WO2003097594A1

WO2003097594A1 - Process for preparing optically pure 3-hydroxy-pyrrolidine

Info

Publication number: WO2003097594A1
Application number: PCT/KR2003/000995
Authority: WO
Inventors: Jongpil Chun; Jae Kwang Hwang; Seung Bum Ha; Yik-Haeng Cho; Ji Uk Yoo
Original assignee: Samsung Fine Chemicals Co., Ltd.
Priority date: 2002-05-20
Filing date: 2003-05-20
Publication date: 2003-11-27
Also published as: KR100461569B1; AU2003230438A1; KR20030089949A

Abstract

The present invention relates to a method for preparing optically pure 3-hydroxy-pyrrolidine, more particularly to a novel method for preparing 3-hydroxy-pyrrolidine economically, conveniently and efficiently, by reacting optically active 3,4-epoxy-1-butanol with ammonia and an aldehyde compound to prepare 4-protected-imino-butane-1,3-diol, selectively activating a hydroxy group at C-1 and then converting an imino group to an amine group by acid simultaneously or consecutively and performing intramolecular cyclization in the presence of a base.

Description

PROCESS FOR PREPARING OPTICALLY PURE 3-HYDROXY-PYRROLIDINE

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a method for preparing optically pure

3-hydroxy-pyrrolidine, more particularly to a novel method for preparing

3-hydroxy-pyrrolidine represented by the following Formula 1 economically,

conveniently and efficiently, by reacting optically active 3,4-epoxy-l-butanol with

ammonia and an aldehyde compound to prepare 4-protected-imino-butane-l,3-diol,

selectively activating a hydroxy group at C-1 and then converting an imino group to

an amine group by acid simultaneously or consecutively and performing

intramolecular cyclization in the presence of a base.

H (1)

In Formula 1, * represents (S) or (R) configuration.

Optically pure (S)- or (R)-3-hydroxy-pyrrolidine derivatives are used as

intermediate compounds for preparing a variety of chiral compounds. For example,

they are used as key intermediate materials for preparing chiral medicines, such as

vasodilators (calcium antagonist: barnidipine) [European Patent Publication No.

160,451, /. Med. Chem. 1986, 29, 2504-2511, Japanese Patent Publication No. Sho 61-267577, Japanese Patent Publication No. Sho 61-63652], carbapenem antibiotics

[Heteroc_ji cles, vol 24, No 5, 1986, Tetrahedron Lett. 25, 2793, 1984, W088/ 08845, /. Org.

Chem. 1992, 57, 4352-4361], quinolone antibiotics [US Patent No. 4,916,141, European

Patent Publication No. 391,169, European Patent Publication No. 304,087], anodynes

(κ-receptor agonists) [European Patent Publication No. 398,720, European Patent

Publication No. 366,327, /. Med. Chem., 1994, 37, 2138-2144] and neurotransmitters

[WO01/ 19817].

Description of Related Art

The conventional methods for preparing optically pure (S)- or

(R)-3-hydroxy-pyrrolidine derivatives are as follows.

There is a method of preparing (R)-3-hydroxy-pyrrolidine by decarboxylation

using L-hydroxy-proline [Chem. Lett. 893, 1986, Syn. Commun. 23, 2691, 1993, Syn.

Commun. 24, 1381, 1994]. Disadvantage of this method is that it uses expensive

L-hydroxy-proline as a starting material.

There is a method of obtaining cyclized amide by multi-step from L-malic acid

or L-glutamic acid and reducing it with LiAlH₄ or B2H6 [Syn. Commun. 15, 587-598,

1985, /. Med. Chem. 1994, 37, 2138-2144, Syn. Commun. 16, 1815-1822, 1986].

Disadvantage of this method is that it requires several steps and LiAlH₄ or B₂H₆

reducing agents are expensive and difficult to handle.

There is a method of obtaining l-benzyl-3-hydroxy-pyrrolidine by preparing 4-halo-3-hydroxy-butanoate by reduction of β-ketoester using catalyst, reducing

with Ca(BH4)2, selectively activating hydroxy group to sulfonic acid derivative and

carrying out intramolecular cyclization [European Patent Publication No. 452,143].

Disadvantage of this method is that it requires an expensive catalyst and reduction

should be processed selectively only in one direction during induction of chiral center

at carbon.

There is a method of obtaining 3-hydroxy-pyrrolidine by preparing chiral C4

derivative through optical resolution of racemic C3 compound using an enzyme and

carbon chain elongation (KCN) and carrying out reduction in the presence of a metal

catalyst and intramolecular cyclization [European Patent Publication No. 347,818,

European Patent Publication No. 431,521]. This method also should be processed in

one direction during induction of chiral center at carbon.

There is a method of introducing a chiral hydroxy group by asymmetric

hydroboration of N-substituted-3-ρyrroline [/. Org. Chem. 1986, 51, 4296-4298, /. Am.

Chem. Soc, 1986,108, 2049]. However, this method is not yet commercially

applicable.

Also, there are classical optical resolution, hydrolysis using an enzyme and

esterification using an enzyme [Japanese Patent Publication No. Hei 5-32620, Japanese

Patent Publication No. Hei 4-164066, Japanese Patent Publication No. Sho 61-63652,

Bull. Chem. Soc. Jpn. 1996, 69, 207, Enantiomer, 1997, 2, 311-314, Biochem. 1995, 59, 1287].

But, theoretical maximum yield of these methods cannot exceed 50% irrespective of optical purity.

There is a method of obtaining 3-hydroxy-pyrrolidine by preparing

2-halo-l,4-butanediol through halogenation and B₂H₆ reduction of D- or L-aspartic

acid, preparing 4-methanesulfonyloxy-l,2-epoxybutane by epoxidation and

sulfonation and carrying out reaction with ammonia [Heterocycles, 1986, 24, 5].

Although the starting material of this method is similar to that of the present

invention, this method uses B₂H₆, which is expensive and difficult to handle, as a

reducing agent. Also, during the reaction with ammonia, which is the key process,

excess by-products are formed, so that the reaction yield is below 28%. And,

introduction of a protection group is required during the purification of

3-hydroxy-pyrrolidine.

As yet, a method preparing 3-hydroxy-pyrrolidine using 3,4-epoxy-l-butanol

as a starting material as disclosed in the present invention has not been known.

SUMMARY OF THE INVENTION

The present inventors have made enormous efforts to find a method for

preparing optically pure 3-hydroxy-pyrrolidine conveniently and economically.

As a result, they identified that: if optically active 3,4-epoxy-l-butanol is reacted with

ammonia and aldehyde compound, 4-protected imino-butane-l,3-diol is obtained as

an intermediate without a by-product, and then, through intramolecular cyclization

while selectively activating a hydroxy group at C-1 with a leaving group, optically pure target compound can be prepared in good yield.

Accordingly, an object of the present invention is to provide a method for

preparing commercially available optically pure 3-hydroxy-pyrrolidine in good yield

and in large quantity.

The preparing method according to the present invention comprises:

a step of reacting optically active 3,4-epoxy-l-butanol represented by the

following Formula 2 with ammonia and an aldehyde compound to obtain 4-protected

imino-butane-l,3-diol represented by the following Formula 3;

a step of selectively activating a hydroxy group at C-1 of the compound

represented by Formula 3 with a leaving group (halogen or sulfonyloxy group) by

halogenation or sulfonation to obtain an intermediate represented by the following

Formula 4, and treating it with an acid simultaneously or consecutively to obtain

3-hydroxy-l-substituted-butylamine salt represented by the following Formula 5; and

a step of intramolecular cyclizing the compound represented by Formula 5 in

the presence of a base to obtain 3-hydroxy-pyrrolidine represented by the following

Formula 1:

Scheme 1

wherein: R¹ is an aryl or a substituted aryl group; R² is a hydrogen atom or an acyl

group; HX is halogen acid or aliphatic acid; and Y is a halogen, a Cι-C ₂

alkylsulfonyloxy, arylsulfonyloxy or a substituted arylsulfonyloxy group.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Hereinafter, the present invention is described in more detail.

The present invention relates to a method for preparing optically pure (S)- or

(R)-3-hydroxy-pyrrolidine from optically active (S)- or (R)-3,4-epoxy-l-butanol

effectively and economically without a by-product.

Each step of the preparing method of the present invention represented in

Scheme 1 is described in more detail in the followings.

The first step is imination of reacting optically pure 3,4-epoxy-l-butanol

represented by Formula 2 with ammonia and an aldehyde compound to obtain

4-protected-imino-butane-l,3-diol represented by Formula 3.

The starting material, or optically pure (S)- or (R)-3,4-epoxy-l-butanol represented by Formula 2, can be prepared from commercially available

(S)-3-hydroxy-γ-butyrolactone by known methods [Japanese Patent Publication No.

Hei 2-174733].

For the aldehyde compound used in the imination step, aldehyde having an

aryl or a substituted aryl group, preferably benzaldehyde, is used. In the

imination step: ammonia is used in 1 to 20 equivalents, preferably in 2 to 5

equivalents; and the aldehyde compound is used in 1 to 5 equivalents, preferably in 1

to 2 equivalents. This step proceeds well without using a reaction solvent. If

necessary, an organic solvent or water may be used as a solvent. The imination is

proceeded at a temperature ranging from 20 to 80 ^°C, preferably from 20 to 40 ^°C .

The reaction time is 1 to 24 hours, and preferably 3 to 5 hours.

In the second step of the present invention, a hydroxy group at C-1 of the

compound represented by Formula 3 is selectively activated to form the intermediate

represented by Formula 4, and it is treated with an acid simultaneously or

consecutively to convert an imino group to an amine group, thereby obtaining

3-hydroxy-l-substituted-butylamine salt represented by Formula 5. That is, a

hydroxy group at C-1 of the compound represented by Formula 3 is activated and the

imino group is converted to amine in the presence of an acid catalyst simultaneously

or in situ. Several selective activation methods similar to that of the present

invention are reported. However, they are about selective activation at C-1 of

1,3-butanediol or 3-benzyloxy-2-methylpropane-l,2-diol, different from the present invention [Tetrahedron: Asymmetry 12, 1383-1388, 2001, /. Org. Chem. 53, 4081-4084,

1988, /. Chem. Soc, Perkin Trans., 1973, 1214, Organic Sji nthesis, 63, 140].

The selective activation at C-1 of the present invention can be done by

halogenation or sulfonation.

In case the selective activation at C-1 is done by halogenation via the

intermediate represented by Formula 4, deprotection is carried out during water

addition for purification. In the halogenation, any common halogenating agent can

be used, and preferably hydrobromic acid. The halogenating agent is used in 1 to 5

equivalents, preferably in 2 to 3 equivalents. The halogenation can be proceeded

without a reaction solvent. If necessary, an organic solvent can be used. The

halogenation is proceeded at a temperature ranging from 20 to 60 °C , preferably 30 to

50 °C . The reaction time is 1 to 24 hours, and preferably 3 to 6 hours.

In case the selective activation at C-1 is done by sulfonation, an intermediate

represented by formula 4 can be purified or proceeded in situ depending on the

situation. For the sulfonating agents, alkylsulfonic acid anhydride, alkylsulfonyl

chloride or aryl sulfonyl chloride can be used. Specifically, G1-C12 alkylsulfonic acid

anhydride, alkylsulfonyl chloride or aryl sulfonyl chloride, preferably

methanesulfonyl chloride or p-toluenesulfonyl chloride, can be used. The

sulfonating agent is used in 1 to 3 equivalents, preferably in 1 to 2 equivalents.

For the base, aliphatic or aromatic amines, preferably triethylamine,

diisopropylethylamine or pyridine, can be used. The base is used in 1 to 3 equivalents, preferably in 1 to 2 equivalents. For the reaction solvent of the

sulfonation, an organic solvent, preferably dichloromethane, dichloroethane,

chloroform or dioxane, can be used. The reaction is proceeded at a temperature

ranging from -20 to 30 ^°C, preferably -10 to 10 ^°C . The reaction time is 1 to 12 hours,

and preferably 1 to 3 hours.

After the sulfonation is completed, the imino group is converted to an amine

group in the presence of an acid catalyst after purification, or in situ using an acid

catalyst. For the acid, halogen acid or aliphatic acid, preferably hydrochloric acid,

hydrobromic acid, acetic acid or methanesulfonic acid can be used. The acid is used

in 1 to 5 equivalents, preferably in 1 to 3 equivalents. The reaction is proceeded at a

temperature ranging from 5 to 40 ^°C, preferably 5 to 20 ^°C . The reaction time is 1 to 5

hours, and preferably 1 to 3 hours.

In the third step of the present invention, the compound represented by

Formula 5 is accomplishing intramolecular cyclization in the presence of a base to

obtain the compound represented by Formula 1, the target compound of the present

invention. For the base, inorganic base or organic base can be used. Inorganic base

refers to alkali metal salt or alkali earth metal salt. To be specific, it includes

hydroxide, alkoxide and carbonate of alkali metal or alkali earth metal. Organic

base refers to aliphatic or aromatic amine. To be specific, it includes alkylamine and

arylamine. The base is used in 1 to 10 equivalents, preferably in 2 to 4 equivalents.

For the reaction solvent, an organic solvent or water, preferably water, methanol or ethanol can be used. The reaction is proceeded at a temperature ranging from 0 to

80 °C , preferably 0 to 30 ^°C . The reaction time is 1 to 24 hours, and preferably 1 to 6

hours.

The preparing method of the present invention minimizes generation of

by-products and provides good yield.

In Synth. Commun., 1973, 3, 177, the compound represented by Formula 2 was

directly aminated to obtain 4-amino-butane-l,3-diol. That is, 3,4-epoxy-l-butanol

was treated with ammonia to aminate the C-4 position. However, if

3,4-epoxy-l-butanol represented by Formula 2 is reacted with ammonia, dimer and

trimer are generated as by-products.

On the other hand, the present invention prepares the compound represented

by Formula 5 from 3,4-epoxy-l-butanol by way of the imine intermediate represented

by Formula 3. Therefore, generation of a dimer or a trimer is prevented and the

production yield can be maximized.

Also, with the introduction of the protection group (imine), the selective

activation at C-1 can be done efficiently without by-products.

Hereinafter, the present invention is described in more detail through

Examples. However, the following examples are only for the understanding of the

present invention, and the present invention is not limited by the following Examples. In the examples, chirality is not marked distinctively.

Example 1: Preparation of 4-benzimino-butane-l,3-diol

3,4-Epoxy-l-butanol (100 g, 1.13 mol) was dissolved in 400m£ of ethanol in a

26 reactor. Benzaldehyde (121.6g, 1.15 mol) and 28% aqueous solution of ammonia

(275.6g, 4.54 mol) was added to the reactor, and the reactor was stirred at 40 ^°C for 3

hours. After the reaction was completed, the reaction mixture was cooled to room

temperature and the reaction solvent was concentrated under reduced pressure.

The concentrate was diluted in 500m^ of dichloromethane and washed with 50ml of

saturated brine. The dichloromethane layer was dried with anhydrous magnesium

sulfate and concentrated under reduced pressure to obtain 201.8g of target compound

(yield: 92%).

Η-NMR (CDCls, ppm) δ 1.85 (m, 2H), 3.2 (br, 1H), 3.63 (m, 1H), 3.74 (m, 1H), 3.88

(m, 2H), 4.16 (m, 1H), 7.36-7.73 (m, 5H), 8.33 (s, 1H)

Example 2: Preparation of 4-benzimino-3-hydroxy-l-methanesulf onyloxybutane

4-Benzimino-butane-l,3-diol (123g, 0.64 mol) was dissolved in όOOmβ of

dichloromethane in a 21 reactor, and the reaction solution was cooled to -10 °C .

Diisopropylethylamine (90.5g, 0.70 mol) was added at the same temperature, and

methanesulfonyl chloride (76.6g, 0.67 mol) was added dropwise for 1 hour keeping

the temperature at -10 ^°C . The reaction solution was stirred at the same temperature for 1 hour and warmed to 0°C to complete the reaction. 100 nι(. of water was

slowly added to the reaction solution at 0 to 5^°C to wash it. Then, the

dichloromethane layer was dried with anhydrous magnesium sulfate and

concentrated under reduced pressure to obtain 152g of target compound (yield: 88%).

Η-NMR (CDCb, ppm) δ 1.93 (m, IH), 2.05 (m, IH), 3.05 (s, 3H), 3.57 (dd, IH), 3.76

(m, IH), 4.0 9(m, IH), 4.46 (m, 2H), 7.38-7.73 (m, 5H), 8.35 (s, IH)

Example 3: Preparation of 3-hydroxy-l-methanesulfonyloxy-butylamine hydrogen

chloride salt

The compound (lOOg, 0.37 mol) prepared in Example 2 was dissolved in 400m£

of dichloromethane and cooled to 5^°C . 10% aqueous solution of hydrochloric acid

(269g, 0.74 mol) was added dropwise at 5°C for 1 hour while stirring the reaction

solution. The water layer was concentrated and azotropically distillated with

ethanol to obtain 77.7g of hydrogen chloride salt of target compound (yield: 96%).

Η-NMR (D₂0, ppm) δ 1.74 (m, IH), 1.88 (m, IH), 2.82 (m, IH), 3.03 (dd, IH), 3.89 (m,

IH), 4.32 (m, 2H)

Example 4: Preparation of 3-hydroxy-l-methanesulfonyloxy-butylamine hydrogen

chloride salt

The reaction according to Example 2 was carried out in situ, without

separation according to Example 3 to obtain 123. lg of hydrogen chloride salt of the target compound (yield: 88%).

IH), 4.32 (m, 2H)

Example 5: Preparation of 3-hydroxy-l-bromo-butylamine hydrogen bromide salt

4-Benzimino-butane-l,3-diol (100g, 0.52 mol) and 33% hydrobromic

acid-acetic acid solution (380.6g, 1.55 mol) were added in a 11 reactor, and the reactor

was sealed. The reactor was heated at 40 ^°C for 5 hours to complete the reaction.

The reaction solution was cooled to room temperature and 150m£ of water was added.

The reaction solution was stirred at the same temperature for 1 hour and

concentrated under reduced pressure. 300ιn£ of toluene was added to the

concentrate. After concentration under reduced pressure, toluene was added again,

and was then concentrated under reduced pressure once more. The concentrate was

dissolved in 600m^ of dichloromethane and 200ut£ of water, and the water layer was

separated. The dichloromethane layer was added to 200m of water and the water

layer was separated again. The combined water layers were washed with 200m£ of

dichloromethane, and the target compound in the water layer was analyzed.

The NMR analysis showed that the water layer contains

3-acetoxy-l-bromo-butylamine hydrogen bromide salt and

3-hydroxy-l-bromo-butylamine hydrogen bromide salt (4:6 ratio).

Η-NMR (D₂0, ppm) δ 2.03 (s, 3H), 2.12 (m, 2H), 3.12 (m, 2H), 3.34 (m, 2H), 5.18 (m, IH)

The water layer was heated at 40 ^°C for 1 hour for deacetylation. Then, the

target compound was distillated under reduced pressure and azotropically distillated

with ethanol to obtain 121.lg of hydrogen bromide salt of the target compound (yield:

94%).

Η-NMR (D₂0, ppm) δ 1.93 (m, 2H), 2.82 (m, IH), 3.03 (dd, IH), 3.46 (q, 2H), 3.95 (m,

IH)

Example 6: Preparation of 3-hydroxy-pyrrolidine

3-Hydroxy-l-methanesulfonyloxy-butylamine hydrogen chloride salt (70g,

0.32 mol) was dissolved in 400ra£ of methanol in a 11 reactor. The reactor was

cooled to 5^°C. After slowly adding sodium hydroxide (38.2g, 0.96 mol) at the same

temperature, the reactor was heated to room temperature and stirred for 2 hours.

After the reaction was completed, the reaction solution was filtered and concentrated

under reduced pressure. Then, the concentrate was dissolved in 500ιιι£ of

dichloromethane. Undissolved material was removed with celite, and the solution

was concentrated under reduced pressure. The target compound was distilled

under reduced pressure of 0.2 torr at 65 ^°C to obtain 25.6g of pure target compound

(yield: 92%).

Η-NMR (CDC1₃, ppm) δ 1.72 (m, IH), 1.95 (m, IH), 2.79 (br, 2H), 2.86 (m, 3H), 3.12

(m, IH), 4.39 (m, IH) Example 7: Preparation of 3-hydroxy-pyrrolidine

3-Hydroxy-l-bromo-butylamine hydrogen bromide salt (lOOg, 0.40 mol) was

dissolved in 500ιn# of methanol in a 11 reactor. The reactor was cooled to 5^°C.

After slowly adding sodium hydroxide (48.2g, 1.21 mol) at the same temperature, the

reactor was heated to room temperature and stirred for 1 hour. After the reaction

was completed, the reaction solution was filtered and concentrated under reduced

pressure. Then, the concentrate was dissolved in 600nι of dichloromethane.

Undissolved material was removed with celite, and the solution was concentrated

under reduced pressure. The target compound was distilled under reduced

pressure of 0.2 torr at 65 ^°C to obtain 30.4g of pure target compound (yield: 87%).

-NMR (CDC1₃, ppm) δ 1.72 (m, IH), 1.95 (m, IH), 2.79 (br, 2H), 2.86 (m, 3H), 3.12

(m, IH), 4.39 (m, IH)

Experimental Example 1: Optical purity analysis of (S)- or

(R)-3-hydroxy-pyrrolidine

To analyze optical purity of 3-hydroxy-pyrrolidine prepared by the present

invention, N-trifluoroacetyl-3-trifluoroacetoxy-pyrrolidine was synthesized as

follows.

50mg of 3-hydroxy-pyrrolidine (0.57 mmol) was dissolved in 5nt£ of

dichloromethane. Then, 362mg of trifluoroacetic anhydride (1.72 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After the reaction

was completed, the reaction solution was evaporated and concentrated. After

adding 10ιιt£ of dichloromethane, the reaction solution was evaporated and

concentrated again to obtain N-rrifluoroacetyl-3-trifluoroacetoxy-pyrrolidine.

Η-NMR (CDC , ppm) δ 2.26-2.41 (m, 2H), 3.70-4.04 (m, 4H), 5.62 (m, IH)

Thus obtained N-trifluoroacetyl-3-trifluoroacetoxy-pyrrolidine was dissolved

in 5ιιt£ of dichloromethane. Then, l.O β of the sample was taken with a syringe and

then the optical purity was measured by GC analyzer.

The preparing method according to the present invention synthesizes

4-protected-imino-butane-l,3-diol intermediate from optically active

3,4-epoxy-l-butanol, as a starting material. Then, amine-induced

3-hydroxy-l-substituted-butylamine intermediate is prepared without by-products

by selectively activating a hydroxy group at C-1. In this way, the target compound

can be obtained conveniently and effectively.

Accordingly, the present invention can maximize productivity of optically

pure 3-hydroxy-pyrrolidine production.

While the present invention has been described in detail with reference to the

preferred embodiments, those skilled in the art will appreciate that various

modifications and substitutions can be made thereto without departing from the spirit and scope of the present invention as set forth in the appended claims.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A method of preparing 3-hydroxy-pyrrolidine, which comprises:

a) a step of reacting optically active 3,4-epoxy-l-butanol represented by the

following Formula 2 with ammonia and an aldehyde compound to obtain

4-protected- imino-butane-l,3-diol represented by the following Formula 3;

b) a step of halogenating or sulfonating the compound represented by

Formula 3 to selectively activate a hydroxy group at C-1 with a leaving group

(halogen or sulfonyloxy group) to prepare an intermediate represented by the

following Formula 4, and simultaneously or consecutively, treating the same with an

acid to obtain 3-hydroxy-l-substituted-butylamine salt represented by the following

Formula 5; and

c) a step of intramolecular cyclizing the compound represented by Formula 5

in the presence of a base to obtain 3-hydroxy-pyrrolidine represented by the

following Formula 1:

4 5 wherein: R¹ is an aryl or a substituted aryl group; R² is a hydrogen atom or an acyl

group; HX is halogen acid or aliphatic acid; and Y is a halogen, a G-C ₂

alkylsulfonyloxy group, arylsulfonyloxy or substituted arylsulfonyloxy group.

2. The method preparing 3-hydroxy-pyrrolidine according to Claim 1, wherein said

imination is proceeded at a temperature ranging from 20 to 80 ^°C .

3. The preparing method according to Claim 1, wherein said selective

halogenation at C-1 is carried out using a halogenating agent.

4. The preparing method according to Claim 3, wherein the halogenation is

proceeded at a temperature ranging from 20 to 60 ^°C .

5. The preparing method according to Claim 1, wherein said selective

sulfonation at C-1 is carried out using alkylsulfonic acid anhydride, alkylsulfonyl chloride, arylsulfonyl chloride or substituted arylsulfonyl chloride.

6. The preparing method according to Claim 5, wherein said sulfonation is

proceeded at a temperature ranging from -20 to 30 ^°C in the presence of a base.

7. The preparing method according to Claim 6, wherein said sulfonation is

carried out using diisopropylethylamine as a base.

8. The preparing method according to Claim 1, wherein b) the deprotection

after the selective activation is proceeded at a temperature ranging from 5 to 40 ^°C in

the presence of acid.

9. The preparing method according to Claim 8, wherein said deprotection is

carried out using aqueous solution of halogen acid as an acid.

10. The preparing method according to Claim 1, wherein said intramolecular

cyclization is proceeded at a temperature ranging from 0 to 80 ^°C in the presence of a

base.