# US 8,569,520 B2 · Crystal of spiroketal derivatives and process for preparation of spiroketal derivatives

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- Number: US 8,569,520 B2
- Document ID: US8569520B2
- Status: Granted
- Kind: B2
- Application number: 13/000,208
- Filed: 2009-06-19
- Published: 2011-12-15
- Granted: 2013-10-29
- Earliest claimed: 2008-06-20
- Assignees: Chugai Seiyaku Kabushiki Kaisha
- Applicants: Masatoshi Murakata; Takuma Ikeda; Nobuaki Kimura; Akira Kawase; Masahiro Nagase; Keisuke Yamamoto
- Inventors: Masatoshi Murakata; Takuma Ikeda; Nobuaki Kimura; Akira Kawase; Masahiro Nagase; Keisuke Yamamoto
- Web page: https://patentgrep.com/patent/US8569520B2

## CPC

- C07H 19/01: sharing oxygen
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07D 493/10: Spiro-condensed systems
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 7/04: Carbocyclic radicals
- C07H 13/04: having the esterifying carboxyl radicals attached to acyclic carbon atoms
- C07H 23/00: Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12 (esters with inorganic acids C07H11/00)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a process for preparing a spiroketal derivative, via an intermediate represented by Formula (VI): wherein variable groups and numbers are as defined in the specification, which can be produced from dihalobenzene derivatives in one pot reaction.

## Claims

### Claim 1

A process for preparing a compound represented by Formula (I):
wherein n is 0, m is an integer selected from 0 and 1;
R2 is selected from C1-4 alkyl;
which comprises:
Step a): treating a compound of Formula (II):
wherein X1 and X2 are independently selected from a bromine atom or an iodine atom;
P1 is a metal ion, a hydrogen atom or a protecting group of hydroxy;
and n is as defined above;
with an organometal reagent, and then reacting with a compound of Formula (III):
wherein P2, P3, P4, and P5 are independently selected from a protecting group of hydroxy; or P2 and P3, P3 and P4, and P4 and P5 together may independently represent a divalent group to protect two hydroxy groups and to form a ring;
to obtain a compound represented by Formula (IVa):
wherein n, X2, P1, P2, P3, P4, Y and P5 are as defined above; and
X is a metal ion, or a hydrogen atom;
Step b): treating a compound represented by Formula (IVb):
wherein n, X2, P1, P2, P3, P4, and P5 are as defined above; and
P6 is a metal ion, a hydrogen atom or a protecting group of hydroxy;
with an organometal reagent, and then reacting with a compound represented by Formula (V):
wherein R42 is a group defined as R2 and m is as defined above; and
which may further comprise one or more steps to introduce a protecting group and/or to remove a protecting group, in the steps defined above and/or in any stage prior to or after any one of the steps defined above.

### Claim 2 (depends on 1)

The process according to claim 1, which further comprises
Step c): subjecting a compound represented by Formula (VI):
wherein R42, m, n, P1, P2, P3, P4, P5, and P6 are as defined in claim 1; to the two following steps:
Step (1): treating a compound represented by Formula (VI) wherein P1 is a hydrogen atom under an acidic condition, with the proviso that when P1 is a protecting group, the step further comprises a deprotection step before the treatment; and
Step (2): removing a hydroxy group, which is formed in Step b), by reduction reaction; with the proviso that any one of the two steps may be carried out in first;
to obtain a compound represented by Formula (VII):
wherein R42, m, n, P2, P3, P4, and P5 are as defined above.

### Claim 3 (depends on 1)

The process according to claim 1, in which the organometal reagent is added over 15 to 300 minutes in Step a).

### Claim 4 (depends on 1)

The process according to claim 1, in which addition of an organometal reagent is carried out intermittently in Step a).

### Claim 5 (depends on 1)

The process according to claim 1, in which a first portion of the organometal reagent is added in an amount of 0.4 to 0.9 equivalents relative to the compound of Formula (II), and after interruption of the addition a second portion of the reagent is further added in an amount of 0.1 to 0.7 equivalents relative to the compound of Formula (II), wherein P1 is a metal ion or a protecting group in Step a).

### Claim 6 (depends on 1)

The process according to claim 1, in which a first portion of the organometal reagent is added in an amount of 1.4 to 1.9 equivalents relative to the compound of Formula (II), and after interruption of the addition a second portion of the reagent is further added in an amount of 0.1 to 0.7 equivalents relative to the compound of Formula (II), wherein P1 is a hydrogen atom in Step a).

### Claim 7 (depends on 1)

The process according to claim 1, in which the organometal reagent is added to the reaction system containing the compound of Formula (II) wherein P1 is a metal ion, or a protecting group of hydroxy, and then the compound of Formula (II) is further added thereto in Step a).

### Claim 8 (depends on 1)

The process according to claim 1, in which a compound of Formula (II) wherein P1 is a protecting group of hydroxyl is used in Step a).

### Claim 9 (depends on 1)

The process according to claim 1, in which a compound of Formula (IVb) wherein P6 is a protecting group of hydroxy is used in Step b).

### Claim 10 (depends on 1)

The process according to claim 1, wherein Steps a) and b) are carried out in one pot reaction.

### Claim 11 (depends on 2)

The process according to claim 2, further comprising:
Step d): converting a compound of Formula (I) to a compound of Formula (X):
wherein R42, m, and n are as previously defined, and P7 is a protecting group of hydroxy;
Step e): crystallizing the compound of Formula (X) and purifying the compound by recrystallization;
Step f): removing a protecting group(s) from a compound of Formula (X) to give a high-purity compound of Formula (I).

### Claim 12 (depends on 1)

The process according to claim 1, further comprising a step for introducing a protecting group into the compound represented by Formula (IVa) to obtain a compound represented by Formula (IVb) wherein P6 is a protecting group of hydroxy.

### Claim 13 (depends on 1)

The process according to claim 1, wherein P1 and P6 are independently selected from an alkali metal ion, an alkali earth metal ion, a hydrogen atom, C1-10 alkyl optionally substituted with one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more R52, C2-10 alkenyl, —Si(R53)3—C(═O)R54, —B(OR55)2;
P2, P3, P4 and P5 are independently selected from C1-10 alkyl optionally substituted with one or more R51, saturated, partially unsaturated or unsaturated heterocyclyl optionally substituted with one or more R52, C2-10 alkenyl, —Si(R53)3—C(═O)R54, —B(OR55)2; or P2 and P3, P3 and P4, and P4 and P5 together may independently represent C1-10 alkylene group or carbonyl group to protect two hydroxyl groups and to form a ring;
wherein R51 is independently selected from aryl optionally substituted with one or more R56, C1-10 alkoxy optionally substituted with one or more C1-10 alkylthio, and arylselenyl;
R52 is independently selected from C1-10 alkyloxy;
R53 and R55 are independently selected from C1-10alkyl and aryl;
R54 is independently selected from a hydrogen atom, C1-10alkyl, aryl optionally substituted with one or more C1-10alkoxy, heteroaryl, amino optionally substituted with one or more R57, C1-10alkoxy optionally substituted with one or more aryl, or aryloxy optionally substituted with one or more nitro;
R56 is independently selected from C1-10 alkyl, C1-10alkoxy, aryl, and heteroaryl;
R57 is independently selected from C1-10 alkyl and aryl; and
X is an alkali metal ion, an alkali earth metal ion, or a hydrogen atom.

### Claim 14 (depends on 1, 13)

The process according to claim 1, wherein P1 is selected from a lithium ion, a hydrogen atom, C1-6alkoxyC1-6alkyl, arylmethyloxyC1-6alkyl, tetrahydropyranyl, a group —Si(R53)3, benzyl, 4-methoxybenzyl, triphenylmethyl, and a group —B(OR55)2;
P2, P3, P4 and P5 are independently selected from C1-6alkoxyC1-6alkyl, arylmethyloxyC1-6alkyl, tetrahydropyranyl, a group —Si(R53)3, benzyl, 4-methoxybenzyl, triphenylmethyl, a group —B(OR55)2, C1-6alkycarbon C1-6alkoxycarbonyl, benzyloxycarbonyl, t-butyl; or P4 and P5 together may independently represent a divalent group selected from —CH2—, —CH(CH3)—, —C(CH3)2, and —CHPh- to protect two hydroxy groups and to form a ring; and
X, P6, R53, and R55 are as defined in claim 13.

### Claim 15 (depends on 1)

The process according to claim 1, wherein P1 is C1-6alkoxyC1-6alkyl;
P2, P3, P4 and P5 are independently selected from a group —Si(R53)3;
R53 is independently selected from C1-10alkyl and aryl; and
X is an alkali metal ion.

### Claim 16 (depends on 11)

The process according to claim 11, wherein P7 is selected from
C1-6alkylcarbonyl, C1-6alkoxycarbonyl, —SiR23R24R25, and R23, R24 and R25 are independently selected from C1-10alkyl and aryl.

### Claim 17 (depends on 11)

The process according to any one of claim 11, wherein P7 is selected from t-butylcarbonyl and methoxycarbonyl.

### Claim 18 (depends on 1)

A compound represented by Formula (IVb):
wherein n, X2, P1, P2, P3, P4, P5, and P6 are as defined in claim 1.

### Claim 19 (depends on 1)

A compound represented by Formula (VI):
wherein R42, m, n, P1, P2, P3, P4, P5 and P6 are as defined in claim 1.

### Claim 20 (depends on 18)

The compound according to claim 18, wherein P1 is C1-6alkoxyC1-6alkyl;
P2, P3, P4, P5 and P6 are independently selected from a group: —Si(R53)3;
R53 is independently selected from C1-10alkyl and aryl.

### Claim 21 (depends on 19)

The compound according to claim 19, wherein P1 is C1-6alkoxyC1-6alkyl;
P2, P3, P4, P5 and P6 are independently selected from a group: —Si(R53)3;
R53 is independently selected from C1-10alkyl and aryl.