# US 11,440,920 B2 · Chemical method of producing SMTP groups or SMTP-7 and intermediates used in the method

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- Number: US 11,440,920 B2
- Document ID: US11440920B2
- Status: Granted
- Kind: B2
- Application number: 16/671,545
- Filed: 2019-11-01
- Published: 2020-05-07
- Granted: 2022-09-13
- Earliest claimed: 2018-11-02
- Assignees: Showa University
- Applicants: Showa University
- Inventors: Takashi Itoh; Kazuhiro Nagata; Takuya Kanemitsu; Michiko Miyazaki; Yuichiro Tomisawa; Misa Mori
- Web page: https://patentgrep.com/patent/US11440920B2

## CPC

- C07D 493/04: Ortho-condensed systems
- C07C 67/30: by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 67/343: by increase in the number of carbon atoms
- C07D 311/58: other than with oxygen or sulphur atoms in position 2 or 4
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention provides a compound having a dihydropyran structure, a method of producing a compound having a dihydropyran structure, a method of producing Pre-SMTP, a method of producing a group of SMTPs, and a pharmaceutical composition. The compound having a dihydropyran structure can be a useful intermediate in the chemically producing a group of Pre-SMTP and SMTP. Specifically, the compound having a dihydropyran structure is represented by the following formula (1), wherein: R3Si is a silyl group selected from TMS: trimethylsilyl, TES: triethysilyl, TBS (TBDMS): tert-butyldimethylsil, TIPS: triisopropylsilyl, TBDPS: tert-butyldiphenylsilyl, X is selected from COOH, CHO, and —CH═C(CH3)—(CH2)2—CH═C(CH3)2.

## Claims

### Claim 1

A method of producing a compound of formula (1), comprising a production step I,
wherein the production step I is represented as:
wherein:
the eighth step is a step of obtaining a compound, which is represented by the formula (3), by oxidizing the compound represented by the formula (4a) with an oxidizing agent selected from the group consisting of osmium tetroxide (OsO4), cold alkaline potassium permanganate (KMnO4), and performic acid (HCO2OH),
the ninth step is a step of obtaining the compound represented by the formula (2) by substituting the compound represented by the formula (3) with a protecting group, and
the tenth step is a step of constructing a functional group X consisting of any one of COOH, CHO, and —CH═C(CH3)—(CH2)2—CH═C(CH3)2, and
wherein
Y1 and Y2 are each independently selected from the group consisting of trimethylsilyl, triethylsilyl (TES), triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or methyl, methoxymethyl, t-butyl, allyl, and benzyl.

### Claim 2 (depends on 1)

The method according to claim 1,
wherein:
a compound represented by the following formula (4) is used as a starting material, and
in the tenth step, the compound represented by the formula (2) is dissolved in CH3OH, and is stirred after being adding with CH3ONa under ice-cooling condition, a reaction product is extracted therefrom after neutralization, an organic layer of the extracted product is then washed with brine and dried with MgSO4 to obtain a solvent, the solvent is then distilled off under reduced pressure, and the residue is separated and purified by silica gel chromatography,
wherein the production step I is a production step IA represented as:
wherein Y1 is TES and Y2 is a methyl group.

### Claim 3 (depends on 1)

The method according to claim 1, further comprising:
performing a reaction with the compound represented by the formula (2) under anhydrous conditions to obtain a compound represented by the following formula (1B), and
obtaining a compound represented by the following formula (1C) by reducing the obtained compound represented by the formula (1B) with a reducing agent

### Claim 4 (depends on 1)

The method according to claim 1, further comprising an eleventh step after the tenth step, wherein in the eleventh step the compound of formula (1) is the compound of formula (1A), and wherein the compound of formula (1A) is reacted with MeOH in the presence of a dehydrating agent, and reduced using a reducing agent:
wherein: the dehydrating agent is a dehydrating condensing agent composed of a group containing a carbodiimide group selected from the group consisting of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, N,N′-dicyclohexylcarbodiimide, and diisopropylcarbodiimide,
wherein the reducing agent is diisobutylaluminum hydride or lithium aluminum hydride.

### Claim 5 (depends on 1)

The method according to claim 1, further comprising a twelfth step of synthesizing the olefin after the tenth step, wherein in the twelfth step the compound of formula (1) is compound of formula (1C):
wherein: the twelfth step is a reaction selected from the group consisting of a Takai-Lombard reaction, Takeda olefin synthesis, and Julia-Lithgo olefin synthesis.

### Claim 6 (depends on 5)

The method according to claim 5, wherein the compound represented by formula (4a) is the compound of formula (4), wherein the compound of formula (4) is produced by a production step II comprising first to seventh steps, the production step II using methyl 3,5-dimethoxybenzoate as a starting material:
the production step II is represented as:
wherein:
(a) in the first step, methyl 3,5-dimethoxybenzoate is dissolved in CH2Cl2, and is added with TiCl4 using a dropping funnel, the reaction solution is cooled, added with dichloromethyl methyl ether, and stirred at room temperature, the reaction solution is then added with HCl and stirred, an organic layer thereof is separated, washed, and dried, and the solvent is distilled off under reduced pressure to obtain the compound represented by the formula (10);
(b) in the second step, the obtained compound represented by the formula (10) is dissolved in CH2Cl2, and added with BCl3 under cooling, the mixture is stirred at room temperature, the reaction solution is poured into chilled HCl, an organic layer thereof is separated therefrom, washed, and dried, and the solvent is distilled off under reduced pressure to obtain the compound represented by the formula (9);
(c) in the third step, the obtained compound represented by the formula (9) is dissolved in acetone and added with K2CO3 and allyl bromide, the mixture is heated to reflux, then returned to room temperature, and added with H2O until a precipitated solid is dissolved, the reaction solution is then neutralized with HCl, acetone is distilled off from the reaction solution, ethyl acetate is then added thereto, an organic layer thereof is washed with H2O and brine, and dehydrated, and the solvent is distilled off under reduced pressure to obtain the compound represented by the formula (8);
(d) in the fourth step, the obtained compound represented by the formula (8) is dissolved in MeOH, and added with NaBH4 at low temperature, the mixture is stirred for 30 minutes at room temperature, and then neutralized with HCl, and a precipitated solid is suction filtered to obtain the compound represented by the formula (7);
(e) in the fifth step, the obtained compound represented by the formula (7) is mixed with N,N-diethylaniline, heated under an inert atmosphere, cooled down to room temperature, and the mixture is subjected to silica gel column chromatography (ethyl acetate/Hexane) to obtain the compound represented by the formula (6);
(f) in the sixth step, the obtained compound represented by the formula (6) is dissolved in DCM, added with N,N-Diisopropylethylamine, trifluoromethanesulfonic anhydride is dropped thereto and stirred under ice-cooling condition, the mixture is then added with aq.NaHCO3 to shift the mixture weakly basic, an organic layer thereof is separated, the aqueous layer is further extracted with CH2Cl2, the organic layer is collected and washed with H2O and brine, dehydrated, and the solvent is distilled off under reduced pressure, and the residue is separated and purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the compound represented by the formula (5);
(g) in the seventh step, the obtained compound represented by the formula (5) is dissolved in Et2O, added with ethyl 4-methyl-4-pentenoate and Hoveyda-Grubbs 2nd cat, the mixture is heated to reflux, the solvent is distilled off, and the residue is separated and purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the compound represented by the formula (4).

### Claim 7 (depends on 5)

The method of claim 5, wherein the compound of formula (1) is represented by the following formula (1B):