13.2, 3.0Hz, 1H, C H Ar), 2.41-2.34 (m, 1H, C H CH3), 1.90-1.70 (m, 3H, CH2), 1.55-1.41 (m, 4H, CH2), 1.34 (brs, 1H, OH), 0.66 (d, J = 7.8 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 154.5, 133.2, 128.1, 126.8, 121.2, 113.7, 94.5, 73.7, 56.1, 39.1, 38.2, 28.7, 24.4, 23.2, 5.9. IR (ATR) 3399, 2931, 2863, 2825, 1723, 1600, 1584, 1489, 1449, 1291, 1229, 1202, 1184, 1152, 1074, 1006, 924, 753 cm -1 . HR-MS m / z = calcd for C 15 H 22 NaO3[M+Na] + : 273.14666, found 273.14538.

[0200] <Synthesis Example 4-2> [ka]

[0201] Compound 7b (2.3g) was obtained in 91% of the yield of compound (R)-4b (2.6g, 10.1 mmol) in the same manner as the synthesis of compound 7a from compound (R)-4a.

[0202] 1 H NMR (600 MHz, CDCl3) δ 7.21 (t, J = 7.8 Hz, 1H, Ar), 6.88 (d, J = 8.4 Hz, 1H, Ar), 6.85 (s, 1H, Ar), 6.83 (d, 1H, J = 7.8 Hz, Ar), 5.17 (d, J = 6.6 Hz, H, 1), 5.16 (d, J = 6.6 Hz, 1H, OCH2O), 3.92 (dt, J = 12.0, 4.2 Hz, 1H, CHO), 3.48 (s, 3H, OCH3), 2.79 (dt, J = 13.2, 3.6 Hz, 1H, C H Ar), 2.28-2.22 (m, 1H, C HCH3), 1.92-1.86 (m 1H, CH2), 1.78-1.68 (m 2H, CH2), 1.59 (dd, J = 12.6, 2.4 Hz, 1H, CH2), 1.55 (brs, 1H, OH), 1.49 (ddd, J = 12.0, 4.2, 3.6 Hz, 1H, CH2), 1.40 (tq, 4.2, 13.2 Hz, 1H, CH2), 0.66 (d, J = 7.2 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 157.2, 146.4, 129.0, 121.1, 115.7, 113.4, 94.5, 73.7, 55.9, 45.5, 41.4, 28.4, 24.1, 22.9, 5.5. IR (ATR) 3383, 2931, 2863, 2825, 1601, 1583, 1487, 1445, 1240, 1150, 1076, 1011, 995, 944, 922, 793, 775, 699 cm -1 . HR-MS m / z = calcd for C 15 H 22 NaO3[M+Na] + : 273.14666, found 273.14538.

[0203] <Synthesis Example 4-3> [ka]

[0204] Compound 7c (4.5g) was obtained in 97% of the yield of compound (R)-4c (5.8g, 23.5 mmol) in the same manner as the synthesis of compound 7a from compound (R)-4a.

[0205] 1H NMR (600 MHz, CDCl3) δ 7.09 (d, J = 7.8 Hz, 2H, Ar), 6.97 (d, J = 7.8 Hz, 2H, Ar), 5.16 (s, 2H, OCH2O), 3.93-3.91 (m, 1H, CHO), 3.48 (s, 3H, OCH3), 2.77 (dt, J = 13.2, 3.6 Hz, 1H, C H Ar), 2.24-2.18 (m, 1H, C H CH3), 1.91-1.85 (m, 1H, CH2), 1.74 (dd, J = 4.2, 13.2 Hz, 1H, CH2), 1.70 (dd, J = 3.6, 12.6 Hz, 1H, CH2), 1.58 (brs, 1H, OH), 1.49 (dq, J = 4.2, 12.0 Hz, 1H, C H 2), 1.45-1.36 (m, 2H, CH2), 0.65 (d, J = 7.8 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 155.4, 138.0, 128.4, 115.9, 94.6, 73.8, 56.0, 44.9, 41.6, 28.5, 24.2, 23.2, 5.4. IR (ATR) 3395, 2931, 2895, 2862, 2826, 1610, 1509, 1467, 1446, 1232, 1199, 1177, 1151, 1077, 1008, 924, 831 cm -1 . HR-MS m / z = calculated for C 15 H 22 NaO3[M+Na] + : 273.14666, found 273.14542.

[0206] <Synthesis Example 5>

Chem.

[0207] <Synthesis Example 5-1> [ka]

[0208] To a 34 mL solution of compound 7a (0.85 g, 3.4 mmol, 1.0 equivalent) in methylene chloride, pyridinium chlorochromate (1.1 g, 5.1 mmol, 1.5 equivalents) and Celite (1.1 g) were added at 0°C and the mixture was stirred at room temperature for 3 hours. The solid was filtered off, and the filtrate was concentrated to obtain the crude product of compound 8a. To a methanol (15 mL) solution of the obtained crude product 8a, potassium carbonate (1.4 g, 10.2 mmol, 3.0 equivalents) was added. After stirring at room temperature for 24 hours, water was added. The mixture was extracted with hexane, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain compound 9a (0.77 g) in 91% yield.

[0209] 1 H NMR (600 MHz, CDCl3) δ 7.22 (d, J = 7.8 Hz, 1H, Ar), 7.18 (t, J = 7.8 Hz, 1H, Ar), 7.09 (d, J = 7.8 Hz, 1H, Ar), 7.01 (t, J = 7.8 Hz, 1H, Ar), 5.20 (d, J = 7.2 Hz, 1H, OCH2O), 5.17 (d, J = 7.2 Hz, 1H, OCH2O), 3.46 (s, 3H, OCH3), 3.15 (brt, J = 10.2 Hz, 1H, CH2), 2.79-2.72 (m, 1H, CH2), 2.53-2.48 (m, 2H, CH2and C H CH3), 2.46 (dd, J = 6.0, 13.2 Hz, 1H, C H Ar), 2.17-2.11 (m, 1H, CH2), 2.03-1.92 (m, 2H, CH2), 1.82-1.73 (m, 1H, CH2), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 212.9, 154.7, 132.5, 127.5, 127.4, 122.0, 114.2, 94.4, 56.0, 49.8, 45.3, 41.9, 33.0, 26.6, 12.0. IR (ATR) 2933, 2865, 2826, 1708, 1600, 1585, 1491, 1453, 1233, 1201, 1182, 1153, 1078, 1045, 1001, 924, 755 cm -1 . HR-MS m / z = calcd for C 15 H 20 NaO3[M+Na] + : 271.13101, found 271.13008.

[0210] <Synthesis Example 5-2> [ka]

[0211] Compound 9b (3.2 g) was obtained in 93% of the yield of compound 7b (3.5 g, 13.9 mmol) in the same manner as the synthesis of compound 9a from compound 7a.

[0212] 1 H NMR (600 MHz, CDCl3) δ 7.24 (t, J = 8.1 Hz, 1H, Ar), 6.92 (dd, J = 2.4, 8.4 Hz, 1H, Ar), 6.87 (s, 1H, Ar), 6.85 (d, J = 7.2 Hz, 1H, Ar), 5.18 (d, J = 7.2 Hz, 1H, OCH2O), 5.17 (d, J = 7.2 Hz, 1H, OCH2O), 3.49 (s, 3H, OCH3), 2.61 (dq, J = 12.0, 6.0 Hz, 1H, C H CH3), 2.52 (dd, J = 4.2, 12.0 Hz, 1H, CH2), 2.51-2.48 (m, 1H, C HAr), 2.46 (dd, J = 6.0, 13.8 Hz, 1H, CH2), 2.17-2.12 (m, 1H, CH2), 2.00 (dd, J = 3.0, 13.8 Hz, 1H, CH2), 1.93 (dq, J = 3.6, 12.0 Hz, 1H, CH2), 1.75 (tq, J = 4.2, 12.6 Hz, 1H, CH2), 0.83 (d, J = 6.0 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 212.3, 157.6, 145.6, 129.6, 120.8, 115.3, 114.1, 94.5, 56.0, 53.1, 50.5, 41.8, 34.4, 26.5, 12.3. IR (ATR) 2933, 2871, 2826, 1708, 1599, 1584, 1487, 1449, 1260, 1246, 1150, 1079, 1015, 995, 950, 923, 785, 701 cm -1 . HR-MS m / z = calcd for C 15 H 20 NaO3[M+Na] + : 271.13101, found 271.13039.

[0213] <Synthesis Example 5-3> [ka]

[0214] Compound 9c (1.13 g) was obtained in 91% yield from compound 7c (1.25 g, 5.0 mmol) in the same manner as the synthesis of compound 9a from compound 7a.

[0215] 1¹H NMR (600 MHz, CDCl₃) δ 7.11 (d, J = 8.4 Hz, 2H, Ar), 7.00 (d, J = 8.4 Hz, 2H, Ar), 5.17 (s, 2H, OCH₂O), 3.49 (s, 3H, OCH₃), 2.58 (dq, J = 12.0, 6.6 Hz, 1H, C H CH₃), 2.50 (dd, J = 3.0, 12.0 Hz, 1H, CH₂), 2.49-2.48 (m, 1H, C H Ar), 2.44 (dd, J = 6.0, 13.2 Hz, 1H, CH₂), 2.17-2.11 (m, 1H, CH₂), 1.97 (dd, J = 3.0, 13.2 Hz, 1H, CH₂), 1.91 (dq, J = 3.6, 13.2 Hz, 1H, CH₂), 1.75 (tq, J = 4.8, 12.6 Hz, 1H, CH₂), 0.81 (d, J = 6.0 Hz, 3H, CHC H 3). 13 ¹³C NMR (150 MHz, CDCl₃) δ 212.4, 155.9, 137.3, 128.1, 116.3, 94.5, 56.0, 52.4, 50.8, 41.8, 34.6, 26.4, 12.2. IR (ATR) 2933, 2825, 1708, 1610, 1510, 1446, 1309, 1234, 1199, 1178, 1152, 1078, 1003, 923, 832 cm -1 ⁻¹. HR-MS m / z = calcd for C 15 H 20 NaO₃[M+Na] + : 271.13101, found 271.13152.

[0216] <Synthesis Example 6>

Formula

[0217] <Synthesis Example 6-1> [ka]

[0218] To a mixture of (bromomethyl)triphenylphosphonium bromide (5.4 g, 12.3 mmol, 1.5 equivalents) and tetrahydrofuran (12.0 mL), lithium diisopropylamide (0.5 M tetrahydrofuran solution, 23.0 mL, 11.5 mmol, 1.4 equivalents) was added at -78°C, and the mixture was heated to 0°C and stirred for 1 hour. The mixture was cooled again to -78°C, and a tetrahydrofuran solution of compound 9a (2.0 g, 8.05 mmol, 1.0 equivalent) was added, and the mixture was heated to 0°C while stirring for 12 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 10a.

[0219] To the methanol (16.0 mL) solution of the obtained 10a, 3M hydrochloric acid (8.0 mL) was added at 0°C. After stirring for 24 hours, saturated sodium bicarbonate solution was added to stop the reaction, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 11a (2.0 g) in 88% yield.

[0220] 1 H NMR (600 MHz, CDCl3) δ 7.17 (d, J = 7.8 Hz, 1H, Ar), 7.07 (t, J = 7.8 Hz, 1H, Ar), 6.91 (t, J = 7.8 Hz, 1H, Ar), 6.72 (d, J = 7.8 Hz, 1H, Ar), 5.94 (s, 1H, C=CHBr), 4.67 (brs, 1H, OH), 3.10 (brd, 1H, C H Ar), 2.68 (dt, J = 3.6, 12.0 Hz, 1H, C HCH3), 2.51-2.44 (m, 1H, allylic CH2), 1.95-1.84 (m, 3H, CH2), 1.76 (dq, J = 3.0, 12.6 Hz, 1H, CH2), 1.46 (tq, J = 3.6, 12.6 Hz, 1H, CH2), 0.87 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 153.0, 148.5, 131.1, 127.8, 126.9, 121.1, 115.5, 98.9, 45.4, 43.1, 33.6, 32.4, 26.6, 15.3. IR (ATR) 3526, 2963, 2929, 2855, 1590, 1501, 1489, 1451, 1376, 1330, 1269, 1251, 1235, 1209, 1172, 1127, 1082, 1039, 870, 848, 826, 802, 782, 751, 707cm -1 . HR-MS m / z = calcd for C 14 H 16 BrO [MH] - : 279.03845, found 279.03320.

[0221] <Synthesis Example 6-2> [ka]

[0222] Compound 11b (2.9 g) was obtained in 90% of the yield of compound 9b (2.5 g, 10.0 mmol) in the same manner as the synthesis of compound 9a to compound 11a.

[0223] 1¹H NMR (600 MHz, CDCl₃) δ 7.16 (t, J = 7.8 Hz, 1H, Ar), 6.74 (d, J = 7.8 Hz, 1H, Ar), 6.67 (d, J = 9.0 Hz, 1H, Ar), 6.65 (s, 1H, Ar), 5.93 (s, 1H, C=CHBr), 4.59 (s, 1H, OH), 3.10 (brd, J = 11.4 Hz, 1H, C H Ar), 2.32 (dq, J = 11.4, 6.6 Hz, 1H, C H CH₃), 2.18 (dt, J = 3.6, 12.0 Hz, 1H, CH₂), 1.94-1.86 (m, 3H, CH₂), 1.67 (dq, J = 3.0, 12.6 Hz, 1H, CH₂), 1.43 (tq, J = 3.6, 12.6 Hz, 1H, CH₂), 0.83 (d, J = 6.6 Hz, 3H, CHC H H₃). 13 ¹³C NMR (150 MHz, CDCl₃) δ 155.6, 148.3, 147.3, 129.6, 120.0, 114.2, 113.2, 99.1, 53.2, 43.7, 35.2, 32.4, 26.6, 15.7. IR (ATR) 3338, 2962, 2928, 2875, 2854, 1613, 1590, 1491, 1456, 1376, 1330, 1277, 1247, 1156, 970, 885, 856, 834, 801, 784, 761, 699 cm -1 ⁻¹. HR-MS m / z = calcd for C 14 H 16 BrO [M-H] - : 279.03845, found 279.03489.

[0224] <Synthesis Example 6-3>

Chemical Formula

[0225] Compound 11c (0.3g) was obtained in 87% yield from compound 9c (0.3g, 1.2 mmol) in the same manner as the synthesis of compound 9a to compound 11a.

[0226] 1 H NMR (600 MHz, CDCl3) δ 7.03 (d, J = 8.4 Hz, 2H, Ar), 6.77 (d, J = 8.4 Hz, 2H, Ar), 5.92 (s, 1H, C=CHBr), 4.65 (s, 1H, OH), 3.09 (brd, J = 15.0 Hz, 1H,C H Ar), 2.28 (dq, J = 12.0, 6.6 Hz, 1H, C H CH3), 2.17 (dt, J = 3.6, 12.0 Hz, 1H, CH2), 1.94-1.83 (m, 3H, CH2), 1.65 (dq, J = 3.6, 12.6 Hz, 1H, CH2), 1.42 (tq, J = 3.6, 12.6 Hz, 1H, CH2), 0.81 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 153.8, 148.5, 137.7, 128.4, 115.2, 98.9, 52.5, 44.0, 35.5, 32.4, 26.6, 15.7. IR (ATR) 3334, 2962, 2927, 2873, 2854, 1612, 1598, 1512, 1455, 1443, 1375, 1331, 1227, 1173, 849, 827, 800, 783, 763, 708cm -1 . HR-MS m / z = calcd for C 14 H 16 BrO [MH] - : 279.03845, found 279.03612.

[0227] <Synthesis Example 7> [ka]

[0228] <Synthesis Example 7-1> [ka]

[0229] To a solution of compound 11a (0.24 g, 0.85 mmol, 1.0 equivalent) in N,N-dimethylformamide (1.7 mL), anhydrous potassium carbonate (0.47 g, 3.4 mmol, 4.0 equivalents) and triethyl((4-iodo-2-methylbutan-2-yl)oxy)silane (13B) (1.1 g, 3.4 mmol, 4.0 equivalents) were added. The mixture was stirred at 50°C for 24 hours. After cooling to room temperature, water was added, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 12aB (0.33 g) in 81% yield.

[0230] 1 H NMR (600 MHz, CDCl3) δ 7.16 (d, J = 7.8 Hz, 1H, Ar), 7.15 (d, J = 7.2 Hz, 1H, Ar), 6.91 (t, J = 7.2 Hz, 1H, Ar), 6.87 (d, J = 7.2 Hz, 1H, Ar), 5.92 (s, 1H, C=CHBr), 4.10 (t, J = 7.2 Hz, 2H, OCH2), 3.09 (brd, J = 13.8 Hz, 1H, C H Ar), 2.78 (brt, J = 8.4 Hz, 1H, CH2), 2.47 (brs, 1H, CH2), 1.94 (t, J = 7.2 Hz, 2H, OCH2C H 2), 1.95-1.84 (m, 2H, CH2and C HCH3), 1.80 (brd, J = 12.6 Hz, 1H, CH2), 1.72 (brq, J = 11.4 Hz, 1H, CH2), 1.43 (tq, J = 4.2, 12.6 Hz, 1H, CH2), 1.30 (s, 3H, C(C H 3)2), 1.29 (s, 3H, C(C H 3)2), 0.95 (t, J = 7.8 Hz, 9H, Si(CH2C H 3)3), 0.82 (d, J = 6.6 Hz, 3H, CHC H 3), 0.59 (q, J = 7.8 Hz, 6H, Si(C H 2CH3)3). 13 C NMR (150 MHz, CDCl3) δ 156.6, 149.0, 133.4, 127.4, 126.8, 120.4, 111.5, 98.6, 72.4, 64.8, 43.8, 43.0, 33.8, 32.5, 30.5, 30.4, 26.7, 15.4, 7.1, 6.7. IR (ATR) 2956, 2931, 2874, 1599, 1585, 1492, 1450, 1378, 1365, 1231, 1159, 1051, 1025, 740, 723 cm -1 .

[0231] <Synthesis Example 7-2> [ka]

[0232] Compound 12aC (0.38 g) was obtained from compound 11a (0.24 g, 0.85 mmol) and 13C in 89% yield, in the same manner as the synthesis of compound 12aB from compound 11a.

[0233] 1¹H NMR (600 MHz, CDCl₃) δ 7.15 (d, J = 7.8 Hz, 1H, Ar), 7.14 (d, J = 7.8 Hz, 1H, Ar), 6.90 (t, J = 7.8 Hz, 1H, Ar), 6.83 (d, J = 7.8 Hz, 1H, Ar), 5.92 (s, 1H, C=CHBr), 3.94 (t, J = 6.6 Hz, 2H, OCH₂), 3.09 (brd, J = 13.8 Hz, 1H, C H Ar), 2.77 (brt, J = 6.9 Hz, 1H, CH₂), 2.51 (brs, 1H, CH₂), 1.93-1.72 (m, 6H, CH₂and C H CH₃), 1.59-1.56 (m, 2H, CH₂), 1.44 (tq, J = 4.2, 12.6 Hz, 1H, CH₂), 1.24 (s, 6H, C(C H ₃)₂), 0.95 (t, J = 7.8 Hz, 9H, Si(CH₂C H ₃)₃), 0.83 (d, J = 6.6 Hz, 3H, CHC H ₃), 0.57 (q, J = 7.8 Hz, 6H, Si(C H ₂CH₃)₃). 13 ¹³C NMR (150 MHz, CDCl₃) δ 156.7, 148.9, 133.5, 127.7, 120.5, 111.7, 98.6, 73.0, 68.7, 42.9, 41.7, 33.6, 32.5, 29.9, 26.7, 24.6, 17.7, 15.4, 7.1, 6.8. IR (ATR) 2954, 2932, 2873, 1599, 1584, 1492, 1450, 1378, 1363, 1233, 1214, 1157, 1050, 1016, 742, 723 cm -1

[0234] <Synthesis Example 7-3>

Formula

[0235] Compound 12bB (0.13 g) was obtained from compound 11b (84 mg, 0.30 mmol) and 13B in 88% yield, in the same manner as the synthesis of compound 11a to compound 12aB.

[0236] 1 H NMR (600 MHz, CDCl3) δ 7.20 (t, J = 7.8 Hz, 1H, Ar), 6.75 (d, J = 7.8 Hz, 1H, Ar), 6.74 (dd, J = 7.8 Hz, 1H, Ar), 6.71 (s, 1H, Ar), 5.93 (s, 1H, C=CHBr), 4.12 (t, J = 7.2 Hz, 2H, OC H 2CH2), 3.10 (brd, J = 13.2 Hz, 1H, C H Ar), 2.37-2.30 (m, 1H, CH2), 2.19 (dt, J = 3.6, 11.4 Hz, 1H, CH2), 1.94 (t, J = 7.2 Hz, 2H, OC H 2CH2), 1.95-1.86 (m, 4H, CH2, and CHCH3), 1.69 (dq, J = 6.0, 12.6 Hz, 1H, CH2), 1.43 (tq, J = 3.6, 13.2 Hz, 1H, CH2), 1.30 (s, 6H, C(C H 3)3), 0.95 (t, J = 7.8 Hz, 9H, Si(CH2C H 3)3), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3) , 0.59 (q, J = 7.8 Hz, 6H, Si(C H 2CH3)3). 13C NMR (150 MHz, CDCl3) δ 159.2, 148.4, 146.9, 129.4, 119.6, 113.9, 111.8, 99.0, 72.4, 64.6, 53.4, 43.8, 43.7, 35.3, 32.5, 30.4, 30.3, 26.6, 15.7, 7.1, 6.7. IR (ATR) 2955, 2932, 2875, 1730, 1600, 1583, 1457, 1444, 1381, 1365, 1264, 1242, 1222, 1157, 1032, 785, 743, 723, 700 cm -1 .

[0237] <Synthesis Example 7-4> [ka]

[0238] Compound 12bC (0.134 g) was obtained from compound 11b (84 mg, 0.30 mmol) and 13C in 90% yield, in the same manner as the synthesis of compound 11a to compound 12aB.

[0239] 1 H NMR (600 MHz, CDCl3) δ 7.19 (t, J = 7.8 Hz, 1H, Ar), 6.76-6.69 (m, 3H, Ar), 5.93 (s, 1H, C=CHBr), 3.95 (t, J = 7.2 Hz, 2H, OC H 2CH2), 3.10 (brd, J = 12.6 Hz, 1H, C H Ar), 2.34 (dq, J = 10.8, 6.6 Hz, 1H, C H CH3), 2.19 (dt, J = 11.4, 3.6 Hz, 1H, CH2), 1.95-1.83 (m, 5H, CH2and OCH2C H 2), 1.69 (dq, J = 3.0, 12.6 Hz, 1H, C H 2), 1.59-1.56 (m, 2H, OCH2CH2CH 2), 1.43 (tq, J = 3.0, 13.2 Hz, 1H, CH2), 1.24 (s, 6H, C(CH3)2), 0.95 (t, J = 8.1 Hz, 9H, Si(CH2C) H 3)3), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3) , 0.57 (q, J = 7.8 Hz, 6H, Si(C H 2CH3)3). 13 C NMR (150 MHz, CDCl3) δ 159.3, 148.4, 146.9, 129.3, 119.6, 113.8, 111.8, 99.0, 73.0, 68.4, 53.4, 43.7, 41.3, 35.3, 32.4, 29.9, 26.6, 24.4, 15.7, 7.1, 6.8. IR (ATR) 2954, 2932, 2874, 1729, 1600, 1583, 1456, 1444, 1380, 1363, 1262, 1238, 1215, 1156, 1052, 1034, 1015, 801, 784, 741, 721, 699, 671cm -1 .

[0240] <Synthesis Example 8> In the following formula, "Me" represents a methyl group. [ka]

[0241] <Synthesis Example 8-1> [ka]

[0242] To a solution of compound 11b (0.14 g, 0.5 mmol, 1.0 equivalent) in N,N-dimethylformamide (1.0 mL), anhydrous potassium carbonate (28 mg, 2.0 mmol, 4.0 equivalents) and methyl-2-iodoacetate (24 mg, 2.0 mmol, 4.0 equivalents) were added. The mixture was stirred at 50°C for 24 hours. After cooling to room temperature, water was added, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 14b (0.14 g) in 80% yield.

[0243] 1 H NMR (600 MHz, CDCl3) δ 7.22 (t, J = 7.8 Hz, 1H, Ar), 6.81 (d, J = 7.8 Hz, 1H, Ar), 6.73 (s, 1H, Ar), 6.72 (dd, J = 2.4, 8.4 Hz, 1H, Ar), 5.93 (s, 1H, C=CHBr), 4.63 (s, 2H, C H 2C(O)OCH3), 3.81 (s, 3H, CH2C(O)OC H 3), 3.10 (brd, J = 12.9 Hz, 1H, C H Ar), 2.32 (dq, J = 10.8, 6.6 Hz, 1H, C H CH3), 2.20 (dt, J = 3.6, 12.0 Hz, 1H, CH2), 1.96-1.87 (m, 3H, CH2), 1.67 (dq, J = 3.0, 12.6 Hz, 1H, CH2), 1.43 (tq, J = 3.0, 12.6, 1H, CH2), 0.82 (d, J = 6.6 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 169.4, 157.9, 148.2, 147.2, 129.5, 121.0, 114.3, 111.7, 99.1, 65.4, 53.3, 52.3, 43.7, 35.3, 32.4, 26.6, 15.7. IR (ATR) 2954, 2929, 2877, 2855, 1763, 1740, 1608, 1585, 1486, 1439, 1376, 1289, 1207, 1159, 1089, 879, 857, 786, 700 cm -1 . HR-MS m / z = calcd for C 17 H 21 BrNaO3[M+Na] + : 375.05718, found 375.05864.

[0244] <Synthesis Example 8-2> [ka]

[0245] Compound 14c (0.17 g) was obtained in 96% yield from compound 11c (0.14 g, 0.5 mmol) and methyl 2-iodoacetate (24 mg, 2.0 mmol) in the same manner as the synthesis of compound 14b from compound 11b.

[0246] 1 H NMR (600 MHz, CDCl3) δ 7.08 (d, J = 8.4 Hz, 2H, Ar), 6.85 (d, J = 8.4 Hz, 2H, Ar), 5.92 (s, 1H, C=CHBr), 4.62 (s, 2H, C H 2C(O)OCH3), 3.81 (s, 3H, CH2C(O)OC H 3), 3.09 (brd, J = 12.9 Hz, 1H, C H Ar), 2.28 (dq, J = 12.0, 6.6 Hz, 1H, C HCH3), 2.19 (dt, J = 3.6, 11.4 Hz, 1H, CH2), 1.94-1.83 (m, 3H, CH2), 1.65 (dq, J = 3.6, 12.6 Hz, 1H, CH2), 1.42 (tq, J = 3.6, 12.6 Hz, 1H, CH2), 0.80 (d, J = 6.6 Hz, 3H, CHC H 3). 13 13C NMR (150 MHz, CDCl3) δ 169.5, 156.2, 148.4, 138.7, 128.3, 114.6, 99.0, 65.5, 52.5, 52.2, 44.0, 35.5, 32.4, 26.6, 15.7. IR (ATR) 2954, 2929, 2873, 2855, 1762, 1740, 1609, 1586, 1510, 1438, 1376, 1308, 1288, 1203, 1177, 1085, 849, 828, 801, 705 cm -1 . HR-MS m / z = calculated for C 17 H 21 BrNaO3[M+Na] + : 375.05718, found 375.05975.

[0247] <Synthesis Example 9>

Chemical Formula

[0248] <Synthesis Example 9-1>

Chemical Formula

[0249] To a methanol (8.0 mL) solution of compound 9b (0.94 g, 3.8 mmol, 1.0 equivalent), 3 M hydrochloric acid (4.0 mL) was added at 0°C. After stirring for 24 hours, saturated sodium bicarbonate solution was added to stop the reaction, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 15b.

[0250] To a solution of the crude product 15b obtained and triethylamine (1.1 mL, 7.6 mmol, 2.0 equivalents) in methylene chloride (7.6 mL), trifluoromethanesulfonic anhydride (0.94 mL, 5.7 mmol, 1.5 equivalents) was added at 0°C. After stirring at room temperature for 1 hour, water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 16b (1.26 g) in 93% yield.

[0251] 1 H NMR (600 MHz, CDCl3) δ 7.42 (t, J = 7.8 Hz, 1H, Ar), 7.24 (d, J = 7.8 Hz, 1H, Ar), 7.16 (dd, J = 2.4, 8.4 Hz, 1H, Ar), 7.12 (s, 1H, Ar), 2.64-2.56 (m, 2H), 2.53 (brd, J = 13.8 Hz, 1H), 2.48 (dt, J = 6.0, 13.2 Hz, 1H), 2.21-2.16 (m, 1H), 2.02 (brd, J = 12.0 Hz, 1H), 1.93 (dq, J = 3.6, 12.0 Hz, 1H), 1.78 (tq, J = 4.2 13.2 Hz, 1H), 0.82 (d, J = 6.0 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 211.1, 149.8, 146.9, 130.5, 127.3, 120.0, 119.5, 117.7, 52.7, 50.2, 41.6, 34.3, 26.2, 12.1. IR (ATR) 2970, 2936, 2873, 1711, 1613, 1580, 1446, 1419, 1247, 1207, 1139, 1119, 968, 904, 850, 818, 793, 734, 695, 653 cm -1 . HR-MS m / z = calcd for C 14 H 15 F3NaO4S [M+Na] + : 359.05408, found 359.05860.

[0252] <Synthesis Example 10> [ka]

[0253] <Synthesis Example 10-1> [ka]

[0254] To a mixture of copper iodide (27 mg, 0.14 mmol, 5.0 mol%) and bis(triphenylphosphine)palladium(II) dichloride (0.10 g, 0.14 mmol, 5.0 mol%), compound 16b (0.94 g, 1.0 equivalent), 2-methylpenta-4-in-2-ol (2.75 g, 28 mmol, 10.0 equivalents), and triethylamine (3.9 mL, 28.0 mmol, 10.0 equivalents) in a solution of N,N-dimethylformamide (5.6 mL) was added. After stirring at 60°C for 18 hours, the reaction solution was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 17b (0.73 g) in 92% yield.

[0255] 1¹H NMR (600 MHz, CDCl₃) δ 7.30 (d, J = 7.8 Hz, 1H, Ar), 7.28 (s, 1H, Ar), 7.26 (t, J = 7.8 Hz, 1H, Ar), 7.13 (d, J = 7.2 Hz, 1H, Ar), 2.64-2.58 (m, 1H), 2.61 (s, 2H, C≡C‑C H 2), 2.53 (dd, J = 4.2, 11.4 Hz, 1H), 2.53-2.47 (m, 1H), 2.46 (dd, J = 6.0, 13.2 Hz, 1H), 2.18-2.13 (m, 1H), 2.00-1.93 (m, 2H), 1.93 (dq, J = 3.0, 12.6 Hz, 1H), 1.76 (tq, J = 4.2, 13.2 Hz, 1H), 1.39 (s, 6H, C(C H ₃)₂), 0.81 (d, J = 6.0 Hz, 3H, CHC H ₃). 13 ¹³C NMR (150 MHz, CDCl₃) δ 212.0, 144.0, 130.3, 130.0, 128.6, 127.0, 123.7, 86.4, 83.4, 70.2, 52.9, 50.3, 41.8, 35.1, 34.4, 28.8, 26.4, 12.3. IR (ATR) 3429, 2971, 2932, 2871, 2227, 1705, 1599, 1579, 1482, 1448, 1427, 1377, 1361, 1246, 1218, 1138, 1020, 973, 905, 797, 699 cm -1 ⁻¹. HR‑MS m / z = calcd. for C 19 H 24 NaO [M+Na] + : 307.16740, found 307.16691.

[0256] <Synthesis Example 11>

Formula

[0257] <Synthesis Example 11-1> [ka]

[0258] To a solution of compound 17b (1.1 g, 3.8 mmol, 1.0 equivalent) in ethyl acetate (38 mL), 10% by mass of palladium (charcoal-supported, 50.5 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product of compound 18b.

[0259] To a solution of the crude product of compound 18b and imidazole (0.52 g, 7.6 mmol, 2.0 equivalents) in N,N-dimethylformamide (7.6 mL), chlorotriethylsilane (0.95 mL, 5.7 mmol, 1.5 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, saturated sodium bicarbonate solution was added at 0°C, and the mixture was extracted with hexane. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 19b.

[0260] To a mixture of (bromomethyl)triphenylphosphonium bromide (3.3 g, 7.6 mmol, 2.0 equivalents) and tetrahydrofuran (7.6 mL), lithium diisopropylamide (0.5 M tetrahydrofuran solution, 15.2 mL, 7.6 mmol, 2.0 equivalents) was added at -78°C, and the mixture was heated to 0°C and stirred for 1 hour. The mixture was cooled again to -78°C, and a tetrahydrofuran solution of the crude product of compound 19b was added. The mixture was heated to 0°C and stirred for 12 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 20b (1.0 g) in 76% yield.

[0261] 1¹H NMR (600 MHz, CDCl₃) δ 7.20 (t, J = 7.2 Hz, 1H, Ar), 7.02 (d, J = 7.2 Hz, 1H, Ar), 6.97 (d, J = 7.2 Hz, 1H, Ar), 6.96 (s, 1H, Ar), 5.93 (s, 1H, C=CHBr), 3.13-3.08 (m, 1H, C H Ar), 2.57 (t, J = 7.8 Hz, 2H, ArC H ₂CH₂CH₂), 2.35 (dq, J = 11.4, 6.6 Hz, 1H, C H CH₃), 2.20 (dt, J = 3.6, 11.4 Hz, 1H), 1.96-1.86 (m, 3H), 1.73-1.64 (m, 3H), 1.47-1.42 (m, 3H), 1.18 (s, 6H, C(C H ₃)₂), 0.93 (t, J = 8.1 Hz, 9H, Si(CH₂C H ₃)₃), 0.81 (d, J = 6.6 Hz, 3H, C H CH₃), 0.54 (q, J = 8.1 Hz, 6H, Si(C H ₂CH₃)₃). 13 ¹³C NMR (150 MHz, CDCl₃) δ 148.5, 145.1, 143.0, 128.3, 127.5, 126.4, 124.6, 98.9, 73.3, 53.4, 44.6, 43.8, 36.4, 35.4, 32.5, 29.9, 26.7, 26.3, 15.7, 7.1, 6.8. IR (ATR) 2932, 2912, 2873, 1606, 1458, 1444, 1378, 1363, 1234, 1201, 1151, 1126, 1045, 1031, 1015, 889, 791, 741, 721, 705, 670 cm -1 .

[0262] <Synthesis Example 12>

Chemical Formula

[0263] <Synthesis Example 12-1> [ka]

[0264] A 1.0 mL methanol solution of compound 9b (0.12 g, 0.5 mmol, 1.0 equivalent) was mixed with 0.5 mL of 3 M hydrochloric acid at 0°C. After stirring for 24 hours, the reaction was stopped by adding saturated sodium bicarbonate solution, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 15b.

[0265] To the obtained solution of 15b in N,N-dimethylformamide (1.0 mL), anhydrous potassium carbonate (0.28 g, 4.0 mmol, 4.0 equivalents) and triethyl((4-iodo-2-methylbutan-2-yl)oxy)silane (13B) (0.66 g, 2.0 mmol, 4.0 equivalents) were added. The mixture was stirred at 50°C for 24 hours. After cooling to room temperature, water was added, and the mixture was extracted with hexane. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 21bB (0.20 g) in 98% yield.

[0266] 1 H NMR (600 MHz, CDCl3) δ 7.23 (t, J = 7.8 Hz, 1H, Ar), 6.77 (d, J = 7.8 Hz, 2H, Ar), 6.74 (s, 1H, Ar), 4.12 (t, J = 7.2 Hz, 2H, OCH2), 2.61 (dq, J = 12.0, 6.6 Hz, 1H, C HCH₃), 2.52 (dd, J = 3.6, 12.0 Hz, 1H), 2.51-2.47 (m, 1H), 2.45 (dd, J = 6.0, 13.2 Hz, 1H), 2.17-2.13 (m, 1H), 2.02-1.89 (m, 2H), 1.95 (dd, J = 7.2 Hz, 2H, OCH₂C H 2), 1.75 (tq, J = 4.2, 13.2 Hz, 1H), 1.31 (s, 6H, C(C H 3)2), 0.95 (t, J = 7.8 Hz, 9H, Si(CH₂C H 3)3), 0.82 (d, J = 6.6 Hz, 3H, CHC H 3), 0.59 (q, J = 7.8 Hz, 6H, Si(C H 2CH₃)3). 13 ¹³C NMR (150 MHz, CDCl₃) δ 212.3, 159.3, 145.5, 129.5, 119.3, 113.8, 112.0, 72.4, 64.7, 53.2, 50.5, 43.6, 41.8, 34.4, 30.4, 26.5, 12.2, 7.1, 6.7. IR (ATR) 2954, 2934, 2912, 2874, 1711, 1600, 1583, 1488, 1447, 1381, 1365, 1284, 1266, 1240, 1219, 1156, 1078, 1050, 1029, 1017, 961, 849, 785, 742, 721, 698, 671 cm⁻¹ -1 . HR-MS m / z = calcd for C 24 H 40 NaO₃Si [M+Na]⁺ + : 427.26444, found 427.26627.

[0267] <Synthesis Example 13>

Chemical Formula

[0268] <Synthesis Example 13-1> [ka]

[0269] Under an argon atmosphere, a mixture of 1-bromo-3-(methoxymethoxy)benzene (1.63 g, 7.5 mmol, 1.5 equivalents) and THF (11.2 mL) was mixed with a hexane solution of n-butyllithium (1.59 M hexane solution, 5.0 mL, 7.8 mmol, 1.5 equivalents) at -78°C. The mixture was stirred for 1 hour, and (S)-(+)-carbone (C1) (0.75 g, 5.0 mmol, 1.0 equivalent) was added to the resulting alkyllithium reaction solution at -78°C. The mixture was then heated to room temperature and stirred for 2 hours. The reaction was stopped by adding saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered by Celite, and concentrated under reduced pressure to obtain the crude product of compound C2b.

[0270] Under an argon atmosphere, a 21 mL solution of pyridinium chlorochromate (1.6 g, 7.5 mmol, 1.5 equivalents) and 4 Å molecular sieves (0.5 g) in methylene chloride was added at 0°C. After stirring at room temperature for 3 hours, the solid was filtered off, and the filtrate was concentrated to obtain the crude product of compound C3a.

[0271] To a 50 mL ethyl acetate solution of the obtained crude product C3a, 10% by mass of palladium (charcoal-supported, 72 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 24 hours. The mixture was filtered through Celite, and the filtrate was concentrated to obtain the crude product of compound C8b.

[0272] To a methanol (10 mL) solution of the obtained crude product C8b, potassium carbonate (2.0 g, 15 mmol, 3.0 equivalents) was added. After stirring at room temperature for 24 hours, water was added. The mixture was extracted with hexane, and the organic layer was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound C9b (0.53 g) in 37% yield.

[0273] 1 H NMR (600 MHz, CDCl3) δ 7.25 (t, J = 7.8 Hz, 1H, Ar), 6.93 (dd, J = 2.4, 7.8 Hz, 1H, Ar), 6.87 (d, J = 2.4 Hz, 1H, Ar), 6.85 (d, J = 7.8 Hz, 1H, Ar), 5.19 (d, J = 6.6 Hz, 1H, OCH2O), 5.17 (d, J = 6.6 Hz, 1H, OCH2O), 3.50 (s, 3H, OCH3), 2.57 (dq, J = 12.6, 6.6 Hz, 1H, C H CH3), 2.50 (dt, J = 12.6, 2.4 Hz, 1H, C H Ar), 2.47 (dt, J = 3.6, 12.0 Hz, 1H), 2.26-2.19 (m, 1H), 1.99 (dt, J = 10.8, 2.4 Hz, 1H), 1.71-1.64 (m, 2H), 1.59 (dq, J = 13.2, 6.6 Hz, 1H), 0.91 (d, J = 6.6 Hz, 3H, CH(C H 3)2), 0.90 (d, J = 6.6 Hz, 3H, CH(C H 3)2), 0.82 (d, J = 6.6 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 212.5, 157.6, 145.7, 129.6, 120.7, 115.3, 114.0, 94.5, 56.0, 51.9, 49.9, 45.2, 44.8, 38.2, 32.7, 19.5, 19.3, 12.1. IR (ATR) 2958, 2932, 2873, 2826, 1708, 1584, 1486, 1450, 1370, 1313, 1252, 1216, 1149, 1078, 1010, 994, 941, 922, 872, 779, 700cm -1 . HR-MS m / z = calcd for C 18 H 26 NaO3[M+Na] + : 313.17796, found 313.17905.

[0274] <Synthesis Example 14> [ka]

[0275] <Synthesis Example 14-1> [ka]

[0276] To a mixture of (bromomethyl)triphenylphosphonium bromide (1.1 g, 2.5 mmol, 2.0 equivalents) and THF (2.5 mL), lithium diisopropylamide (0.5 M THF solution, 5.0 mL, 2.5 mmol, 2.0 equivalents) was added at -78°C, and the mixture was heated to 0°C and stirred for 1 hour. The mixture was cooled again to -78°C, and a solution of compound C9b (0.31 g, 1.25 mmol, 1.0 eq.) in tetrahydrofuran (3.0 mL) was added, and the mixture was heated to 0°C while stirring for 12 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound C10b.

[0277] To a methanol (2.5 mL) solution of the obtained crude product C10b, 3M hydrochloric acid (1.25 mL) was added at 0°C. After stirring for 24 hours, saturated sodium bicarbonate solution was added to stop the reaction, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound C11b (0.31 g) in 76% yield.

[0278] 1 H NMR (600 MHz, CDCl3) δ 7.17 (t, J = 7.5 Hz, 1H, Ar), 6.75 (d, J = 7.2 Hz, 1H, Ar), 6.67 (dd, J = 1,8, 7.8 Hz, 1H, Ar), 6.66 (s, 1H, Ar), 5.92 (s, 1H, C=CHBr), 4.63 (s, 1H, OH), 3.12 (dt, J = 12.6, 2.4 Hz, 1H, C H Ar), 2.27 (dq, J = 11.4, 6.0 Hz, 1H, C H CH3), 2.16 (dt, J = 3.0, 11.4 Hz, 1H, CH2), 1.87 (dq, J = 13.2, 2.4 Hz, 1H), 1.61 (t, J = 12.6 Hz, 1H), 1.8-1.52 (m, 1H), 1.40 (q, J = 12.6 Hz, 1H), 1.34-1.27 (m, 1H), 0.94 (d, J = 7.2 Hz, 3H, CH(C H 3)2), 0.91 (d, J = 7.2 Hz, 3H, CH(C H 3)2), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 155.6, 148.3, 147.4, 129.7, 119.9, 114.1, 113.2, 99.1, 53.0, 44.5, 43.6, 38.8, 36.0, 32.6, 19.7, 19.5, 15.4. IR (ATR) 3347, 2957, 2932, 2912, 2872, 1704, 1612, 1589, 1484, 1454, 1368, 1331, 1262, 1234, 1155, 970, 886, 864, 842, 783, 757, 730, 699cm -1 . HR-MS m / z = calcd for C 17 H 22 BrO [MH] - : 321.08540, found 321.08745.

[0279] <Synthesis Example 15> [ka]

[0280] <Synthesis Example 15-1> [ka]

[0281] To a solution of compound C11b (0.34 g, 1.05 mmol, 1.0 equivalent) in N,N-dimethylformamide (3 mL), anhydrous potassium carbonate (1.45 g, 10.5 mmol, 10.0 equivalents) and triethyl((4-iodo-2-methylbutan-2-yl)oxy)silane (13B) (1.72 g, 5.25 mmol, 5.0 equivalents) were added. The mixture was stirred at 50°C for 24 hours. After cooling to room temperature, water was added, and the mixture was extracted with hexane. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound C12b (0.52 g) in 94% yield.

[0282] 1H NMR (600 MHz, CDCl3) δ 7.22 (t, J = 7.8 Hz, 1H, Ar), 6.75 (d, J = 7.8 Hz, 1H, Ar), 6.74 (d, J = 7.8 Hz, 1H, Ar), 6.71 (s, 1H, Ar), 5.92 (s, 1H, C=CHBr), 4.12 (t, J = 7.2 Hz, 2H, OCH2), 3.12 (dt, J = 13.2, 2.4 Hz, 1H, C H Ar), 2.28 (dq, J = 11.4, 6.6 Hz, 1H, C H CH3), 2.17 (dt, J = 3.0, 12.0 Hz, 1H), 1.94 (t, J = 7.2 Hz, 2H, OCH2C H 2), 1.88 (brd, J = 13.2 Hz, 1H), 1.61 (t, J = 12.6 Hz, 1H), 1.59-1.52 (m, 1H), 1.41 (q, J = 12.6 Hz, 1H), 1.33-1.28 (m, 1H), 1.30 (s, 6H, C(C H 3)2), 0.95 (t, J = 7.8 Hz, 9H, Si(CH2C H 3)3), 0.94 (d, J = 7.2 Hz, 3H, CH(CH3)2), 0.90 (d, J = 7.2 Hz, 3H, CH(CH3)2), 0.82 (d, J = 6.0 Hz, 3H, CHC H 3), 0.59 (q, J = 7.8 Hz, 6H, Si(C H 2CH3)3). 13 C NMR (150 MHz, CDCl3) δ 159.2, 148.4, 147.0, 129.4, 119.6, 113.9, 111.7, 99.0, 72.4, 64.7, 53.2, 44.5, 43.7, 38.8, 36.0, 32.7, 30.4, 19.8, 19.5, 15.4, 7.1, 6.7. IR (ATR) 2955, 2934, 2911, 2874, 1730, 1600, 1583, 1457, 1382, 1365, 1289, 1263, 1222, 1157, 1031, 1016, 870, 784, 725, 700cm -1 .

[0283] <Synthesis Example 16> [ka]

[0284] <Synthesis Example 16-1> [ka]

[0285] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (5.9 mg, 8.0 μmol, 8.0 mol%) was mixed with tetrahydrofuran (1.0 mL) solution of compound 12aB (48.2 mg, 0.1 mmol, 1.0 equivalent) and compound 22b (53 mg, 0.11 mmol, 1.1 equivalent) and 3N potassium hydroxide (33 μL) solution, and the mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 23.

[0286] To a tetrahydrofuran solution (0.1 mL) of the crude product of compound 23, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.6 mL, 0.6 mmol, 6.0 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor aB (24.5 mg) in 59% yield.

[0287] 1H NMR (600 MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 1H, Ar), 7.16 (dd, J = 8.4, 7.8 Hz, 1H, Ar), 6.96 (t, J = 7.8 Hz, 1H, Ar), 6.89 (d, J = 7.8 Hz, 1H, Ar), 6.33 (d, J = 10.8 Hz, 1H, CH=C), 6.08 (d, J = 10.8 Hz, 1H, CH=C), 4.19-4.09 (m, 4H, CHO, OCH2), 2.95 (brd, J = 13.2 Hz, 1H, C H Ar), 2.76-2.69 (m, 1H), 2.57 (brd, J = 13.2 Hz, 1H), 2.54 (dd, J = 3.0, 13.2 Hz, 1H), 2.47 (dd, J = 3.6, 13.2 Hz, 1H), 2.43 (dd, J = 7.2, 13.2 Hz, 1H), 2.37 (brs, 1H), 2.25-2.14 (m, 2H), 2.05-1.96 (m, 2H), 1.95-1.61 (m, 7H), 1.47-1.37 (m, 1H), 1.31 (s, 6H, C(CH3)2), 0.84 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 156.0, 146.4, 142.0, 134.3, 132.6, 126.6, 123.8, 121.1, 114.6, 111.4, 70.6, 67.5, 67.1 (2C), 65.4, 45.2, 43.0, 42.0, 41.8, 36.9, 30.0, 29.6 (2C), 29.3, 27.7, 15.5. IR (ATR) 3349, 2965, 2927, 2885, 2853, 1598, 1492, 1449, 1365, 1289, 1228, 1158, 1088, 1049, 974, 940, 885, 813, 752 cm -1 . HR-MS m / z = calcd for C26 H 38 NaO4[M+Na] + : 437.26678, found 437.26733.

[0288] <Synthesis Example 16-2> [ka]

[0289] Compound des-D-19-nor aC (30.0 mg) was obtained in 71% yield from compounds 12aC (49.6 mg, 0.1 mmol) and 22b (53 mg, 0.11 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB.

[0290] 1 H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 7.2 Hz, 1H, Ar), 7.14 (dd, J = 7.2, 8.4 Hz, 1H, Ar), 6.92 (t, J = 7.2 Hz, 1H, Ar), 6.83 (d, J = 8.4 Hz, 1H, Ar), 6.36 (d, J = 10.8 Hz, 1H, CH=C), 6.09 (d, J = 10.8 Hz, 1H, CH=C), 4.11 (brs, 2H, OCH2), 3.99-3.91 (m, 2H, CHO), 2.97 (brd, J = 13.2 Hz, 1H, C HAr), 2.83 (brs, 1H), 2.62 (dd, J = 3.0, 13.2 Hz, 1H), 2.54 (dd, J = 3.0, 13.2 Hz, 1H), 2.48 (dd, J = 3.6, 13.2 Hz, 1H), 2.39 (dd, J = 7.2, 13.2 Hz, 1H), 2.45-2.37 (m, 1H), 2.21 (dd, J = 7.2, 13.2 Hz, 1H), 2.16 (dd, J = 7.2, 13.2 Hz, 1H), 2.01 (brs, 1H), 1.97-1.58 (m, 10H), 1.47-1.36 (m, 1H), 1.25 (s, 6H, C(CH3)2), 0.85 (d, J = 6.0 Hz, 3H, CHC H 3). 13 13C NMR (150 MHz, CDCl3) δ 156.5, 147.0, 134.5, 132.3, 126.6, 124.0, 120.7, 114.3, 113.4, 111.6, 70.8, 68.4, 67.4, 67.2, 45.1, 43.0, 42.1, 40.6, 36.8, 34.1, 30.1 (2C), 29.2, 29.1, 27.8, 24.7, 15.6. IR (ATR) 3353, 2963, 2927, 2881, 2854, 1599, 1492, 1450, 1365, 1289, 1234, 1157, 1127, 1087, 1046, 973, 939, 886, 814, 752 cm -1 . HR-MS m / z = calcd for C 27 H 40 NaO4[M+Na] + : 451.28243, found 451.28674.

[0291] <Synthesis Example 16-3>

Chemical Formula

[0292] Compound des-D bB (16.7 mg) was obtained in 40% yield from compound 12bB (48 mg, 0.1 mmol) and 22a (55 mg, 0.11 mmol) in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB.

[0293] 1 H NMR (600 MHz, CDCl3) δ 7.20 (dd, J = 7.2, 8.4 Hz, 1H, Ar), 6.79 (d, J = 7.2 Hz, 1H, Ar), 6.75-6.74 (m, 2H, Ar), 6.41 (d, J = 10.8 Hz, 1H, CH=C), 6.25 (d, J = 10.8 Hz, 1H, CH=C), 5.34 (s, 1H, C=CH2), 5.04 (s, 1H, C=CH2), 4.45 (brt, 1H, CHO), 4.24 (brs, 1H, CHO), 4.18 (t, J = 6.0 Hz, 2H, OCH2), 2.96 (brd, J = 13.2 Hz, 1H, C H Ar), 2.63 (dd, J = 3.0, 13.2 Hz, 1H), 2.40 (brs, 1H), 2.34 (dd, J = 7.2, 13.2 Hz, 1H), 2.35-2.27 (m, 1H), 2.21 (dt, J = 3.0, 10.8 Hz, 1H,C H Ar), 2.00 (t, J = 6.0 Hz, 2H, OCH2C H 2), 2.02-1.97 (m, 1H), 1.95-1.87 (m, 3H), 1.72-1.57 (m, 3H), 1.46-1.38 (m, 1H), 1.32 (s, 6H, C(CH3)2O), 0.80 (d, J = 6.0 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 148.1, 147.5, 146.2, 134.1, 129.3, 125.2, 120.3, 116.6, 113.9, 112.3, 111.5, 71.1, 70.5, 66.8, 65.1, 53.6, 45.5, 43.6, 42.8, 41.6, 35.4, 29.8, 29.6, 27.4, 16.1. IR (ATR) 3357, 2965, 2927, 2877, 1716, 1698, 1653, 1600, 1583, 1446, 1377, 1263, 1243, 1157, 1038, 911, 882, 784, 754, 701 cm -1 . HR-MS m / z = calcd for C 27 H 38 NaO4[M+Na] + : 449.26678, found 449.26855.

[0294] <Synthesis Example 16-4> [ka]

[0295] Compound des-D-19-nor bB (19 mg) was obtained in 46% yield from compounds 12bB (48.2 mg, 0.1 mmol) and 22b (53 mg, 0.11 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB.

[0296] 1H NMR (600 MHz, CDCl3) δ 7.21 (dd, J = 7.8, 8.4 Hz, 1H, Ar), 6.79 (d, J = 7.8 Hz, 1H, Ar), 6.76 (s, 1H, Ar), 6.75 (d, J = 8.4 Hz, 1H, Ar), 6.34 (d, J = 11.4 Hz, 1H, CH=C), 6.10 (d, J = 11.4 Hz, 1H, CH=C), 4.18 (t, J = 6.0 Hz, 2H, OCH2), 4.16-4.06 (m, 2H, CHO), 2.94 (brd, J = 13.2 Hz, 1H, C H Ar), 2.78 (dd, J = 3.6, 13.2 Hz, 1H), 2.51 (dd, J = 3.0, 13.2 Hz, 1H), 2.48 (dd, J = 3.0, 13.2 Hz, 1H), 2.41 (brs, 1H), 2.37-2.31 (m, 1H), 2.27 (dd, J = 7.2, 13.2 Hz, 1H, C H 2), 2.25-2.20 (m, 2H), 2.16 (dd, J = 7.2, 13.2 Hz, 1H), 2.00 (t, J = 6.0 Hz, 2H, OCH2C H 2), 2.01-1.80 (m, 3H), 1.74-1.51 (m, 3H), 1.43-1.37 (m, 1H), 1.32 (s, 6H, C(CH3)2), 0.86 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 158.6, 148.1, 146.2, 132.4, 129.3, 124.0, 120.3, 114.8, 113.9, 111.5, 70.5, 67.4, 67.2, 65.1, 53.7, 44.8, 43.6, 42.2, 41.6, 37.3, 35.4, 29.7, 29.6, 29.5, 27.4, 16.2. IR (ATR) 3359, 2965, 2925, 2881, 2854, 1607, 1583, 1476, 1444, 1367, 1285, 1267, 1232, 1156, 1081, 1044, 974, 940, 886, 813, 783, 753, 700cm -1 . HR-MS m / z = calcd for C 26 H 38 NaO4[M+Na] + : 437.26678, found 437.26497.

[0297] <Synthesis Example 16-5> [ka]

[0298] Compound epi-des-D-19-nor bB (25 mg) was obtained in 67% yield from compounds epi-12bB (48.0 mg, 0.1 mmol) and 22b (43.3 mg, 0.09 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB.

[0299] 1 H NMR (600 MHz, CDCl3) δ 7.21 (dd, J = 7.8, 8.4, 7.8 Hz, 1H, Ar), 6.79 (d, J = 7.8 Hz, 1H, Ar), 6.76 (s, 1H, Ar), 6.75 (d, J = 8.4 Hz, 1H, Ar), 6.35 (d, J = 11.4 Hz, 1H, CH=C), 6.09 (d, J = 11.4 Hz, 1H, CH=C), 4.18 (t, J = 6.0 Hz, 2H, OCH2), 4.12 (brs, 2H, CHO), 2.94 (brd, J = 13.2 Hz, 1H,C HAr), 2.66 (dd, J = 3.6, 13.2 Hz, 1H), 2.53 (dd, J = 3.6, 13.2 Hz, 1H), 2.39 (brs, 1H, OH), 2.37 (dd, J = 7.2, 13.2 Hz, 1H), 2.40-2.31 (m, 1H), 2.24-2.20 (m, 2H), 2.00 (t, J = 6.0 Hz, 2H, OCH2C H 2), 1.95-1.86 (m, 4H), 1.69 (dq, J = 3.6, 13.2 Hz, 1H), 1.55 (brd, 1H), 1.48 (brd, 1H), 1.44-1.36 (tq, J = 3.6, 13.2 Hz, 1H), 1.32 (s, 6H, C(CH3)2), 0.86 (d, J = 6.6 Hz, 3H, CHC H 3). 13 13C NMR (150 MHz, CDCl3) δ 158.6, 148.1, 146.1, 132.5, 129.3, 123.9, 120.3, 114.8, 113.9, 111.5, 70.5, 67.4, 67.1, 65.0, 53.7, 45.0, 43.6, 42.2, 41.6, 36.9, 35.4, 29.7, 29.6, 27.4, 16.1. IR (ATR) 3366, 2966, 2926, 2877, 2854, 1607, 1583, 1476, 1443, 1367, 1314, 1285, 1267, 1244, 1156, 1081, 1043, 975, 940, 909, 878, 812, 783, 755, 700 cm -1 -1. HR-MS m / z = calcd for C 26 27 38 NaO4[M+Na] + : 437.26678, found 437.26508.

[0300] <Synthesis Example 16-6> [Formula]

[0301] Compound des-D-19-nor bC (21.4 mg) was obtained in 50% yield from compounds 12bC (49.6 mg, 0.10 mmol) and 22b (53.0 mg, 0.11 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB.

[0302] 1 H NMR (600 MHz, CDCl3) δ 7.20 (dd, J = 7.2, 7.8 Hz, 1H, Ar), 6.76 (d, J = 7.2 Hz, 1H, Ar), 6.74 (s, 1H, Ar), 6.73 (d, J = 7.8 Hz, 1H, Ar), 6.34 (d, J = 11.4 Hz, 1H, CH=C), 6.09 (d, J = 11.4 Hz, 1H, CH=C), 4.13 (brs, 1H, CHO), 4.08 (brs, 1H, CHO), 3.98 (t, J = 6.6 Hz, 2H, OCH2), 2.95 (brd, J = 13.2Hz, 1H, C H Ar), 2.75 (dd, J = 3.0, 13.2 Hz, 1H), 2.51 (dd, J = 3.0, 13.2 Hz, 1H), 2.37-2.15 (m, 4H), 1.97-1.80 (m, 8H), 1.72-1.65 (m, 3H), 1.54 (brd, 1H), 1,47 (brd, J = 4.8 Hz, 1H), 1.53-1.45 (m, 2H), 1.43-1.37 (m, 1H), 1.27 (s, 6H, C(CH3)2), 0.85 (d, J = 6.0 Hz, 3H, CHC H 3). 1313C NMR (150 MHz, CDCl3) δ 159.0, 148.0, 146.3, 132.2, 129.3, 124.0, 119.9, 114.6, 113.9, 111.6, 70.7, 68.2, 67.4, 67.2, 53.9, 44.8, 43.7, 42.2, 40.3, 37.2, 35.5, 29.8, 29.3 (2C), 27.5, 24.4, 16.0. IR (ATR) 3363, 2965, 2926, 2877, 2854, 1606, 1583, 1444, 1367, 1285, 1267, 1248, 1212, 1157, 1085, 1048, 974, 939, 876, 858, 811, 790, 753, 700 cm -1 . HR-MS m / z = calculated for C 27 H 40 NaO4[M+Na] + : 451.28243, found 451.28313.

[0303] <Synthesis Example 17>

Chemical Formula

[0304] <Synthesis Example 17-1>

Chemical Formula

[0305] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (5.9 mg, 8.0 μmol, 8.0 mol%) was mixed with tetrahydrofuran (1.0 mL) solutions of compound 20aB (38.3 mg, 0.11 mmol, 1.1 equivalent) and compound 22a (47.0 mg, 0.10 mmol, 1.0 equivalent) and 3N potassium hydroxide (56 μL) solution, and the mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 24.

[0306] To a tetrahydrofuran solution (0.1 mL) of the crude product of compound 24, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.6 mL, 0.6 mmol, 6.0 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D b (19.1 mg) in 45% yield.

[0307] 1 H NMR (600 MHz, CDCl3) δ 7.20 (dd, J = 7.2, 7.8 Hz, 1H, Ar), 7.01 (d, J = 7.8 Hz, 1H, Ar), 6.99 (d, J = 7.2 Hz, 1H, Ar), 6.98 (s, 1H, Ar), 6.42 (d, J = 11.4 Hz, 1H, CH=C), 6.25 (d, J = 11.4 Hz, 1H, CH=C), 5.34 (s, 1H, C=CH2), 5.04 (s, 1H, C=CH2), 4.44 (brt, J = 4.8 Hz, 1H, CHO), 4.23 (brs, 1H, CHO), 2.98 (brd, J = 13.2 Hz, 1H, C HAr), 2.67-2.61 (m, 1H), 2.60 (t, J = 7.5 Hz, 2H, ArCH2), 2.33 (dd, J = 7.2, 13.2 Hz, 1H), 2.35-2.29 (m, 1H). 2.20 (dt, J = 3.6, 11.4 Hz, 1H), 1.98 (t, J = 5.4 Hz, 2H), 1.96-1.82 (m, 5H), 1.73-1.64 (m, 4H), 1.54-1.46 (m, 2H), 1.42 (tq, J = 3.6, 13.2 Hz, 1H), 1.20 (s, 6H, C(CH3)2O), 0.77 (d, J = 6.6 Hz, 3H, CHC H 3). 13 13C NMR (150 MHz, CDCl3) δ 147.5, 146.4, 146.3, 142.4, 134.1, 128.2, 127.5, 126.0, 125.2, 124.7, 116.5, 112.4, 71.1, 71.0, 66.7, 53.7, 45.4, 43.7, 43.5, 42.8, 36.3, 35.6, 29.9, 29.2, 27.5, 26.3, 16.0. IR (ATR) 3362, 2964, 2926, 2855, 1715, 1658, 1647, 1605, 1487, 1443, 1368, 1217, 1146, 1119, 1053, 957, 910, 797, 754, 707 cm -1 -1. HR-MS m / z = calcd for C 28 27 40 H39NaO3[M+Na] + : 447.28751, found 447.28969.

[0308] <Synthesis Example 17-2>

Chemical Formula

[0309] Compound des-D-19-nor b (57.0 mg) was obtained in 69% yield from compounds 20aB (76.6 mg, 0.22 mmol) and 22b (96.5 mg, 0.20 mmol), in the same manner as the synthesis of compound des-D b from compound 20aB.

[0310] 1 H NMR (600 MHz, CDCl3) δ 7.20 (dd, J = 7.2, 7.8 Hz, 1H, Ar), 7.02 (d, J = 7.8 Hz, 1H, Ar), 7.00 (d, J = 7.2 Hz, 1H, Ar), 6.99 (s, 1H, Ar), 6.35 (d, J = 11.4 Hz, 1H, CH=C), 6.09 (d, J = 11.4 Hz, 1H, CH=C), 4.13 (brs, 1H, CHO), 4.08 (brs, 1H, CHO), 2.96 (brd, J = 13.2 Hz, 1H, C H Ar), 2.75 (dd, J = 3.6, 13.2 Hz, 1H), 2.60 (t, J = 7.8 Hz, 2H, ArC H 2), 2.51 (dd, J = 3.6, 13.2 Hz, 1H), 2.34 (dq, J = 10.8, 6.0 Hz, 1H), 2.27 (dd, J = 7.2, 13.2 Hz, 1H), 2.24 (dd, J = 7.2, 13.2 Hz, 1H), 2.22 (dd, J = 3.6, 10.8 Hz, 1H), 1.97-1.80 (m, 5H), 1.74-1.66 (m, 3H), 1.64 (brs, 1H), 1.56 (brs, 1H), 1.53-1.48 (m, 2H), 1.40 (tq, J = 3.6, 12.6 Hz, 1H), 1.21 (s, 6H, C(CH3)2), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3). 13C NMR (150 MHz, CDCl3) δ 146.4, 146.2, 142.4, 132.4, 128.2, 127.5, 126.1, 124.8, 123.9, 114.6, 71.0, 67.4, 67.1, 53.8, 44.8, 43.7, 43.5, 42.1, 37.1, 36.3, 35.6, 29.8, 29.2 (C2), 27.6, 26.2, 16.0. IR (ATR) 3358, 2965, 2927, 2877, 2854, 1606, 1486, 1443, 1366, 1302, 1215, 1149, 1122, 1084, 1047, 974, 940, 907, 892, 795, 753, 706cm -1 . HR-MS m / z = calcd for C 27 H 40 NaO3[M+Na] + : 435.28751, found 435.28765.

[0311] <Synthesis Example 18> [ka]

[0312] <Synthesis Example 18-1> [ka]

[0313] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (16.4 mg, 22.4 μmol, 8.0 mol%) was mixed with tetrahydrofuran (2.8 mL) solution of compound 14c (93.8 mg, 0.26 mmol, 1.0 equivalent) and compound 22b (137 mg, 0.28 mmol, 1.1 equivalent) and 3N potassium hydroxide (0.15 mL) solution, and the mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through silica gel using diethyl ether, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 25.

[0314] To a tetrahydrofuran solution (2.6 mL) of the crude product of compound 25 obtained, methylmagnesium iodide (0.38 M diethyl ether solution, 1.5 mL, 0.57 mmol, 2.2 equivalents) was added at 0°C. After stirring at room temperature for 1 hour, saturated ammonium chloride was added and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered through silica gel using diethyl ether, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 26.

[0315] To a tetrahydrofuran solution (0.26 mL) of the crude product of compound 26, tetrabutylammonium fluoride (1.56 mL, 1.56 mmol, 6.0 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor cA (70.7 mg) in 69% yield.

[0316] 1 H NMR (600 MHz, CDCl3) δ 7.09 (d, J = 7.8 Hz, 2H, Ar), 6.86 (d, J = 7.8 Hz, 2H, Ar), 6.35 (d, J = 10.8 Hz, 1H, CH=C), 6.09 (d, J = 10.8 Hz, 1H, CH=C), 4.16 (brs, 1H, CHO), 4.08 (brs, 1H, CHO), 3.78 (s, 2H, OCH2), 2.97 (brd, J = 13.2 Hz, 1H, C HAr), 2.75 (dd, J = 3.6, 13.2 Hz, 1H), 2.51 (dd, J = 3.6, 13.2 Hz, 1H), 2.32-2.27 (m, 2H), 2.24 (dd, J = 6.6, 13.2 Hz, 1H), 2.18 (dt, J = 3.6, 12.0 Hz, 1H), 1.97-1.80 (m, 5H), 1.67 (dq, J = 3.6, 13.2 Hz, 1H), 1.59 (brs, 1H), 1.51 (brs, 1H), 1.48 (brs, 1H), 1.40 (brd, J = 12.6 Hz, 1H), 1.34 (s, 6H, C(CH3)2), 0.83 (d, J = 6.6 Hz, 3H, CHC H 3). 13 13C NMR (150 MHz, CDCl3) δ 157.0, 146.3, 138.9, 132.4, 128.2, 123.9, 114.5, 114.4, 75.9, 70.1, 67.3, 67.1, 53.0, 44.8, 44.0, 42.2, 37.1, 35.8, 29.9, 27.6, 26.1, 15.9. IR (ATR) 3358, 2968, 2925, 2875, 1609, 1510, 1456, 1366, 1301, 1235, 1176, 1046, 975, 923, 851, 825, 754 cm -1 . HR-MS m / z = calcd for C 25 H 36 NaO4[M+Na] + : 423.25113, found 423.25293.

[0317] <Synthesis Example 19>

Formula

[0318] <Synthesis Example 19-1>

Formula

[0319] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (1.6 mg, 2.2 μmol, 8.0 mol%) was mixed with tetrahydrofuran (0.3 mL) solutions of compound 11c (7.6 mg, 27 μmol, 1.0 equivalent) and compound 22b (14.5 mg, 30 μmol, 1.1 equivalent) and 3N potassium hydroxide (18 μL) solutions, and the mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 27.

[0320] To a tetrahydrofuran solution (0.3 mL) of the crude product of compound 27, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 70 μL, 70 μmol, 2.5 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor OH c (5.0 mg) in 56% yield.

[0321] 1 H NMR (600 MHz, CD3OD) δ 7.03 (d, J = 7.8 Hz, 2H, Ar), 6.73 (d, J = 7.8 Hz, 2H, Ar), 6.28 (d, J = 10.8 Hz, 1H, CH=C), 6.14 (d, J = 10.8 Hz, 1H, CH=C), 4.11-4.03 (m, 2H, CHO), 3.01 (brd, J = 12.6 Hz, 1H, C HAr), 2.64 (dd, J = 3.6, 13.8 Hz, 1H), 2.47 (dd, J = 3.6, 13.8 Hz, 1H), 2.30 (dd, J = 7.2, 13.8 Hz, 2H), 2,34-2.27 (m, 1H), 2.22 (dd, J = 7.2, 13.8 Hz, 1H), 2.13 (dt, J = 3.6, 12.0 Hz, 1H), 1.97-1.79 (m, 5H), 1.72 (dq, J = 3.0, 12.6 Hz, 1H), 1.40 (tq, J = 3.6, 12.6 Hz, 1H), 0.85 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CD3OD) δ 1574, 146.9, 135.6, 130.1, 129.8, 124.7, 117.0, 116.9, 68.9, 68.6, 55.6, 46.4, 46.1, 43.5, 38.5, 38.0, 31.7, 29.7, 17.3. IR (ATR) 3334, 2920, 2850, 1612, 1567, 1514, 1453, 1369, 1231, 1098, 1045, 974, 827, 752 cm -1 . HR-MS m / z = calcd for C 21 H 28 NaO3[M+Na] + : 351.19361, found 351.19372.

[0322] <Synthesis example 20> In the following formula, "Ph" means "Ph".

change

[0323] <Synthesis example 20-1>

change

[0324] To a solution of compound 22c (15.8 mg, 27.7 μmol, 1.0 equivalent) in tetrahydrofuran (0.27 mL), a solution of n-butyllithium in hexane (1.59 M hexane solution, 18 μL, 19.1 μmol) was added at -78°C. After stirring at -78°C for 30 minutes, a solution of compound 21bB (13.4 mg, 33.2 μmol) in tetrahydrofuran (0.33 mL) was added at -78°C. After stirring at 0°C for 3 hours, saturated ammonium chloride was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered by Celite using diethyl ether, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 23.

[0325] To a solution of the crude product of compound 23 in tetrahydrofuran (0.28 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.17 mL, 166 μmol, 6.0 equivalents) was added at 0°C. After stirring at room temperature for 18 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor bB (4.8 mg) in 42% yield.

[0326] In addition, 1 1H NMR, 13 The 13C NMR, IR, and HR-MS data are the same as those described in Synthesis Example 16-4.

[0327] <Synthesis Example 21> [ka]

[0328] <Synthesis Example 21-1> [ka]

[0329] To a toluene (0.17 mL) solution of palladium(II) acetate (3.0 mg, 13.6 μmol, 20 mol%) and triphenylphosphine (14.3 mg, 54.4 μmol, 80 mol%), compound 24 (25 mg, 67.8 μmol, 1.0 equivalent) and compound 12bB (65.3 mg, 135.6 μmol, 2.0 equivalents) in triethylamine (0.5 mL) were added and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the mixture was filtered using Celite with hexane, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 23.

[0330] To a solution of the crude product of compound 23 in tetrahydrofuran (0.1 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.5 mL, 0.5 mmol, 7.4 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor bB (9.4 mg) in 34% yield.

[0331] In addition, 1 1H NMR, 13 The 13C NMR, IR, and HR-MS data are the same as those described in Synthesis Example 16-3.

[0332] <Synthesis Example 22> [ka]

[0333] <Synthesis Example 22-1> [ka]

[0334] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (5.8 mg, 8 μmol, 8.0 mol%) was mixed with a solution of compound C12bB (57.6 mg, 0.11 mmol, 1.1 equivalent) and compound 22b (48.3 mg, 0.1 mmol, 1.0 equivalent) in tetrahydrofuran (1.0 mL) and a solution of 3N potassium hydroxide (56 μL), and the mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound C23.

[0335] To a tetrahydrofuran solution (0.1 mL) of the crude product of compound C27, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.6 mL, 0.6 mmol, 6.0 equivalents) was added at 0°C. After stirring at room temperature for 12 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound des-D-19-nor CbB (35.3 mg) in 77% yield.

[0336] 1 H NMR (600 MHz, CDCl3) δ 7.22 (dd, J = 7.8, 8.4 Hz, 1H, Ar), 6.79 (d, J = 7.8 Hz, 1H, Ar), 6.76 (dd, J = 1.8, 8.4 Hz, 1H, Ar), 6.74 (d, J = 1.8 Hz, 1H, Ar), 6.34 (d, J = 10.8 Hz, 1H, CH=C), 6.08 (d, J = 10.8 Hz, 1H, CH=C), 4.19 (t, J = 6.0 Hz, 2H, OCH2), 4.14 (brs, 1H, CHO), 4.08 (brs, 1H, CHO), 2.96 (brd, J = 13.2 Hz, 1H, C HAr), 2.75 (dd, J = 3.6, 13.2 Hz, 1H), 2.52 (dd, J = 3.6, 13.2 Hz, 1H), 2.37 (brs, 1H), 2.29-2.23 (m, 3H), 2.17 (dt, J = 3.0, 12.0 Hz, 1H), 2.00 (t, J = 6.0 Hz, 2H, OCH2C H 2), 1.98-1.93 (m, 1H), 1.86 (dq, J = 13.2, 1.8 Hz, 1H), 1.82 (ddd, J = 3.6, 8.4, 13.2 Hz, 1H), 1.61 (t, J = 12.6 Hz, 1H), 1.58-1.51 (m, 3H), 1.41 (q, J = 12.6 Hz, 1H), 1.32 (s, 6H, C(CH3)2), 1.31-1.23 (m, 1H), 0.93 (d, J = 6.6 Hz, 3H, CH(C H 3)2), 0.89 (d, J = 6.6 Hz, 3H, CH(C H 3)2), 0.84 (d, J = 6.0 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 158.6, 148.2, 146.0, 132.5, 129.4, 123.8, 120.2, 114.6, 113.8, 111.6, 70.4, 67.4, 67.1, 65.0, 53.6, 45.2, 44.8, 43.5, 42.2, 41.7, 38.9, 37.2, 33.5, 32.9, 29.6, 19.9, 19.4, 15.6. IR (ATR) 3356, 2961, 2930, 2873, 1607, 1583, 1476, 1448, 1384, 1367, 1309, 1288, 1262, 1216, 1156, 1085, 1043, 973, 940, 872, 812, 783, 754, 729 cm -1 . HR-MS m / z = calcd for C 29 H 44NaO4[M+Na] + : 479.31373, found 479.31490.

[0337] <Synthesis Example 22-2> [ka]

[0338] Compound epi-des-D-19-nor CbB (33.4 mg) was obtained in 73% yield from compounds epi-C12bB (57.6 mg, 0.11 mmol) and 22b (48.3 mg, 0.1 mmol), similar to the synthesis of compound des-D-19-nor CbB from compound C12bB.

[0339] 1 H NMR (600 MHz, CDCl3) δ 7.22 (dd, J = 7.8, 8.4 Hz,1H, Ar), 6.79 (d, J = 7.8 Hz,1H, Ar), 6.76 (dd, J = 8.4, 1.8 Hz, 1H, Ar), 6.74 (d, J = 1.8 Hz, 1H, Ar), 6.36 (d, J = 10.8 Hz, 1H, CH=C), 6.08 (d, J = 10.8 Hz, 1H, CH=C), 4.19 (t, J = 6.0 Hz, 2H, OCH2), 4.12 (brs, 2H, CHO), 2.95 (brd, J = 13.2 Hz, 1H, C H Ar), 2.67 (dd, J = 3.6, 13.2 Hz, 1H), 2.54 (dd, J = 3.6, 13.2 Hz), 2.37-2.34 (m, 2H), 2.29-2.22 (m, 2H), 2.16 (dt, J = 3.0, 12.0 Hz, 1H), 2.00 (t, J = 6.0 Hz, 2H, OCH2C H2), 1.93-1.85 (m, 3H), 1.63-1.47 (m, 5H), 1.40 (q, J = 12.6 Hz, 1H), 1.32 (s, 6H, C(CH3)2), 1.32-1.24 (m, 1H), 0.93 (d, J = 6.6 Hz, 3H, CH(CH3)2), 0.90 (d, J = 6.6 Hz, 3H, CH(C H 3)2), 0.84 (d, J = 6.6 Hz, 3H, CHC H 3). 13 C NMR (150 MHz, CDCl3) δ 158.6, 148.1, 146.0, 132.5, 129.3, 123.8, 120.2, 114.6, 113.9, 111.5, 70.4, 67.4, 67.1, 65.0, 53.6, 45.1, 45.0, 43.5, 42.1, 41.7, 38.8, 36.9, 33.5, 32.8, 29.6, 20.0, 19.3, 15.6. IR (ATR) 3358, 2960, 2930, 2873, 1606, 1583, 1476, 1448, 1385, 1367, 1313, 1288, 1262, 1217, 1156, 1081, 1042, 974, 939, 907, 891, 872, 810, 783, 755, 728, 701 cm -1 . HR-MS m / z = calcd for C 29 H 44 NaO4[M+Na] + : 479.31373, found 479.31486.

[0340] <Synthesis example 23> In the following formula, "nPr" is represented by n-プロピルbase.

change

[0341] <Synthesis Example 23-1>

change

[0342] The crude product of compound SC-Et-1b was obtained from compound 16b (152 mg, 0.45 mmol) and 3-ethylhex-5-yn-3-ol (85 mg, 0.675 mmol) in the same manner as the synthesis of compound 17b from compound 16b.

[0343] The crude product of compound SC-Et-1b obtained and a solution of imidazole (153 mg, 2.25 mmol) in N,N-dimethylformamide (2.2 mL) were mixed with triethylsilyl chloride (0.23 mL, 1.35 mmol) at room temperature and stirred for 5 hours. Saturated sodium bicarbonate solution was added and the mixture was extracted with hexane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was filtered through silica gel to obtain the crude product of compound SC-Et-2b.

[0344] To a mixture of (bromomethyl)triphenylphosphonium bromide (0.59 g, 1.35 mmol) and tetrahydrofuran (2.7 mL), lithium diisopropylamide (0.5 M tetrahydrofuran solution, 2.6 mL, 1.3 mmol) was added at -40°C, and the mixture was heated to 0°C and stirred for 1 hour. The mixture was then cooled again to -78°C, and a tetrahydrofuran solution of the crude product of compound SC-Et-2b was added. The mixture was heated to 0°C and stirred for 12 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound SC-Et-3b (80.1 mg) in 35% yield.

[0345] 1 H NMR (400 MHz, CDCl3) δ 7.17-7.24 (m, 3H, Ar), 7.00-7.07 (m, 1H, Ar), 5.93 (s, 1H, C=CH), 3.07-3.14 (m, 1H, ArC H), 2.55 (s, propargylic CH2), 2.26-2.27 (m, 1H, CH3C H ), 2.19 (dt, J = 4.0, 11.6 Hz, 1H), 1.84-1.95 (m, 1H), 1.66 (q, J = 6.4 Hz, 4H, CH3C H 2C), 1.58-1.70 (m, 1H), 1.35-1.45 (m, 1H), 0.96 (t, J = 8.4 Hz, 9H, C H 3CH2Si), 0.93 (t, J = 7.2 Hz, 6H, C H 3CH2C), 0.81 (d, J = 6.8 Hz, 3H, C H 3CH), 0.63 (q, J =8.4 Hz, 6H, SiCH2). 13 C NMR (100 MHz, CDCl3) δ 148.3, 145.2, 130.4, 129.5, 128.4, 126.7, 124.2, 99.1, 87.6, 82.4, 77.9, 53.1, 43.6, 35.3, 32.5, 32.0, 30.6, 26.6, 15.7, 8.3, 7.2, 6.9. TLC analysis:R f = 0.9 (Hexane:ethyl acetate = 10:1 (v / v))

[0346] <Synthesis Example 23-2> [ka]

[0347] Compound SC-nPr-3b (110 mg) was obtained in 49% yield from compound 16b (142 mg, 0.42 mmol) and 4-propylhept-1-yn-4-ol (0.11 mL, 0.63 mmol) in the same manner as the synthesis of compound SC-Et-3b from compound 16b.

[0348] 1¹H NMR (400 MHz, CDCl₃) δ 7.18-7.26 (m, 3H, Ar), 7.06-7.09 (m, 1H, Ar), 5.94 (s, 1H, C=CH), 3.08-3.14 (m, 1H, ArC H ), 2.55 (s, 2H, propargylic CH₂), 2.30-2.37 (m, 1H, C H ₃CH), 2.20 (dt, J = 3.2, 11.6 Hz, 1H), 1.85-1.96 (m, 3H), 1.51-1.71 (m, 5H), 1.30-1.48 (m, 4H), 0.96 (t, J = 8.4 Hz, 9H, C H ₃CH₂Si), 0.93 (t, J = 7.6 Hz, 6H, C H ₃CH₂C), 0.82 (d, J = 6.4 Hz, 3H, C H ₃CH), 0.62 (q, J = 8.0 Hz, 6H, SiCH₂). 13 ¹³C NMR (100 MHz, CDCl₃) δ 148.2, 145.3, 130.4, 129.5, 128.4, 126.7, 124.2, 99.1, 87.7, 82.4, 77.5, 53.1, 43.6, 42.5, 35.3, 32.4, 31.5, 26.6, 17.1, 15.7, 14.7, 7.2, 6.9. TLC analysis: R f f = 0.9 (hexane:ethyl acetate = 10:1 (v / v))

[0349] <Synthesis Example 24>

Chemical Formula

[0350] <Synthesis Example 24-1>

Chemical Formula

[0351] Compound des-D-19-nor-SC-Et-5b (29.6 mg) was obtained in 72% yield from compound SC-Et-3b (47.4 mg, 0.094 mmol) and compound 22b (50 mg, 0.104 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB and compound 22b.

[0352] 1 H NMR (400 MHz, CDCl3) δ 7.19-7.24 (m, 3H, Ar), 7.11 (d, J = 7.2 Hz, 1H, Ar), 6.34 (d, J = 10.8 Hz, 1H, CH=C), 6.09 (d, J = 10.8 Hz, 1H, C=CH), 4.03-4.18 (m, 2H, CHO), 2.96 (br d, J = 14.0 Hz, 1H), 2.75 (br d, J = 9.2 Hz, 1H), 2.58 (s, 1H, propargylic CH2), 2.51 (br d, J = 10.0 Hz, 1H), 2.11-2.39 (m, 5H), 1.58-2.00 (m, 18H), 1.22-1.43 (m, 2H), 0.94 (t, J = 7.2 Hz, 6H, C H 3CH2), 0.84 (d, J = 6.4 Hz, 3H, C H 3CH). 13 C NMR (100 MHz, CDCl3) δ 146.0, 132.5, 130.5, 129.4, 128.3, 127.2, 123.9, 123.4, 114.7, 99.9, 85.8, 83.6, 74.2, 67.4, 67.1, 53.6, 44.8, 43.5, 42.2, 37.1, 35.5, 30.8, 30.3, 29.8, 27.5, 16.0, 8.0, 7.7.

[0353] <Synthesis Example 24-2> [ka]

[0354] Compound des-D-19-nor-SC-nPr-5b (72.8 mg) was obtained in 90% yield from compound SC-nPr-3b (92.6 mg, 0.174 mmol) and compound 22b (92.4 mg, 0.191 mmol), in the same manner as the synthesis of compound des-D-19-nor aB from compound 12aB and compound 22b.

[0355] 1 H NMR (400 MHz, CDCl3) δ 7.18-7.26 (m, 3H, Ar), 7.11 (d, J = 7.6 Hz, 1H, Ar), 6.34 (d, J = 10.8 Hz, 1H, CH=C), 6.09 (d, J = 10.8 Hz, 1H. C=CH), 4.03-4.20 (m, 2H, CHO), 2.96 (br d, J = 14.4 Hz, 1H), 2.74 (br d, J = 9.2 Hz, 1H), 2.58 (s, 2H, propargylic CH2), 2.51 (br d, J = 10.0 Hz, 1H), 2.15-2.38 (m, 3H), 1.45-2.00 (m, 9H), 1.22-1.48 (m, 7H), 0.96 (t, J = 7.6 Hz, 6H, C H 3CH2), 0.84 (d, J = 6.4 Hz, 3H, C H 3CH). 13 C NMR (100 MHz, CDCl3) δ 146.4, 132.6, 130.5, 129.4, 128.3, 128.2, 127.2, 123.9, 123.4, 114.7, 85.8, 83.6, 73.9, 67.4, 67.1, 53.6, 44.7, 43.5, 42.1, 41.3, 37.1, 35.5, 31.3, 29.8, 27.5, 16.9, 16.0, 14.7.

[0356] <Synthesis Example 25> [ka]

[0357] A mixture of compound A-0 (0.21 g, 0.88 mmol), Bu2SnO (0.11 g, 0.44 mmol), n-tetrabutylammonium bromide (0.14 g, 0.44 mmol), isopropyldiethylamine (0.38 mL, 2.2 mmol), allyl bromide (0.082 mL, 0.97 mmol), and acetonitrile (4.4 mL) was stirred at 60°C for 14 hours. Water was added, and the mixture was extracted with ethyl acetate. The mixture was dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain compound A-1 (16.3 mg) in 7% yield.

[0358] 1 H NMR (600 MHz, CDCl3) δ 6.29 (s, 1H, BrCH=C), 5.98 (dt, J = 17.4, 6.0 Hz, 1H, C H =CH2), 5.51 (s, 1H, C=CH2), 5.40 (s, 1H, C=CH2), 5.33 (dd, J = 1.8, 17.4 Hz, 1H, CH=C H 2), 5.24 (d, J = 10.2 Hz, 1H, CH=C H 2), 4.40 (br s, 1H, CHO), 4.25 (d, J = 6.6 Hz, 2H, OCH2), 4.09 (br s, 1H, CHO), 3.59 (br s, 1H, CHO), 2.83 (d, J = 7.8 Hz, 1H, OH), 2.68 (d, J = 6.6 Hz, 1H, OH), 2.66 (dd, J = 5.4, 13.8 Hz, 1H, ring CH2), 2.38 (br d, J = 13.8 Hz, 1H, ring CH2). 13 C NMR (100 MHz, CDCl3) δ 142.4, 136.7, 134.5, 117.9, 117.4, 104.1, 78.9, 74.5, 71.0, 69.3, 40.4.

[0359] <Synthesis Example 26> [ka]

[0360] To a 7.2 mL diethyl ether solution of compound 20b (347 mg, 0.72 mmol), t-BuLi (1.40 mL, 1.56 M hexane solution, 2.18 mmol) was added dropwise at -80°C and the mixture was stirred for 1 hour. 2-Isopropyl-4,4,5,5-trimethyl-1,3,2-dioxaborolane (0.29 mL, 1.44 mmol) was added, and the mixture was heated to room temperature over 2 hours. After stopping the reaction with saturated ammonium chloride aqueous solution, the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to obtain B20b (97.1 mg) in 26% yield.

[0361] 1 H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.6 Hz, 1H, Ar), 6.95-7.03 (m, 3H, Ar), 5.14 (s, 1H, C=CHB), 3.35 (br d, J = 14.4 Hz, 1H, ArC H ), 2.57 (t, J = 7.2 Hz, 2H, ArC H 2), 2.83 (dd, J = 4.8, 6.0 Hz, 1H), 2.23 (dd, J = 3.6, 11.2 Hz, 1H), 1.60-2.02 (m, 8H), 1.42-1.47 (m, 3H), 1.29 (s, 12H, CH3), 1.17 (s, 6H, CH3), 0.93 (t. J = 7.6 Hz, 9H, C H 3CH2Si), 0.77 (d, J = 6.4 Hz, 3H, C H 3CH), 0.54 (q, J = 7.6 Hz, SiCH2). 13C NMR (100 MHz, CDCl3) δ 169.5, 146.1, 142.8, 128.2, 127.5, 126.1, 124.6, 82.7, 73.3, 54.1, 45.3, 44.6, 36.4, 35.8, 34.5, 29.9, 28.6, 26.3, 24.9, 24.8, 16.0, 6.8.

[0362] <Synthesis Example 27> [ka]

[0363] <Synthesis Example 27-1> [ka]

[0364] 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride (2.3 mg, 3.2 μmol, 10 mol%) was mixed with tetrahydrofuran (1.0 mL) solutions of compound A-1 (8.7 mg, 0.032 mmol, 1.0 equivalent) and compound B20b (20.2 mg, 0.038 mmol, 1.19 equivalents) and 3N potassium hydroxide (10 μL) solutions, and the mixture was stirred at 40°C for 6 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound des-D A-3b.

[0365] To a tetrahydrofuran solution (0.1 mL) of the crude product of compound des-D A-3b, 9-BBB (0.224 mL, 0.5 M THF solution, 0.112 mmol) was added at 0°C and stirred at 0°C for 2 hours, followed by 5 hours at room temperature. To this, 1 M NaOH aqueous solution (0.8 mL) and 30% hydrogen peroxide solution (0.21 mL) were added at 0°C and stirred for 30 minutes. After adding saturated sodium thiosulfate aqueous solution (0.5 mL), the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain the crude product of compound des-D A-4b.

[0366] To a tetrahydrofuran solution (0.1 mL) of the crude product of compound des-D A-4b, n-tetrabutylammonium fluoride (0.32 mL, 1.0 M THF solution, 0.32 mmol) was added at room temperature, and the mixture was stirred for 5 hours. After adding saturated aqueous ammonium chloride solution, the mixture was extracted with diethyl ether and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography to obtain compound des-D A-5b (14.1 mg) in 22% yield.

[0367] 1 H NMR (400 MHz, CDCl3) δ 7.15-7.20 (m, 1H, Ar), 6.93-7.03 (m, 3H, Ar), 6.51 (d, J = 10.8 Hz, 1H, CH=C), 6.28 (d, J = 10.8 Hz, 1H, CH=C), 5.39 (s, 1H, C=CH2), 5.12 (s, 1H, C=CH2), 3.75-3.90 (m, 7H, OCH2and CHO), 3.00 (br d, J = 12 Hz, 1H, ArC H ), 2.61-2.76 (m, 3H), 2.57 (t, J = 7.8 Hz, 2H, ArC H 2), 2.20-2.46 (m, 3H), 1.43-1.95 (m, 9H), 1.18 (s, 6H, CH3C), 0.78 (d, J = 6.0 Hz, 3H, C H 3CH).

[0368] <Synthesis Example 28> [ka]

[0369] <Synthesis Example 28-1> [ka]

[0370] Compound des-D 19-nor A-7b (248 mg) was obtained in 38% yield from compound A-2 (483 mg, 0.94 mmol) and compound 19b (480 mg, 1.2 mmol) in the same manner as the synthesis of compound 23 from compound 22c and compound 21bB.

[0371] 1 H NMR (400 MHz, CDCl3) δ 7.20 (t, J = 8.0 Hz, 1H, Ar), 6.95-7.03 (m, 3H, Ar), 6.27 (d, J = 10.8 Hz, 1H, C=CH), 6.02 (d, J = 10.8 Hz, 1H, C=CH), 4.18-4.23 (m, 2H, CHO), 3.89 (br d, J = 9.6 Hz, 1H, CHO), 2.91-2.99 (m, 1H, ArC H ), 2.62-2.72 (m, 2H), 2.57 (t, J = 8.0 Hz, 2H, ArC H 2), 2.13-2.46 (m, 4H), 1.83-1.93 (m, 3H), 1.62-1.74 (m, 3H), 1.54 (s, 3H, CH3), 1.42-1.47 (m, 1H), 1.36 (s, 3H, CH3), 1.18 (s, 6H, CH3), 0.93 (t, J = 8.0 Hz, 9H, SiCH2C H 3), 0.92 (s, 9H, (CH3)3C), 0.80 (d, J = 6.4 Hz, 3H, CHC H 3), 0.54 (q, J = 8.0 Hz, 6H, SiCH2), 0.11 (s, 3H, SiCH3), 0.10 (s, 3H, SiCH3). 13C NMR (100 MHz, CDCl3) δ 146.2, 145.7, 142.8, 132.4, 128.2, 127.5, 126.1, 124.6, 122.3, 114.8, 108.8, 77.2, 74.2, 73.3, 69.8, 54.1, 54.1, 44.6, 43.7, 38.1, 36.4, 35.8, 30.6, 30.0, 27.8, 27.6, 26.0, 25.4, 18.4, 15.8, 7.1, 6.8, -4.5, -4.6. TLC analysis:R f = 0.7 (Hexane:ethyl acetate = 10:1 (v / v))

[0372] <Synthesis Example 28-2> [ka]

[0373] To a THF solution (0.4 mL) of compound des-D 19-nor A-7b (290 mg, 0.42 mmol), n-tetrabutylammonium fluoride (1.7 mL, 1.0 M THF solution, 1.7 mmol) was added at room temperature and the mixture was stirred for 15 hours. Saturated ammonium chloride aqueous solution was added, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, to which methanol (4.2 n L) was added. 1 M hydrochloric acid (0.15 mL) was added at 0°C and the mixture was stirred at room temperature for 5 hours. Saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain the residue, which was purified by silica gel column chromatography to obtain des-D 19-nor A-9b (176 mg) in 98% yield.

[0374] 1H NMR (400 MHz, CD3OD) δ 7.09 (t, J = 8.0 Hz, 1H, Ar), 6.68-6.94 (m, 3H, Ar), 6.20 (d, J = 10.8 Hz, 1H, C=CH), 6.01 (d, J = 10.8 Hz, 1H, C=CH), 3.83 (br s, 1H, CHO), 3.38-3.49 (m, 2H, CHO), 2.85-2.94 (m, 1H, Ar H ), 2.47-2.68 (m 1H), 2.51 (t, J = 7.6 Hz, 2H, ArC H 2), 2.03-2.45 (m, 5H), 1.54-1.88 (m, 6H), 1.25-1.41 (m, 3H), 1.07 (s, 6H, CCH3), 0.73 (d, J = 6.4 Hz, 3H, CHC H 3). 13 C NMR (100 MHz, CD3OD) δ 147.8, 146.8, 144.1, 133.7, 129.6, 128.9, 127.5, 126.1, 123.7, 116.5, 74.3, 72.4, 72.0, 71.6, 45.1, 44.6, 40.6, 37.7, 37.3, 32.2, 31.1, 29.5, 29.1, 27.8, 16.7. TLC analysis: R f f = 0.4 (ethyl acetate:methanol = 10:1 (v / v))

[0375] <Synthesis Example 28-3> [[Chemical Formula]]

[0376] The crude product of compound des-D 19-nor A-10b was obtained from compound des-D 19-nor A-9b (128 mg, 0.30 mmol) in the same manner as the synthesis of compound A-0 to compound A-1. To a tetrahydrofuran solution (1.0 mL) of the obtained crude product, 9-BBN (3.0 mL, 0.5 M THF solution, 1.5 mmol) was added at 0°C and the mixture was stirred at room temperature for 5 hours. To this, 1 M NaOH aqueous solution (0.75 mL) and 30% hydrogen peroxide solution (0.20 mL) were added at 0°C and the mixture was stirred for 30 minutes. After adding saturated sodium thiosulfate aqueous solution (0.5 mL), the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography to obtain compound des-D A-5b (16 mg) in 11% yield.

[0377] 1 H NMR (600 MHz, CDCl3) δ 7.20 (t, J = 7.2 Hz, 1H, Ar), 7.96-7.02 (m, 3H, Ar), 6.37 (d, J = 10.8 Hz, 1H, C=CH), 6.08 (d, J = 10.8 Hz, 1H, C=CH), 3.77-3.95 (m, 7H), 2.97 (br d, J = 13.2 Hz, 1H, ArC H ), 2.65-2.70 (m, 1H), 2.61 (t, J = 7.2 Hz, 2H, ArC H 2), 2.29-2.53 (m, 3H), 2.18-2.23 (m, 1H), 1.40-2.07 (m, 16H), 1.20 (s, 6H, CCH3), 0.83 (d, J = 6.0 Hz, 3H, CHC H 3).

[0378] <Synthesis Example 29> [ka]

[0379] <Synthesis Example 29-1> [ka]

[0380] A solution of compound 15c (2.0 g, 9.8 mmol, 1.0 equivalent) in methylene chloride (20 mL) was cooled to -40°C, and N-bromosuccinimide (1.7 g, 9.8 mmol, 1.0 equivalent) was added in two portions. After stirring for 3 hours, saturated sodium bicarbonate was added to stop the reaction, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with 10% aqueous sodium thiosulfate and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 28 (0.90 g) in 32% yield.

[0381] 1 H NMR (600 MHz, CDCl3) δ 7.30 (br s, 1H, Ar), 7.06 (d, J = 7.8 Hz, 1H, Ar), 6.98 (d, J = 7.8 Hz, 1H, Ar), 2.41-2.57 (m, 4H), 2.12-2.17 (m, 1H), 1.94-1.99 (m, 1H), 1.89 (dq, J = 4.5, 8.4 Hz, 1H), 1.74 (tq, J = 4.2, 9.0 Hz, 1H), 0.82 (d, J = 6.6 Hz, 3H, CH3). 13 C NMR (150 MHz, CDCl3) δ 212.0, 150.9, 137.7, 130.4, 127.9, 116.1, 110.2, 52.1, 50.7, 41.7, 34.6, 26.3, 12.2.

[0382] <Synthesis Example 29-2> [ka]

[0383] To a solution of compound 28 (0.40 g, 1.42 mmol, 1.0 equivalent) and potassium carbonate (0.59 g, 4.26 mmol, 3.0 equivalents) in N,N-dimethylformamide (1.4 mL), iodomethane (0.18 mL, 2.84 mmol, 2.0 equivalents) was added at 0°C. After stirring at 50°C for 3 hours, water was added at 0°C to stop the reaction, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 29-Me.

[0384] Under an argon atmosphere, a mixture of palladium(II) acetate (32 mg, 0.14 mmol, 10 mol%), triphenylphosphine (73 mg, 0.28 mmol, 20 mol%), 2,4,6-trivinylboroxine-pyridine complex (0.34 g, 1.42 mmol, 1.0 equivalent), the crude product of compound 29-Me, and potassium carbonate (0.2 g, 1.42 mmol, 1.0 equivalent) was mixed with toluene (5.5 mL) and water (1.8 mL). After stirring at 80°C for 15 hours, the mixture was extracted with diethyl ether and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 30-Me.

[0385] Under an argon atmosphere, a solution of (bromomethyl)triphenylphosphonium bromide (1.86 g, 4.26 mmol, 3.0 equivalents) in tetrahydrofuran (2.8 mL) was cooled to -10°C, lithium diisopropylamide (0.56 M tetrahydrofuran solution, 7.1 mL, 4.0 mmol, 2.9 equivalents) was added, and the mixture was heated to 0°C and stirred for 30 minutes. The mixture was cooled to -40°C, and a crude solution of compound 30-Me in tetrahydrofuran (7.1 mL) was added, and the mixture was heated to 0°C while stirring for 2 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 31-Me.

[0386] Under an argon atmosphere, 9-BBN (0.5 M tetrahydrofuran solution, 3.6 mL, 1.8 mmol, 1.27 equivalents) was added at 0°C to a 14 mL solution of the crude product of compound 31-Me in tetrahydrofuran. After stirring at room temperature for 7 hours, the mixture was cooled to 0°C, and a 1 M sodium hydroxide solution (9.5 mL) and a 30% hydrogen peroxide solution (2.0 mL) were added. After stirring at room temperature for 1 hour, a 10% sodium thiosulfate solution was added at 0°C, the mixture was stopped, extracted with diethyl ether, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 32-Me (0.25 g) in 53% yield.

[0387] 1 H NMR (400 MHz, CDCl3) δ 7.00 (dd, J = 2.0, 8.4 Hz, 1H, Ar), 6.95 (d, J = 2.4 Hz, 1H, Ar), 6.80 (d, J = 8.4 Hz, 1H, Ar), 5.92 (t, J = 1.6 Hz, 1H, C=CBrH), 3.82 (s, 3H, OCH3), 3.79-3.84 (m, 2H, CH2O), 3.09 (br d, J = 15.2 Hz, 1H, ArC H ), 2.89 (t, J = 6.8 Hz, 2H, ArC H 2), 2.23-2.33 (m, 1H), 2.16 (dt, J = 3.6, 12 Hz, 1H), 1.83-1.96 (m, 3H), 1.55-1.74 (m, 2H), 0.81 (d, J = 6.4 Hz, 3H, C H 3CH). 13 C NMR (100 MHz, CDCl3) δ 156.0, 148.5, 137.5, 129.8, 126.9, 126.4, 110.4, 98.9, 63.0, 55.4, 52.4, 44.0, 35.6, 34.3, 32.4, 26.6, 15.7.

[0388] <Synthesis Example 29-3> [ka]

[0389] Compound 32-nPr (0.161 g) was obtained from compound 28 (0.428 g, 1.51 mmol) in 29% yield, in the same manner as the synthesis of compound 32-Me from compound 28.

[0390] 1 H NMR (400 MHz, CDCl3) δ 6.97 (dd, J = 2.0, 8.0 Hz, 1H, Ar), 6.95 (t, J = 2.0 Hz, 1H, Ar), 6.78 (d, J = 8.8 Hz, 1H, Ar), 5.92 (br s, 1H, C=CBrH), 3.92 (t, J = 6.4 Hz, 2H, ArOC H 2) 3.80-3.87 (m, 2H, C H 2OH), 3.09 (br d, J = 14.0 Hz, 1H, ArC H ), 2.90 (t, J = 6.4 Hz, 2H, ArC H 2), 2.24-2.27 (m, 1H), 2.10-2.17 (m, 1H), 1.76-1.94 (m, 6H), 1.58-1.66 (m, 1H), 1.37-1.48 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H, CH2C H 3), 0.81 (d, J = 6.8 Hz, 3H, CHC H 3). 13 C NMR (100 MHz, CDCl3) δ 155.5, 148.5, 137.3, 129.8, 127.1, 126.3, 111.2, 98.9, 69.6, 63.1, 52.5, 44.0, 35.6, 34.5, 32.4, 26.6, 22.7, 15.7, 10.7.

[0391] <Synthesis Example 29-4> [ka]

[0392] Compound 32-nPent (0.175 g) was obtained from compound 28 (0.408 g, 1.44 mmol) in 31% yield, in the same manner as the synthesis of compound 32-Me from compound 28.

[0393] 1 H NMR (400 MHz, CDCl3) δ 6.97 (dd, J = 2.4, 8.4 Hz, 1H, Ar), 6.94 (d, J = 2.4 Hz, 1H, Ar), 6.78 (d, J = 8.0 Hz, 1H, Ar), 5.92 (s, C=CBrH), 3.95 (t, J = 6.4 Hz, 2H, ArOC H 2), 3.84 (dt, J = 5.2, 6.4 Hz, 2H, C H 2OH), 3.09 (br d, J = 14.0 Hz, 1H, ArC H ), 2.90 (t, J = 6.4 Hz, 2H, ArC H 2), 2.24-2.33 (m, 1H), 2.15 (dt, J = 3.6, 11.2 Hz, 1H), 1.59-1.95 (m, 8H), 1.33-1.50 (m, 5H), 0.93 (t, J = 7.2 Hz, 3H, CH2C H 3), 0.81 (d, J = 6.4 Hz, 3H, CHC H 3). 13 C NMR (100 MHz, CD3OD) δ 155.5, 148.5, 137.3, 129.8, 127.1, 126.3, 111.1, 98.9, 68.0, 63.1, 52.5, 44.0, 35.6, 34.5, 32.4, 29.0, 28.3, 26.6, 22.4, 15.7, 14.0.

[0394] <Synthesis Example 30> [ka]

[0395] <Synthesis Example 30-1> [ka]

[0396] Under an argon atmosphere, a mixture of palladium(II) acetate (22.5 mg, 0.1 mmol, 10 mol%), triphenylphosphine (52.5 mg, 0.2 mmol, 20 mol%), 2,4,6-trivinylboroxine-pyridine complex (0.24 g, 1.0 mmol, 1.0 equivalent), and potassium carbonate (0.14 g, 1.0 mmol, 1.0 equivalent) was mixed with a toluene (3.8 mL) solution of compound 16b (0.336 g, 1.0 mmol, 1.0 equivalent) and water (3.8 mL). After stirring at 80°C for 15 hours, the mixture was extracted with diethyl ether and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of compound 33b.

[0397] Under an argon atmosphere, a solution of (bromomethyl)triphenylphosphonium bromide (0.87 g, 2.0 mmol, 2.0 equivalents) in tetrahydrofuran (2.0 mL) was cooled to -20°C, lithium diisopropylamide (1.0 M tetrahydrofuran solution, 2.0 mL, 2.0 mmol, 2.0 equivalents) was added, and the mixture was heated to 0°C and stirred for 30 minutes. The mixture was cooled to -40°C, a crude solution of compound 33b in tetrahydrofuran (5.0 mL) was added, and the mixture was heated to 0°C while stirring for 12 hours. The mixture was filtered through silica gel using hexane, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 34b.

[0398] Under an argon atmosphere, 9-BBN (0.5M tetrahydrofuran solution, 4.0 mL, 4.0 mmol, 2.0 equivalents) was added at 0°C to a 10 mL solution of the crude product of compound 34b in tetrahydrofuran. After stirring at room temperature for 5 hours, the mixture was cooled to 0°C, and a 1 M sodium hydroxide (6.7 mL) aqueous solution and a 30% hydrogen peroxide (1.4 mL) aqueous solution were added. After stirring at room temperature for 1 hour, a 10% sodium thiosulfate aqueous solution was added at 0°C, the mixture was stopped, extracted with diethyl ether, and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 35b (0.149 g) in 48% yield.

[0399] 1 H NMR (400 MHz, CDCl3) δ 7.22-7.26 (m, 1H, Ar), 7.01-7.08 (m, 3H, Ar), 5.93 (s, 1H, C=CBrH), 3.86 (t, J = 6.4 Hz, 2H, CH2O), 3.10 (br d, J = 14.4Hz, 1H, ArC H ), 2.86 (t, J = 6.4 Hz, 2H, ArC H 2), 2.31-2.38 (m, 1H), 2.23 (dt, J = 3.6, 11.6 Hz, 1H), 1.86-1.96 (m, 3H), 1.40-1.73 (m, 2H), 0.81 (d, J = 6.4 Hz, 3H, CHC H 3). 13 C NMR (100 MHz, CDCl3) δ 148.3, 145.6, 138.5, 128.7, 128.1, 126.9, 125.4, 99.0, 63.6, 53.2, 43.7, 39.2, 35.4, 32.4, 26.6, 15.7.

[0400] <Synthesis Example 31> [ka]

[0401] <Synthesis Example 31-1> [ka]

[0402] Under an argon atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (31.0 mg, 42 μmol, 8.0 mol%) was mixed with a solution of compound 32-Me (0.18 g, 0.53 mmol, 1.0 equivalent) and compound 22b (0.28 g, 0.58 mmol, 1.1 equivalent) in tetrahydrofuran (5.3 mL) and a solution of 3N potassium hydroxide (0.35 mL), and the mixture was stirred at 50°C for 22 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound nor-36-Me.

[0403] Under an argon atmosphere, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.65 mL, 2.65 mmol, 5.0 equivalents) was added at 0°C to a solution of the crude product of compound nor-36-Me in tetrahydrofuran (0.53 mL). After stirring at room temperature for 20 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound nor-37-Me (0.138 g) in 68% yield.

[0404] 1 H NMR (400 MHz, CD3OD) δ 6.93 (d, J = 8.0 Hz, 1H, Ar), 6.91 (s, 1H, Ar), 6.77 (d, J = 8.0 Hz, 1H, Ar), 6.18 (d, J = 10.8 Hz, 1H, C=CH), 6.04 (d, J = 10.8 Hz, 1H, C=CH), 3.90-4.01 (m, 2H, CHO), 3.73 (s, 3H, CH3O), 3.61 (t, J = 7.6 Hz, 2H, C H2OH), 2.91 (br d, J = 13.6 Hz, 1H, ArC H ), 2.75 (t, J = 7.6 Hz, ArC H 2), 2.54 (br d, J = 13.2 Hz, 1H), 2.37 (br d, J = 9.6 Hz, 1H), 2.00-2.26 (m, 4H), 1.56-1.87 (m, 6H), 1.25-1.33 (m, 1H), 0.74 (d, J = 6.8Hz, 3H, C H 3CH). 13 C NMR (100 MHz, CD3OD) δ 157.7, 146.3, 139.9, 135.1, 131.0, 128.1, 127.7, 124.1, 116.5, 111.7, 68.3, 68.0, 63.3, 56.1, 55.0, 45.9, 45.4, 43.0, 38.0, 37.4, 35.4, 31.1, 29.1, 16.7.

[0405] <Synthesis Example 31-2> [ka]

[0406] Compound nor-37-nPr (52.4 mg) was obtained in 79% yield from compound 32-nPr (61 mg, 0.16 mmol) and 22b (85 mg, 0.176 mmol), in the same manner as the synthesis of compound nor-37-Me from compound 32-Me.

[0407] 1 H NMR (400 MHz, CDCl3) δ 6.98 (d, J = 7.6 Hz, 1H, Ar), 6.97 (s, 1H, Ar), 6.78 (d, J = 7.6 Hz, 1H, Ar), 6.34 (d, J = 10.8 Hz, 1H, C=CH), 6.08 (d, J = 10.8 Hz, 1H, C=CH), 4.03-4.16 (m, 2H, CHO), 3.93 (t, J = 6.4 Hz, 2H, ArOCH 2), 3.84 (t, J = 6.4 Hz, 2H, C H 2OH), 2.70-2.90 (m, 1H, ArC H ), 2.91 (t, J = 6.4 Hz, 2H, ArC H 2), 2.75 (br d, J = 9.2 Hz, 1H), 2.51 (br d, J = 13.2 Hz, 1H), 2.10-2.32 (m, 3H), 1.30-1.99 (m, 13H), 1.05 (t, J = 7.6 Hz, 3H, CH2C H 3), 0.84 (d, J = 6.4 Hz, 3H, CHC H 3). 13 C NMR (100 MHz, CDCl3) δ155.3, 146.5, 138.4, 132.3, 129.8, 126.9, 126.4, 124.0, 114.5, 111.1, 69.5, 67.4, 67.2, 63.1, 52.9, 44.8, 43.9, 42.2, 37.2, 35.8, 34.5, 29.8, 27.5, 22.7, 16.1, 10.7.

[0408] <Synthesis Example 31-3> [ka]

[0409] Compound nor-37-nPent (153 mg) was obtained in 91% yield from compound 32-nPent (152 mg, 0.38 mmol) and 22b (200 mg, 0.418 mmol) in the same manner as the synthesis of compound nor-37-Me from compound 32-Me.

[0410] 1¹H NMR (400 MHz, CDCl₃) δ 6.89 (d, J = 8.0 Hz, 1H, Ar), 6.97 (s, 1H, Ar), 6.78 (d, J = 8.0 Hz, 1H, Ar), 6.34 (d, J = 10.8 Hz, 1H, C=CH), 6.08 (d, J = 10.8 Hz, 1H, C=CH), 4.05-4.17 (m, 2H, CHO), 3.95 (t, J = 6.4 Hz, 2H, ArOC H ₂), 3.84 (t, J = 6.4 Hz, 2H, C H ₂OH), 2.88-2.93 (m, 1H, ArC H ), 2.90 (t, J = 6.4 Hz, 2H, ArC H ₂), 2.75 (br d, J = 9.6 Hz, 1H), 2.51 (br d, J = 10.0 Hz, 1H), 2.12-2.32 (m, 3H), 1.30-1.98 (m, 17H), 0.94 (t, J = 6.8 Hz, 3H, CH₂C H ₃), 0.84 (d, J = 6.4 Hz, 3H, CHC H ₃). 13 ¹³C NMR (100 MHz, CDCl₃) δ155.4, 146.5, 138.4, 132.3, 129.9, 126.9, 126.4, 124.0, 114.6, 111.1, 68.1, 67.4, 67.2, 63.1, 52.9, 44.8, 44.0, 42.2, 37.2, 35.8, 34.5, 29.8, 29.1, 28.4, 27.5, 22.4, 16.1, 14.0.

[0411] <Synthesis Example 32>

Chemical Formula

[0412] <Synthesis Example 32-1>

Chemical Formula

[0413] Under an argon atmosphere, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (23.0 mg, 31.4 μmol, 8.0 mol%) was mixed with tetrahydrofuran (3.9 mL) solution of compound 35b (0.12 g, 0.387 mmol, 1.0 equivalent) and compound 22b (0.205 g, 0.43 mmol, 1.1 equivalent) and 3N potassium hydroxide (0.26 mL) solution, and the mixture was stirred at 50°C for 3.5 hours. After cooling to room temperature, the reaction solution was dried over anhydrous sodium sulfate, filtered through diethyl ether using Celite, and the resulting filtrate was concentrated under reduced pressure to obtain the crude product of compound 38b.

[0414] Under an argon atmosphere, tetrabutylammonium fluoride (1.9 mL, 1.94 mmol, 5.0 equivalents, 1.0 M tetrahydrofuran solution) was added to the crude product of compound 38b at 0°C. After stirring at room temperature for 20 hours, the reaction was stopped with saturated ammonium chloride and extracted with diethyl ether. The resulting organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate / methanol) to obtain compound nor-38b (0.115 g) in 84% yield.

[0415] 1 H NMR (400 MHz, CD3OD) δ 7.14 (t, J = 9.2 Hz, 1H, Ar), 6.89-7.01 (m, 3H, Ar), 6.19 (d, J = 10.8 Hz, 1H, C=CH), 6.04 (d, J = 10.8 Hz, 1H, C=CH), 3.90-4.00 (m, 2H, CHO), 3.66 (t, J = 7.2 Hz, 2H, CH2O), 2.92 (br d, J = 13.6 Hz, 1H, Ar H ), 2.73 (t, J = 7.2 Hz, 2H, ArC H2), 2.54 (dd, J = 4.0, 13.6 Hz, 1H), 2.34 (dd, J = 3.6, 14.0 Hz, 1H), 2.23-2.33 (m, 1H), 2.20 (dd, J 8.0, 14.0 Hz, 1H), 2.06-2.14 (m, 2H, 1.65-1.88 (m, 10H), 0.74 (d, J = 6.4 Hz, 3H, CH3). 13 C NMR (100 MHz, CD3OD) δ 148.1, 146.1, 140.6, 135.2, 129.7, 129.5, 128.0, 126.6, 124.1, 116.6, 68.3, 38.0, 64.7, 55.8, 45.9, 45.1, 43.0, 40.6, 37.9, 37.3, 31.1, 29.1, 16.7.

[0416] <Synthesis example 33>R 1 Synthesis of intermediate compounds in which the group is an ethyl group [ka]

[0417] <Synthesis Example 33-1> [ka]

[0418] Compound 1-Et (1.30 g) was obtained from 2-ethylcyclohexane-1,3-dione (1.12 g, 8.0 mmol) in 83% yield, in the same manner as the synthesis of compound 1 from 2-methylcyclohexane-1,3-dione.

[0419] 1 H NMR (400 MHz, CDCl3) δ 3.75 (d, J = 6.4 Hz, 2H, CH2O), 2.54 (t, J = 6.2 Hz, 2H, CH2), 2.26-2.35 (m, 4H), 1.93-2.05 (m, 3H), 1.00 (d, J = 6.8 Hz, 6H, C H3CH), 0.93 (t, J = 7.2 Hz, 3H, CH2C H 3). 13 C NMR (100 MHz, CDCl3) δ 198.2, 171.4, 121.2, 73.8, 36.4, 28.8, 25.4, 21.0, 19.0, 15.4, 13.3.

[0420] <Synthesis Example 33-2>

change

[0421] Compound 1 and compound 3a were synthesized in the same way, and compound 3b-Et (0.30g) and compound 1-Et (0.785g, 4.0mmol) were obtained in a yield of 29%.

[0422] 1 H NMR (600 MHz, CDCl3) δ 7.30 (t, J = 7.8 Hz, 1H, Ar), 7.00 (d, J = 8.4 Hz, Ar), 6.87 (s, 1H, Ar), 6.82 (d, J = 7.8 Hz, 1H, Ar), 5.19 (s, 2H, OCH2O), 3.50 (s, 3H, CH3O), 2.58 (t, J = 6.0 Hz, 2H, CH2), 2.50 (t, J = 6.6 Hz, 2H, CH2), 2.15 (q, J = 7.2 Hz, 2H, C H 2CH3), 2.05-2.10 (m, 2H, CH2), 0.91 (t, J = 7.2 Hz, C H 3CH2). 13 C NMR (150 MHz, CDCl3) δ 199.5, 157.2, 156.3, 142.9, 137.9, 129.5, 120.1, 115.4, 114.6, 94.5, 56.1, 38.2, 33.3, 22.8, 20.0, 14.3.

[0423] <Synthesis Example 33-3> [ka]

[0424] Compound 4b-Et (0.224 g) was obtained from compound 3b-Et (0.303 g, 1.16 mmol) in 74% yield, in the same manner as the synthesis of compound 4a from compound 3a.

[0425] 1 H NMR (600 MHz, CDCl3) δ 7.23 (t, J = 7.2 Hz, 1H, Ar), 6.92 (dd, J = 2.4, 7.2 Hz, 1H, Ar), 6.81 (s, 1H, Ar), 6.77 (d, J = 7.8 Hz, 1H, Ar), 5.17 (s, 2H, OCH2O), 4.30 (br s, 1H, CHO), 3.49 (s, 3H, OCH3), 2.00-2.30 (m, 4H, 1.64-1.90 (m, 4H), 1.45 (d, J = 7.2 Hz, 1H, OH), 0.95 (t, J = 7.2Hz, 3H, C H 3CH2). 13 C NMR (150 MHz, CDCl3) δ 157.1, 145.0, 136.8, 136.2, 129.1, 121.5, 115.8, 114.2, 94.5, 65.9, 56.0, 32.6, 32.0, 23.6, 18.2, 13.7.

[0426] <Synthesis Example 34> Alternative Method to Synthesis Example 3 [ka]

[0427] <Synthesis Example 34-1> [ka]

[0428] Under an argon atmosphere, (S)-5,5-diphenyl-2-methyl-3,4-propano-1,3,2-oxazaborolidine (0.4 mL, 0.2 mmol, 20.0 mol%) and compound 3a (0.25 g, 1.0 mmol) were dissolved in toluene (1.0 mL) and the mixture was heated to -40°C. Catecholborane (0.2 M toluene solution, 6.0 mL, 1.2 mmol, 1.2 equivalents) was added dropwise to the reaction solution over 5 hours, and the mixture was stirred at -40°C for 12 hours. 1 M sodium hydroxide was added to the reaction mixture to stop it, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound (R)-4a (0.24 g) in 97% yield.

[0429] (R)-4a (optical purity; 91%ee): Enantiomeric excess determined by a normal-phase HPLC [2.1 mmI.D. R = 7.9 min, (S)-4a: t R = 9.3 min]

[0430] <Synthesis Example 34-2> [ka]

[0431] Compound (R)-4b (0.25 g) was obtained in a yield >99% higher than compound 3b (0.25 g, 1.0 mmol) using the same method as the synthesis of compound (R)-4 from compound 3a.

[0432] (R)-4b (optical purity; 95%ee): Enantiomeric excess determined by a normal-phase HPLC [2.1 mmI.D. R = 8.3 min, (S)-4a: t R = 9.5 min]

[0433] <Synthesis Example 34-3> [ka]

[0434] Compound (R)-4c (0.23g) was obtained in 93% yield from compound 3c (0.25g, 1.0 mmol) in the same manner as the synthesis of compound (R)-4 from compound 3a.

[0435] (R)-4c (optical purity; 90%ee): Enantiomeric excess determined by a normal-phase HPLC [2.1 mmI.D. R = 7.7 min, (S)-4a: t R = 9.8 min]

[0436] <Synthesis Example 35> Synthesis of a racemic mixture of compound 15b and separation method using an optically active chiral preparative column [ka]

[0437] <Synthesis Example 35-1> [ka]

[0438] Compound 3b (1.23 g, 5.0 mmol) was slowly added at 0°C to a mixture of NaBH4 (264 mg, 7.0 mmol) and methanol (35 mL). After stirring the reaction mixture at room temperature for 1 hour, water (30 mL) was slowly added. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying over anhydrous magnesium sulfate, the mixture was filtered, and the filtrate was concentrated to obtain racemic mixture 4b (1.17 g) in 94% yield. The NMR spectrum of the obtained compound was consistent with that of compound 4b.

[0439] <Synthesis Example 35-2> [ka]

[0440] Racemic mixture 15b (0.55 g) was obtained from racemic mixture 4b (0.93 g, 3.75 mmol) in 72% yield, in the same manner as the synthesis of compound 4b to compound 15b. The NMR spectrum of the obtained compound was consistent with that of compound 15b.

[0441] <Separation and purification of racemic mixture or low optical purity compound 15b by optically active chiral preparative column> Racemic mixture 15b (290 mg) was charged into a normal-phase optically active chiral preparative column [Daicel, CHIRALPAK AY-H, φ20 mm × 250 mm], and eluted with a hexane / ethanol mixed solvent (90:10, v / v) as a fluidized bed (5.7 mL / min). The eluate was continuously detected with a UV absorption detector (254 nm) and dispensed into fractions. The eluted fractions were collected and concentrated to obtain optically active 15b (137 mg, Rt 7.8 min, yield 94%) and its enantiomer (2R, 3S) 15b (144 mg, Rt 10.2 min, yield 99%), respectively.

[0442] 15b: [α] 20 D +14.6 (c 1.00, CHCl3) (2R,3S)15b: [α] 20, D -15.0 (c 1.00, CHCl3)

[0443] [Activity Evaluation] <Test Example 1: Time-resolved fluorescence resonance energy transfer (TR-FRET) vitamin D receptor (VDR) coactivator assay> The GST-tagged ligand-binding domain of VDR (VDR-LBD(GST)), a coactivator peptide conjugated with fluorescein-TRAP220 / DRIP-2 (Fluorescein-peptide), LanthaScreen Tb-anti-GST (Goat) antibody (Tb-anti-GST), TR-FRET co-regulator buffer G, and DTT solution were purchased from Invitrogen as part of the LanthaScreen TR-FRET VDR Coactivator Assay Kit.

[0444] Each compound synthesized above was dissolved in dimethyl sulfoxide (DMSO, for molecular biology, Sigma Aldrich) and diluted to the desired concentration with TR-FRET co-regulator buffer G containing 1% by mass of DMSO. The receptor-tracer-antibody complex solution was added to the compound-containing solution so that the VDR-LBD(GST) concentration was 1.0 nM, Tb-anti-GST was 2.0 nM, and Fluorescein-peptide was 100 nM per well (20 μL), and the resulting mixture was incubated at room temperature for 2 hours.

[0445] TR-FRET was measured using a microplate reader (Infinite F200 PRO, Tecan) equipped with a 340nm excitation filter (30nm wavelength width), a 495nm terbium emission filter (10nm wavelength width), and a 520nm tracer emission filter (25nm wavelength width). Based on the obtained data, a graph plotting program (GraphPad Prism ver.8.2.0.) was used to determine the concentration (EC2) at which each compound exerts 50% activity, with the saturated activity of natural active vitamin D3 being set to 100%. 50 The following was calculated and evaluated:

[0446] (result) The time-resolved fluorescence resonance energy transfer (TR-FRET) vitamin D receptor (VDR) coactivator assay is an assay that tests the first step for a test compound to exhibit agonist activity: the binding of the drug to the vitamin D receptor, followed by the denaturation of the receptor protein from the apo type to the holo type, which leads to its encombination with the coactivator protein. Of the compounds synthesized by this invention, des-D-bB(IIa), des-Db(IIIa), des-D-19-nor-bB(IIb), des-D-19-nor-b(IIIb), epi-des-D-19-nor-bB(epi-IIb), des-D-19-nor-bC(IV), des-D-19-nor-aB(V), des-D-19-nor-aC(VI), des-D-19-nor-cA(VII), des-D-19-nor-OH c(VIII), des-D-19-nor-CbB(IX), and epi-des-D-19-nor-CbB(epi-IX) are considered to be naturally active vitamin D3. When tested with 1α,25(OH)2-VD3(Ia) and the known active derivative 19-nor-1α,25(OH)2-VD3(Ib), the concentration-dependent curve of the emission ratio, which is an indicator of activity (i.e., the ratio of fluorescence emission intensity at 520 nm to fluorescence emission intensity at 495 nm), was as shown in Figure 1 (n=3), indicating that all of the above derivatives showed efficacy in a concentration-dependent manner. As summarized in Table 1, the drug concentrations EC that show 50% of the maximum activity of the natural types 1α,25(OH)2-VD3(Ia), 19-nor-1α,25(OH)2-VD3(Ib), des-D-bB(IIa), des-Db(IIIa), des-D-19-nor-bB(IIb), des-D-19-nor-bB(epi-IIb), des-D-19-nor-bC(IV), des-D-19-nor-aB(V), des-D-19-nor-aC(VI), des-D-19-nor-cA(VII), des-D-19-nor-OH c(VIII), des-D-19-nor-CbB(IX), and epi-des-D-19-nor-CbB(epi-IX) are 50% of the maximum activity. 50These values ​​were 10.8nM, 4.8nM, 7.5nM, 7.4nM, 17.4nM, 6.7nM, 518.4nM, 84.0nM, 243.4nM, 50.3nM, >5000nM, >5000nM, 922.0nM, and 845.7nM, respectively.

[0447] [Table 1]

[0448] <Test Example 2: Vitamin D Receptor (NR1I1, VDR) Reporter Assay> The VDR reporter cells (NR1I1, VDR) containing the VDR target gene and luciferase-compatible gene, cell recovery solution (CRM), compound screening solution (CSM), calcitriol (1.0 mM in DMSO, standard agonist for VDR), detection substrate, detection buffer, and 96-well assay plates (white, sterile, collagen-coated) were purchased from Indigo Biosciences as part of the Human Vitamin D Receptor (NR1I1, VDR) Reporter Assay System.

[0449] Each compound synthesized above was dissolved in dimethyl sulfoxide (DMSO, for molecular biology, Sigma Aldrich) and diluted to a desired concentration using CSM so that the DMSO content was less than 0.4% by mass (the resulting solution will be collectively referred to as "VD3 solution" below). The VDR reporter cell (NR1I1, VDR) solution was dispensed into assay plates (200 μL / well). This was incubated at 37°C for 4-6 hours under conditions of humidity above 85% and 5% CO2.

[0450] After incubation, the solution on the assay plate was discarded, and 100 μL of VD3 solution was dispensed into each assay plate. This was incubated at 37°C for 22-24 hours under conditions of humidity 85% or higher and 5% CO2. After incubation, the VD3 solution was discarded, and 100 μL of LDR, prepared by mixing the above detection substrate and detection buffer, was dispensed into each assay plate. After adding the LDR, the assay plate was left to stand at room temperature for at least 5 minutes. The human vitamin D receptor reporter assay was measured using the luminescence mode with an Infinite F200 PRO microplate reader (Tecan). The EC of each compound was measured. 50 This was calculated using GraphPad Prism (ver. 8.2.0).

[0451] (result) The vitamin D receptor reporter assay is an assay in which a test compound is introduced into VDR reporter cells (NR1I1, VDR) containing the VDR target gene and the luciferase-corresponding gene. After the test compound is introduced into the cell nucleus and binds to the vitamin D receptor protein, it undergoes complexation with various proteins necessary for gene transcription, triggered by the binding of a coactivator protein. This leads to the reading (transcription) of the VDR target gene and the luciferase-corresponding gene, which are the target sites of the genes, and the expression of the corresponding luciferase is then tested. The activity in this assay ensures the agonist activity of the drug. Of the compounds synthesized according to the present invention, des-D-bB(IIa), des-Db(IIIa), des-D-19-nor-bB(IIb), des-D-19-nor-b(IIIb), des-D-19-nor-aC(VI), and des-D-19-nor-CbB(IX) were tested together with naturally occurring active vitamin D3 1α,25(OH)2-VD3(Ia). The drug concentration-dependent curve of the fluorescence emission intensity by luciferase, which serves as an activity indicator, is shown in Figure 2 (n=3), indicating that all of the above derivatives showed efficacy in a concentration-dependent manner. As summarized in Table 2, the drug concentrations EC that show 50% of the maximum activity of the natural forms 1α,25(OH)2-VD3(Ia), des-D-bB(IIa), des-Db(IIIa), des-D-19-nor-bB(IIb), des-D-19-nor-b(IIIb), des-D-19-nor-aC(VI), and des-D-19-nor-CbB(IX) are shown. 50 These values ​​were 3.4nM, 14.9nM, 8.2nM, 22.5nM, 7.5nM, 46.0nM, and >500nM, respectively.

[0452] [Table 2]

Claims

1. Compounds represented by the following formula (1) (excluding the compounds of formula (1-1) and formula (1-2) below). 【Chemistry 1】 [In the formula, m and n are each independently 0 or 1, p is an integer of 0 to 4, and s is an integer of 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR ６ -, which represents a divalent group. R １ represents a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms. R ２ represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. R ３ represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have a substituent and may contain a heteroatom in the carbon chain. R ４ represents a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms. R ５ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have a substituent, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have a substituent. R ６ represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. R ７ and R ８ simultaneously represent a hydrogen atom, or they are combined together to form a methylidene group.]] 【Chemistry 2】

2. Active vitamin D containing the compound described in claim 1 as an active ingredient. ３ A preventive or therapeutic agent for diseases in which the action of [the substance] is effective.

3. The aforementioned activated vitamin D ３ The preventive or therapeutic agent according to claim 2, wherein the disease for which the action of the agent is effective is osteoporosis, rickets, chronic hypocalcemia, renal osteodystrophy, secondary hyperparathyroidism, psoriasis, and cancer.

4. A method for producing a compound represented by the following formula (1), A step of reacting a compound represented by the following formula (7) with a compound represented by the following formula (8) to obtain a compound represented by the following formula (9), A step of removing the group represented by W from the compound represented by the following formula (9) to obtain the compound represented by the following formula (1), A manufacturing method that includes this. 【Transformation 3】 [In the formula, m and n are independently 0 or 1, p is an integer from 0 to 4, and s is an integer from 0 to 4. Y is an oxygen atom, a sulfur atom, or -NR ６ This indicates a divalent group represented by -. R １ R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. ２ R represents an alkyl group having 1 to 8 carbon atoms, a hydroxyl group, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom. ３ R represents a linear or branched saturated or unsaturated divalent aliphatic hydrocarbon group having 1 to 20 carbon atoms, which may have substituents and may contain heteroatoms in the carbon chain. ４ R represents a monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms, either linear or branched, saturated or unsaturated. ５ R represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms which may have substituents, or a linear or branched saturated or unsaturated monovalent aliphatic hydrocarbon group having 1 to 6 carbon atoms which may have substituents. ６ R represents a hydrogen atom or a monovalent aliphatic hydrocarbon group. ７ and R ８ This simultaneously represents a hydrogen atom, or it is integrated to represent a methylidene group. 【Chemistry 4】 [In the formula, m, n, p, s, Y, R １ , R ２ , R ３ , R ４ , and R ６ As stated above, W indicates a protecting group. Z １ This represents a halogen atom or a group represented by the following formula (3). 【Transformation 5】 [In the formula, * indicates a bond.] 【Transformation 6】 [In the formula, R ５ , R ７ , R ８ , and W are as described above. Z ２ represents a halogen atom or a group represented by formula (3) above. However, Z in formula (7) above １ If it is a halogen atom, then Z ２ is a group represented by the above formula (3), and Z １ If the group is represented by the above formula (3), then Z ２ [It is a halogen atom.] 【Transformation 7】 [In the formula, m, n, p, s, W, Y, R １ , R ２ , R ３ , R ４ , R ５ , R ６ , R ７ , and R ８ This is as stated above.

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