KR101794970B1 - Novel derivatives of nucleosides - Google Patents

Abstract

The present invention relates to a novel nucleoside derivative and its synthesis, and as a therapeutic molecule for treating diseases such as cancer, a novel nucleoside derivative has excellent bioavailability and increases the half-life of the drug, Short half-life, and can be administered orally, thus providing convenience of taking.

Description

Novel derivatives of nucleosides < RTI ID = 0.0 >

The present invention relates to novel nucleoside derivatives and their synthesis.

Novel nucleoside derivatives are required as therapeutic molecules for treating diseases such as cancer. There is also a need for a method of synthesizing novel nucleoside derivatives for the treatment of certain diseases.

It is an object of the present invention to provide a compound of formula (I) or (2), or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for the preparation of the compound of formula (2).

The term "nucleoside derivative" means that a partial functional group of the nucleoside is substituted, but not limited thereto, for example, the compound of the formula (1) or (2) defined below.

One embodiment of the present invention includes a nucleoside of the following formula (1).

≪ Formula 1 >

One embodiment of the present invention also includes a nucleoside of formula (2).

(2)

In this formula,

R ₁ and R ₂ are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl, substituted or unsubstituted oxycarbonyl and

로 구성된 군에서 선택된 어느 하나이고;

≪ / RTI >

n is independently an integer from 1 to 3;

R ₃ and R ₄ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₂₂ alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl and substituted or unsubstituted oxycarbonyl Lt; / RTI >;

R ₅ is independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₂₂ alkyl;

The substituted C ₁ -C ₂₂ alkyl, substituted acyl, substituted acyloxyalkylcarbonyl and substituted oxycarbonyl may be substituted by C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl And may be substituted with one or more substituents selected from the group consisting of

In one embodiment of the present invention, the compound may be any one selected from the group consisting of R ₁ and R ₂ are independently hydrogen and substituted or unsubstituted acyl.

이고, n은 1 일 수 있다.In one embodiment, the compounds of the present invention are those wherein R ₁ is

, And n may be 1.

The compounds of the present invention may be any one selected from the group consisting of the following compounds, but are not limited thereto:

Tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidin-2 ( (1H) -one (4-Azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy- 5- hydroxymethyl furan- one;

Tetrahydro-4-hydroxy-5- (L-isoleucinyloxymethyl) furan-2-yl) 2-yl) pyrimidin-2 (1H) -one (4-Azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro- pyrimidine-2 (1 H) -one);

Tetrahydro-4-hydroxy-5- (L-valinyloxymethyl) furan-2-yl) pyrimidine -2 (1H) -one (4-Azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro- 2 (1H) -one);

4-Hydroxy-5- (L-phenylalanine yloxymethyl) furan-2-yl) pyrimidine (2R, -2 (1H) -one (4-Azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro- 2 (1H) -one); And

Synthesis of 4-azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (elaidoyl) (1H) -one (4-Azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro- one).

Further, in one embodiment of the present invention, the compound of Formula 2 may be a compound of Formula 1 below.

≪ Formula 1 >

According to an embodiment of the present invention, there is also provided a method for preparing a compound of Formula 2 by adding NaOMe or a hydrogen ion to a compound of Formula 10 below.

≪ Formula 10 >

In this formula,

R 'is phenyl or methyl.

In the above process, the compound of formula (10) can be prepared by adding LiN ₃ to the compound of formula (9), and the compound of formula (9) can be prepared by adding triazole to the compound of formula May be prepared by reacting a compound of formula (7) with R < 5 > COCl, and the compound of formula (7) may be prepared from a compound of formula (11).

≪ Formula 7 >

(8)

≪ Formula 9 >

≪ Formula 11 >

In the general formulas (7) to (9), R 'is as defined above.

Hereinafter, the present invention will be described in detail. In the following description of the present invention, a detailed description of known functions and configurations incorporated herein will be omitted so as to avoid obscuring the subject matter of the present invention.

The terms " about ", " substantially ", etc. used to the extent that they are used herein are intended to approximate the numerical values when the manufacturing and material tolerances inherent in the meanings mentioned are presented, Absolute numbers are used to prevent unauthorized exploitation by unauthorized intruders of the mentioned disclosure.

The compounds of the present invention can generally be prepared according to the following Reaction Scheme 1.

<Reaction Scheme 1>

(2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) Furan-2-yl) pyrimidin-2 (1H) -one was prepared by converting the N4-amino group in position 4 to an azide group using the compound of formula 11 as starting material. The derivative represented by the formula (2) is prepared by using the formula (1) as a starting material.

In order to deaminate the amino group at the 4-position of the compound of formula (11) in the process of preparing the compound of formula (1) in the reaction scheme 1), there are several methods as described in the reaction scheme 2).

<Reaction Scheme 2>

R is Na or a t-BuO group, X is a halogen atom or an anion, and M is Na or K metal.

In order to prepare the compound of formula (1) in the above reaction scheme 2), there are two methods using intermediate (1) and intermediate (2) as a starting material, but the above-described preparation method is a well-known method for those skilled in the art.

<Reaction Scheme 3>

As another method for preparing the compound of formula (1), a reaction may be carried out by following the steps of (Formula 7), (Formula 8a, 8b), (Formula 9a, 9b), (Formula 10a, .

The deamidation to produce formula (7) takes place in an aqueous solution of less than pH 6.0 at 95 DEG C or in a high acidic aqueous solution at ambient temperature. Acids used here are Bronsted acids that produce protons in water or in solvents, examples being hydrochloric acid, sulfuric acid, acetic acid, and citric acid.

In order to prepare the compound of formula (8) after deamidation, an acylation reaction is carried out in order to protect the compound. In addition to the benzoyl group or the acetyl group shown in the formula, typical protecting groups and methods of preparation are well known.

(9), a suitable leaving group such as 1,2,4-triazole, 3-nitro-1,2,4-triazole or 1H -tetrazole is introduced instead of the carbonyl group at the 4-position.

(9) produced during the reaction is unstable to water and thus is difficult to separate. So it is better to proceed to the next reaction as soon as possible.

In order to prepare the compound of formula (10), the reaction is carried out in an unreactive polar solvent such as N, N-dimethylformamide at 60 ° C with an azide such as azide lithium or sodium azide to give a protected An azide derivative can be obtained.

Compound (1), which is a target compound, can be deprotected under conditions suitable for each protecting group to give the compound of formula (1).

Each reaction was confirmed by thin layer chromatography (TLC) and a suitable solvent system. When the reaction was completed by measurement by TLC, the product was extracted using an organic solvent, followed by chromatography using a suitable solvent system Can be purified by a method.

Tetrahydro-4-hydroxy-5- (hydroxymethyl) -1H-pyrazole-4-carboxylic acid represented by the formula (2) Furan-2-yl) pyrimidin-2 (1H) -one as a starting material.

The derivative of the compound thus obtained can be represented by the formula (2).

(2)

In this formula,

R ₁ and R ₂ are independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl, substituted or unsubstituted oxycarbonyl and

로 구성된 군에서 선택된 어느 하나이고;

&Lt; / RTI &gt;

n is independently an integer from 1 to 3;

R ₃ and R ₄ are independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₂₂ alkyl, substituted or unsubstituted acyl, substituted or unsubstituted acyloxyalkylcarbonyl and substituted or unsubstituted oxycarbonyl Lt; / RTI &gt;;

R ₅ is independently selected from the group consisting of hydrogen and substituted or unsubstituted C ₁ -C ₂₂ alkyl;

The substituted C ₁ -C ₂₂ alkyl, substituted acyl, substituted acyloxyalkylcarbonyl and substituted oxycarbonyl may be substituted by C ₁ -C ₂₂ alkyl, C ₅ -C ₂₂ cycloalkyl, C ₆ -C ₂₂ aryl And may be substituted with one or more substituents selected from the group consisting of

Tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) -1,3-difluoro-tetrahydro- Pyrimidin-2 (1H) -one can be synthesized according to Scheme 4).

<Reaction Scheme 4>

The protected amino acid is esterified at the 5 'position using well known coupling agents. The esterified compound can be converted into a free amino group through a deprotection reaction to obtain a monosubstituted derivative.

More specifically, as shown in Scheme 5), a specific amino acid reaction at the 5 'position can be exemplified, but the amino acid group that can be protected is not limited thereto.

<Reaction Scheme 5>

Each reaction was confirmed by thin layer chromatography (TLC) and a suitable solvent system. When the reaction was completed by measurement by TLC, the product was extracted using an organic solvent, followed by chromatography using a suitable solvent system Can be purified by a method.

Tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2 (2R, 4R, 5R) -3,3-difluoro-tetrahydro- -Yl) pyrimidin-2 (1H) -one can be synthesized according to Scheme 6).

<Reaction Scheme 6>

Esterification reaction using an appropriate acyl chloride can give a monosubstituted derivative. Each reaction was confirmed by thin layer chromatography (TLC) and a suitable solvent system. When the reaction was completed by measurement by TLC, the product was extracted using an organic solvent, followed by chromatography using a suitable solvent system Can be purified by a method.

The following examples are intended to illustrate the method for producing the desired nucleoside derivative of the present invention and to help understand the present invention.

The present invention relates to a novel nucleoside derivative and its synthesis, and as a therapeutic molecule for treating diseases such as cancer, a novel nucleoside derivative has excellent bioavailability and increases the half-life of the drug, Short half-life, and can be administered orally, thus providing convenience of taking.

Figure 1 shows the preparation of 4-azido-1 - ((2R, 4R, 5R) -3,3- difluoro-tetrahydro- -2 (1H) - ¹ H NMR spectrum of the whole shows a (I).
Figure 2 depicts the synthesis of 4-azido-1 - ((2R, 4R, 5R) -3,3- difluoro-tetrahydro-4-hydroxy-5- (hydroxymethyl) -2 (1H) -one. &Lt; tb &gt;&lt; TABLE &gt;

Hereinafter, the present invention will be described in detail. However, the following examples and experimental examples are illustrative of the present invention, and the contents of the present invention are not limited thereto.

Example  1. 1 - ((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Hydroxy -5- (Ha Dideoxymethyl ) Furan -2-yl) pyridine-2,4 (1H, 3H) Dion's  Preparation (7)

Sodium nitrite (16.7 g, 14.5 eq.) Was slowly added thereto, and the mixture was allowed to stand at room temperature for 48 hours. The mixture was adjusted to pH 6-7 with 2N aqueous sodium hydroxide solution and concentrated under reduced pressure. After concentration under reduced pressure, methanol / ethyl acetate (1: 5, 360 ml) was added to remove the insoluble salts. This procedure was repeated several times to remove all of the salts and the filtrate was concentrated under reduced pressure to obtain 4.22 g of a light brown transparent oil of formula (7) in a yield of 95%.

^{1 H-NMR (300MHz, DMSO} -d6) δ 11.5 (s, 1H), 7.79 (d, J = 8Hz, 1H), 6.39 (br, OH), 6.05 (t, J = 7Hz, 1H), 5.73 ( (d, J = 8 Hz, 1H), 5.35 (m, 1H), 4.19

Example  2. 1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Acetoxy -5- ( Acetoxymethyl ) Furan Yl) pyridine-2, 4 (1H, 3H) dione  Preparation 8a)

After dissolving 4-dimethylaminopyridine (0.14 g, 0.5 eq.) And 4-methylmorpholine (1.78 ml, 7 eq.) In tetrahydrofuran (12 ml), 0.32 g Lt; 0 &gt; C. Then, benzoyl chloride (0.67 ml, 2.5 eq.) Was slowly added thereto, followed by stirring at 5 DEG C or lower for 8 hours. After confirming the presence of the compound of formula (7) by thin layer chromatography, it was concentrated under reduced pressure. After diluting with saturated aqueous sodium hydrogen carbonate solution (10 ml), brine (7 ml) and methylene chloride (30 ml), only the organic layer was separated. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After concentration under reduced pressure, the residue was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain 0.79 g of compound (8a) as a white solid in a yield of 72%.

^{1 H-NMR (300MHz, DMSO} -d6) δ 11.6 (s, 1H), 8.06 (d, J = 7Hz, 2H), 7.96 (d, J = 7Hz, 2H), 7.74 (t, J = 7Hz, 2H ), 7.63 (m, 4H), 7.49 (m, 2H), 6.37 (m, IH), 5.82 (IH)

Example  3. 1 - ((2R, 4R, 5R) -3,3- Difluoro - Tetrahydro -4- Acetoxy -5- ( Acetoxymethyl ) Furan Yl) pyridine-2, 4 (1H, 3H) dione  Preparation 8b)

(4.22 g, 15.9 mmol, 1 eq.) Was dissolved in pyridine (63 ml) and cooled to 0 ° C. Acetic anhydride (4.50 ml, 3 eq.) Was slowly added thereto, followed by stirring at 5 ° C or lower for 16 hours. After confirming whether the compound 7) remained by thin layer chromatography, it was concentrated under reduced pressure. After diluting with saturated aqueous sodium bicarbonate solution (30 ml), brine (30 ml) and ethyl acetate (60 ml), only the organic layer was separated and water was removed with anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4.51 g of a dark brown oil Was obtained in a yield of 81%.

^{1 H-NMR (300MHz, DMSO} -d6) δ 11.5 (s, 1H), 7.60 (d, J = 8Hz, 1H), 6.27 (t, J = 8Hz, 1H), 5.84 (d, J = 8Hz, 1H ), 5.42 (m, IH), 4.37 (m, 3H), 2.16 (s, 3H)

Example  4. 4- Azido -1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Benzoyloxy -5- ( Benzoyloxy ) Furan -2-yl) pyridine-2,4 (1H, 3H) Dion's  Preparation 10a)

Compound 8a) (0.42 g, 0.889 mmol, 1 eq.) And 1,2,4-triazole (0.15 g, 1.5 eq.) Were added to acetonitrile (16 ml), followed by stirring at room temperature. Triethylamine (1.24 ml, 10 equivalents) was added to the reaction mixture, and the mixture was stirred at room temperature for about 15 minutes. The temperature was lowered to below 5 ° C and phosphoryl chloride (0.83 ml, 10 eq.) Was added slowly for 15 minutes. The temperature was gradually raised to room temperature and stirred. After 8 hours the thin layer chromatography confirmed that a new material was formed and 10 equivalents of triethylamine and phosphorous chloride were added, respectively. After 8 hours, 10 equivalents of triethylamine and phosphorous chloride were further added to the reaction mixture, respectively, depending on the presence or absence of the compound (8a) by thin layer chromatography. Compound 8a) was confirmed to disappear by thin-layer chromatography. The resulting mixture was concentrated under reduced pressure, diluted with brine (7 ml), saturated sodium hydrogencarbonate (10 ml) and ethyl acetate (30 ml), and only the organic layer was separated. The separated organic layer was dehydrated with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain a mixture of the formula (9a). (9a) was dissolved in N, N-dimethylformamide (8 ml), and azide lithium (1.25 ml, 4 eq.) Was added thereto, followed by stirring at 60 ° C for 6 hours. After confirming the remaining of the compound of formula (9a) by thin layer chromatography, it was concentrated under reduced pressure. The mixture was concentrated under reduced pressure, and the residue was separated by column chromatography (ethyl acetate: hexane = 1: 1) to obtain 0.24 g of a white solid of formula (10a) in a yield of 54%.

Compound ^{9a: 1 H-NMR (DMSO} -d6) δ 9.48 (s, 1H), 8.44 (s, 1H), 8.08 (d, J = 7Hz, 2H), 7.97 (m, 3H), 7.75 (m, 1H ), 7.61 (m, 3H), 7.48 (t, J = 7 Hz, 2H), 7.10 (d, J = 7 Hz, 1H), 6.57 (m, 1 H), 4.80 (m, 2 H);

Compound ^{10a: 1 H-NMR (DMSO} -d6) δ 8.10 (d, J = 7Hz, 2H), 7.99 (m, 3H), 7.75 (m, 1H), 7.62 (m, 3H), 7.50 (m, 2H ), 6.75 (t, J = 8 Hz, IH), 5.89 (m, IH), 4.96

Example  5. 4- Azido -1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Hydroxy -5- ( Hydroxymethyl ) Furan -2-yl) pyrimidin-2 (1H) -one (Formula 1)

(0.24 g, 0.482 mmol, 1 eq.) Was dissolved in methyl alcohol (4 ml), sodium methoxide (0.10 g, 4 eq.) Was added and the mixture was stirred at room temperature for 16 hours. After confirming whether the compound 4 remained by thin layer chromatography, it was adjusted to pH 4 or less with 2N acetic acid, and carbanion was concentrated. The mixture obtained by concentration was separated by column chromatography (ethyl acetate = 1) to obtain a white solid (1) (0.10 g) in a yield of 75% (see FIG. 1 and FIG. 2).

¹ H-NMR (DMSO-d 6)? 8.20 (d, J = 7 Hz, 1H), 7.27 (d, J = 7 Hz, 1H), 6.31 1H), 3.97 (m, 2 H), 3.81 (m,

MS (EI): m / z 289 = [M] ^{&lt; + &gt;}

Example  6. 4- Azido -1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Hydroxy -5- (L- Isoleucinyloxymethyl ) Furan -2-yl) pyrimidin-2 (1H) -one (Formula 3)

Was dissolved in N, N-dimethylformamide (5 ml), and dimethylaminopyridine (5.5 mg, 0.1 equivalent), dicyclohexylcarbodiimide (0.20 g, 2.2 eq.) (0.13 g, 0.450 mmol, ) And L-isoleucine (0.23 g, 2.2 eq.) With protecting group were added. After stirring at room temperature for 9 hours, the resulting solid was filtered off and concentrated under reduced pressure. After concentration under reduced pressure, the residue was separated by column chromatography (ethyl acetate = 1) to obtain a white solid compound (3a) (66 mg) in a yield of 37%. The obtained compound (3a) was added to a mixed solvent of trifluoroacetic acid and methyl alcohol (1: 1, 4 ml), stirred for 3 hours, and concentrated under reduced pressure. The oil phase mixture was separated by column chromatography (ethyl acetate = 1) to obtain white solid (3) (20 mg) in a yield of 37%.

_{^{1 H-NMR (MeOD- d 4}} ) δ 8.20 (d, J = 7Hz, 1H), 7.05 (d, J = 7Hz, 1H), 6.42 (m, 1H), 4.41 (m, 1H), 4.02 (m 2H), 3.82 (m, 2H), 2.03 (m, 1H), 1.76 (m,

Example 7 4-azido -1 - ((2R, 4R, 5R) as a 3,3-difluoro-tetrahydro-4-hydroxy -5- (L- Bali carbonyl oxy methyl) furan-2 Yl) pyrimidin-2 (1H) -one (Formula 4 )

(4) was obtained in a yield of 42%, except that L-valine with a protecting group (0.16 g, 2.2 eq.) Was used.

_{^{1 H-NMR (MeOD- d 4}} ) δ 8.20 (d, J = 7Hz, 1H), 7.05 (d, J = 7Hz, 1H), 6.42 (m, 1H), 5.62 (m, 1H), 4.41 (m 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.82

Example  8. 4- Azido -1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Hydroxy -5- (L- Phenylalanine ioxymethyl ) Furan -2-yl) pyrimidin-2 (1H) -one (Formula 5)

(5) was obtained in a yield of 42%, except that L-phenylalanine with a protecting group (0.20 g, 2.2 eq.) Was used.

_{^{1 H-NMR (MeOD- d 4}} ) δ 8.20 (d, J = 7Hz, 1H), 7.37 (m, 5H), 7.05 (d, J = 7Hz, 1H), 6.42 (m, 1H), 6.11 (m , 5.50 (m, IH), 4.57 (m, IH), 4.02 (m, IH), 3.82

Example  9. 4- Azido -1 - ((2R, 4R, 5R) -3, 3- Difluoro - Tetrahydro -4- Hyde Roxy-5- ( Ellaido ) Furan -2-yl) pyrimidin-2 (1H) -one (Formula 6)

(0.11 g, 1.0 eq.) Was dissolved in N, N-dimethylformamide (2 ml), and the mixture was stirred at room temperature for 1 hour. It melts and goes. The mixture is stirred at room temperature for 12 hours. The residue of the compound 4 is confirmed by thin layer chromatography, and then the solvent is removed by concentration under reduced pressure. After concentration under reduced pressure, the residue was separated by column chromatography (methylene chloride: methanol = 12: 1) to obtain 45 mg of a pale yellow oil in a yield of 23%.

^{1 H-NMR (DMSO- d6)} δ 8.20 (d, J = 7Hz, 1H), 7.05 (d, J = 7Hz, 1H), 6.45 (m, 1H), 6.17 (m, 1H), 5.35 (m, 2H), 1.45 (m, 2H), 1.85 (m, 2H), 0.85 (m, 3H) )

Claims (10)

delete delete delete A compound selected from the following or a pharmaceutically acceptable salt thereof:
Tetrahydro-4-hydroxy-5- (hydroxymethyl) furan-2-yl) pyrimidin-2 ( 1H) -one;
Tetrahydro-4-hydroxy-5- (L-isoleucinyloxymethyl) furan-2-yl) Pyrimidin-2 (lH) -one;
Tetrahydro-4-hydroxy-5- (L-valinyloxymethyl) furan-2-yl) pyrimidine -2 (lH) -one;
4-Hydroxy-5- (L-phenylalanine yloxymethyl) furan-2-yl) pyrimidine (2R, -2 (lH) -one; And
Synthesis of 4-azido-1 - ((2R, 4R, 5R) -3,3-difluoro-tetrahydro-4-hydroxy-5- (elaidoyl) 1H) -one.
delete A method for producing the compound according to claim 4,
Adding NaOMe or a hydrogen ion to a compound of formula (10) to prepare a compound of formula (2): < EMI ID =
(2)

&Lt; Formula 10 &gt;

Wherein the formula 2 represents the compound of claim 4,
In the above formula (10), R 'is phenyl or methyl.
The method according to claim 6,
Further comprising the step of adding LiN ₃ to the compound of formula 9 to prepare a compound of formula 10:
&Lt; Formula 9 >

In this formula,
R 'is phenyl or methyl.
8. The method of claim 7,
Further comprising the step of adding triazole to the compound of formula 8 to prepare a compound of formula 9:
(8)

In this formula,
R 'is phenyl or methyl.
9. The method of claim 8,
Further comprising the step of reacting a compound of formula (VII) with R < C > COCI to prepare a compound of formula (8): &
&Lt; Formula 7 &gt;

R &lt; 6 &gt; is phenyl or methyl.
10. The method of claim 9,
Wherein the compound of formula 7 is prepared from a compound of formula 11:
&Lt; Formula 11 >

.

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