WO1992020652A1

WO1992020652A1 - Process for producing pyrrolidine compound or salt thereof

Info

Publication number: WO1992020652A1
Application number: PCT/JP1992/000648
Authority: WO
Inventors: Satoshi Hirabayashi; Kazuo Ike; Atuhiko Zanka; Takeshi Kawakami; Masaharu Ichihara
Original assignee: Fujisawa Pharmaceutical Co., Ltd.
Priority date: 1991-05-21
Filing date: 1992-05-20
Publication date: 1992-11-26
Also published as: JPH04346971A

Abstract

A novel industrial process for producing a compound (A) which is useful as an intermediate for the production of a clinically excellent synthetic antibacterial, which process comprises the following steps and is excellent in the yield, purity, etc., and simplified in operation α, wherein R1 represents lower alkyl; R?2 and R3¿ represent each hydrogen or an amino-protective group; R2a and R3a represent each an amino-protective group; R?4 and R5¿ represent each a carboxyl-protective group; and X represents a leaving group.

Description

Specification

Method for producing pyrrolidine compound or its salt

INDUSTRIAL APPLICABILITY The present invention is excellent in the yield and purity of a pyrrolidine compound or a salt thereof, which is useful as an intermediate for producing a clinically excellent synthetic antibacterial agent, and has a simplified operation. It concerns a new industrial manufacturing method.

Disclosure of the invention

The pyrrolidine compound of the present invention can be represented by the following formula.

(In the formula, R ¹ represents a lower alkyl group, R ² represents a hydrogen atom or an amino protecting group, and R ³ represents a hydrogen atom or an amino protecting group.)

According to the present invention, the pyrrolidine compound (A) is produced by a series of steps shown in the production method (1).

Manufacturing method (1)

Process 1

(II) (in)

New paper Step 2 Reduction reaction

②

(I) Process 3

Rf-

(I) or a salt thereof in (Α ') or a hydroxy group, a reactive derivative thereof.

Step 4 Elimination reaction of protecting group as desired

④ RI

• (A) or its salt

(Meaning given above wherein R ¹ is, R ^2., And R ³ _b is a hydrogen atom or an Amino protecting groups, respectively, but at the same time not Amino coercive謹基, R ² _a is amino-protecting radical, R ³ _a is an amino protecting group, R ⁴ and R ⁵ Waso respectively carboxy-protecting group, X represents a leaving group.)

The starting material (II) is prepared, for example, by a series of steps shown in the following synthesis method.

New paper Manufactured

Synthesis method

Process a

Introduction of amino protecting groups

Or its salt

(Wherein, R ² _a , R ⁴ and R ⁵ have the same meanings as before)

Suitable salts of compound (A) include both acid addition salts and base addition salts. Examples of the acid addition salts include (ii) salts with mineral acids such as hydrochloric acid and sulfuric acid, (mouth) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, and trifluoroacetic acid; ) Salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, and naphthalenesulfonic acid, and base addition salts such as (ii) sodium and potassium Salts with alkaline metals such as calcium, (mouth) Salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts, (ii) trimethylamine, triethylamine, tributylamine , Pyridine, N, N-dimethylaniline, N-methylbiperidine, N-methylmorpholine, getylamine, cyclohexylamine, brokai , Dibenzilamin, 1-ephenamine, N--N'-dibenzylethylenediamine And a salt with a nitrogen-containing organic base such as amine.

In the foregoing and following description of this specification, preferred examples and explanations of various definitions included within the scope of the present invention are described in detail below.

"Lower j" means a group having 1 to 6, preferably 1 to 4 carbon atoms when the substituent is a straight-chain or branched group, and 3 carbon atoms when the substituent is a straight-chain or branched group. _Β to mean the group of ~ 7

"A carboxy protecting group J refers to an ester residue of a carboxylic acid ester and means any that is relatively easily cleaved to yield the corresponding free carboxyl group. Alkyl group (eg, methyl group, ethyl group, n-propyl group, tertiary butyl group, etc.), for example, lower alkenyl group (eg, vinyl group, aryl group, etc.), eg, aralkyl group (eg, benzyl group, etc.) , A benzhydryl group or the like, or an aryl group (eg, a phenyl group) that is eliminated by treatment under mild conditions such as hydrolysis or catalytic reduction; or a lower alkanoyloxy lower alkyl group ( For example, an acetyloxy group, a bivaloyloxymethyl group, etc.), a lower alkoxycarbonyloxy lower alkyl group (E.g., methoxycarbonyloxymethyl group, 11-ethoxycarbonyloxyshetyl group, etc.), lower alkoxymethyl group (e.g., methoxymethyl group, etc.), lactonyl group (e.g., phthalidyl group, etc.), For example, a boron group (for example, difluoroborone group, etc.) substituted with a halogen atom or a lower alkanoyloxy, halo (lower) alkanoyloxy, [aroyloxy such as benzoyloxy, toluoyloxy, naphthyloxy I, etc.], di-lower alkylamino Examples of such compounds include a lower alkyl (for example, 1-dimethylaminoethyl group) and a (5-methyl-2-oxo-1-yl) methyl group which are easily eliminated.

The “lower alkyl group” includes, for example, a methyl group, an ethyl group, Propyl, tertiary butyl, tertiary pentyl, etc.

"Examples of the leaving group j include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Examples of the "amino protecting group" include lower alkanoyl groups such as formyl, acetyl, propylion, bivaloyl, hexanoyl, etc .; I) halo (lower) alkanol groups, for example, lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, hexyloxycarbonyl, etc. Rubamoyl group, for example, benzyl group, toluoyl, naphthoyl, etc., aryl group, for example, phenylacetyl, phenylpropionyl, etc., al (lower) alkanoyl group, for example, phenyloxycarbonyl, naphthyloxycarbonyl, etc. Aryloxy carbonyl groups such as phenyloxycetyl and phenoxypropionyl, etc. Alkyl (lower) alkoxycarbonyl groups which may have a suitable substituent, such as xyloxycarbonyl, phenethyloxycarbonyl, p-ditrobenzyloxycarbonyl, etc., such as benzylidene, phenyl Substituted or unsubstituted alkyl (lower) alkylidene groups such as droxybenzylidene, such as mono (or di or tri) fuynyl (lower) alkyl groups such as benzyl, phenyl, phenethyl, benzohydryl, and trityl. Al (lower) alkyl groups.

The method for producing the compound (A) of the present invention will be described in detail below.

Manufacturing method 1

Process 1 Compound (ffl) can be produced by reacting compound (π) with compound (IV).

The reaction is usually performed in the presence of a base. Suitable bases include, for example, alkali metals such as lithium and potassium, alkaline earth metals such as calcium, alkali metal hydrides such as sodium hydride and potassium hydride, and the like. For example, alkaline earth metal hydrides such as calcium hydride, etc., alkaline earth metal hydroxides such as calcium hydroxide, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide Substances, for example, alkali metal carbonates such as sodium carbonate, potassium carbonate, etc., for example, sodium bicarbonate, hydrogen carbonate such as sodium bicarbonate, etc., for example, sodium methoxide, sodium methoxide, etc. Alkali metal alkoxides, such as potassium tertiary butoxide, for example, alkali metal alkanoates such as sodium acetate, for example, butyl A combination of a lower alkyllithium such as titanium and an amine such as diisoproviramine and hexamethyldisilazane; for example, a trialkylamine such as triethylamine; for example, pyridines such as pyridine, lutidine, and violin; quinoline , 1,8- diazabicyclo [5.4.0] pendecar 7-ene. For example, when a bulky base such as a combination of butyl lithium and diisoproviramine or hexamethyldisilazane is used, the stereoselectivity of the compound (II) can be improved.

The reaction is usually carried out in a solvent such as water, for example, an alcohol such as methanol or ethanol, η-hexane, methylene chloride, tetrahydrofuran, Ν, Ν-dimethylformamide or dimethylsulfoxide, or a mixture thereof. However, the reaction can be carried out in any other solvent that does not adversely affect the reaction.

The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

Process 2 Compound (i) can be produced by subjecting compound (m) to a reduction reaction.

Reduction methods applicable to this reaction include chemical reduction and catalytic reduction.

The reducing agent used for the reduction may be a chemical reducing agent such as a metal such as tin, zinc and iron or a metal compound such as chromium chloride and chromium acetate, and a metal compound such as formic acid, acetic acid, propionic acid and trifluoro. Combination with organic or inorganic acids such as acetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, lithium aluminum hydride, sodium borohydride, sodium borohydride and trifluoroacetic acid or Platinum catalysts such as platinum plate, platinum sponge, platinum black, colloid platinum, platinum oxide, platinum wire, etc., such as palladium sponge, Palladium black, palladium oxide, palladium monocarbon, colloid palladium, palladium barium monosulfate, palladium barium carbonate Palladium catalysts such as palladium, for example, nickel catalysts such as reduced nickel, nickel oxide, and Raney nickel; for example, cobalt catalysts such as reduced cobalt and Raney cobalt; for example, iron catalysts such as reduced iron and Raney monoiron, such as reduced copper and Raney Usable ones such as copper catalysts such as copper and Ullman copper are exemplified.

The reaction is usually performed in water, for example, alcohols such as methanol, ethanol

The reaction is carried out in a solvent such as methylene chloride, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, but any other solvent which does not adversely affect the reaction is used. The reaction can be carried out with any solvent.

Process 3

Compound (A ') or a salt thereof is prepared by reacting compound (V) with compound (I) or a reactive derivative thereof at a hydroxy group. Can be manufactured. Examples of the reactive derivative of the hydroxy group include halides such as chloride, bromide and sulfide, and sulfonic acid esters such as methanesulfonic acid ester, benzenesulfonic acid ester and toluenesulfonic acid ester. . The reaction is usually performed in water, for example, alcohols such as methanol, ethanol, etc.

The reaction is carried out in a solvent such as, ethyl ethyl acetate, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide or a mixture thereof, provided that the solvent does not adversely affect the reaction. The reaction can be performed in any other solvent.

Process 4

When R ² »of the side chain of the compound (Α ′) obtained in Step 3 and R ³ _a of Ζ or の are amino protecting groups, the ring and the Ζ or the side chain of the compound (Α ′) are The compound (II) can be produced by carrying out an elimination reaction of the amino protecting group.

This reaction is carried out according to a conventional method such as hydrolysis, reduction and the like.

The hydrolysis reaction is preferably performed in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, the bases described above.

Suitable acids include organic acids such as, for example, formic acid, acetic acid, glacial acetic acid, brobionic acid, trichloroacetic acid, trifluoroacetic acid and the like, for example, hydrochloric acid

And inorganic acids such as hydrobromic acid and sulfuric acid.

For example, the elimination using a Lewis acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably performed in the presence of a positive ion scavenger such as anisol or phenol.

The reduction methods applicable to this reaction include chemical reduction and catalytic reduction. The reducing agents used for reduction are as follows. For example, metals such as tin, zinc and iron or metal compounds such as chromium chloride and chromium acetate, and for example, formic acid, acetic acid, brobionic acid, trifluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc. Lithium aluminum hydride, sodium borohydride, sodium borohydride in combination with trifluoracetic acid or pyridine, borane-methyl sulfite Platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc., such as palladium sponge, palladium black, palladium oxide, palladium oxide, Palladium catalysts such as colloid palladium, barium palladium monosulfate, barium palladium monocarbonate, such as reduced nickel, Nickel catalysts such as nickel oxide and Raney nickel, for example, cobalt catalysts such as reduced cobalt and Raney cobalt, for example, iron catalysts such as reduced iron and Raney monoiron, for example, copper catalysts such as reduced copper, Raney copper, Ullman copper, etc. Reactions usually include water, for example, alcohols such as methanol and ethanol, diisopropyl ether, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, and the like. The reaction is carried out in a solvent or a mixture thereof, but the reaction can be carried out in any other solvent that does not adversely influence the reaction. Liquid bases or acids can also be used as solvents.

The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating. In this catalytic reduction reaction, ammonium formate can be used instead of hydrogenation, using a palladium catalyst as a hydrogen generating source.

The compounds obtained in Steps 1 to 4 of Production Method 1 are separated or purified by conventional methods such as extraction, precipitation, fractional crystallization, recrystallization, and chromatography.

Reagents to be used in the synthesis of the starting material (Π) The reaction conditions such as the reaction temperature may be referred to, for example, the production examples described below.

Hereinafter, the present invention will be described with reference to Production Examples and Examples.

Production Example 1

N, N-Dimethylformamide (1.46 g) was added to a suspension of (S) -aspartic acid (133.lg) in methanol (100,000 ml), and thionyl chloride was added while stirring under ice-cooling. (262 g) was dripped slowly and stirred at about 50 for 5 hours. Further, thionyl chloride (60 g) was added, and the mixture was stirred at the same temperature for about 1 hour, and concentrated under reduced pressure to obtain crude crystals of (S) -dimethylaspartate hydrochloride. The suspension was washed with methanol to obtain purified crystals (121 g).

_{NR (CDC1 3, 5):} 3.24 (lH, dd, J = 18,5.4Hz), 3.37 (lH.dd,

J = 18, 4.9Hz), 3.75 (3H, s), 3.85 (3H, s), 4.62 (1H, t, J = 5.2Hz),

8.83 (3H, br)

Production Example 2

CS) A mixture of a suspension of dimethylaspartate hydrochloride (50 g) in methylene chloride (200 ml) and a saturated aqueous solution of sodium bicarbonate (200 ml) was stirred at room temperature with stirring at room temperature. A solution of ditertiary butyl (66.3 g) in methylene chloride was added, and the mixture was further stirred overnight. The reaction solution was condensed and recrystallized from diisopropyl ether to obtain dimethyl (S) -N-tert-butoxycarborylaspartate (57.0 g).

_{NMR (CDC1 3, δ):} 1.45 (9Η, s), 2.82 (1H, dd, J = 17, 4.5Hz), 2.97 (1H, dd, J = 17,4.5Hz), 3.70 (3H, s), 3.? 6 (3H, s), 4.50-4.70 (1H, m), 5.40-5.60 (lH, br-d)

Example 1

To a solution of hexamethyldisilazane (48.4 g) in tetrahydrofuran (260 ml) was added dropwise a hexane solution (159 ml) of 1.38 M n-butyltyllithium while stirring under ice-cooling. Cooled to 40 ° C. A solution of (S) -N-dimethyl tert-butoxycarbonylaspartate (26.1 g) in tetrahydrofuran (130 ml) was added dropwise while maintaining the temperature at 140 to 130 ° C. Subsequently, methyl iodide (17.0 g) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. After addition of methanol (2 6 ml) to the reaction solution, to adjust the 1 N hydrochloric acid dropwise to p H 7 to 8 at 0 ^e C. Concentrate, remove the solvent, extract with methylene chloride, wash the organic layer with saturated saline, dry over magnesium sulfate, concentrate and concentrate (2S) -N-tert-butoxycarbonyl 3-methylaspara A mixture (28.0 g) of dimethyl formate in threo: eluate (1: 1) was obtained.

_{NMR (CDC1 3, δ):} 1.21 (1.5Η, d,

, 125 (1.5Η, d, J = 8.6Ηζ), 1.43 (4.5H, s), 1.46 (4.5H, s), 2.82-3.10 (0.5H, m), 3.ίθ- 3.40 (0.5H , ra), 3.69 (1.5H, s), 3.71 (1.5H, s), 3.74 (1.5H, s), 3.76 (1.5H, s), 4.52 (0.5H, dd, J = 9.6, 3.8Hz) , 4.58-4.72 (0.5H, m), 5.10-5.30 (0.5H, br-d), 5.30-5.50 (0.5H, br-d)

Example 2

Hydrogenation of a solution of (2S) -N-tert-butoxycarbonyl 3-methyl dimethylaspartate (28.0 g) in tetrahydrofuran (200 mi) under a nitrogen stream at room temperature with stirring. Sodium boron (15.3 g) was suspended. 35 After raising the temperature to 55 ° C, a solution of methanol (56.1 ml) in tetrahydrofuran (100 ml) was added dropwise over about 1 hour, and the mixture was stirred at 35-50 for another 4 hours. After that, the reaction solution was concentrated. After adding methylene chloride (200 ml) and then 10% hydrochloric acid to the obtained residue to make the reaction solution acidic, the organic layer was separated and extracted with methylene chloride. The organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, concentrated, and concentrated to give (2S) -2-tert-butoxycarbonylamino-3-methyl-1,4. One-butanediol (19-5 g) was obtained.

NMRiCDCla, δ): 0.83 (d, J = 6.9 Hz), 102 (d, J = 6.9Ηζ), 1.45 (9Η, s), 1.70-2.08 (lH, m), 3.10-3.90 (7H , m), 5.04-5.16 (br-d), 48

12

5.28-5.40 (br-d)

Example 3

A solution of (2S) -2-tert-butoxycarbonylamino-3-methyl-1,4-butanediol (19.5 g) in methylene chloride (6 Omi) was cooled to 120 and stirred. While adding triethylamine (22.5 g), a solution of methanesulfonic acid chloride (22.4 g) in methylene chloride (40 ml) was added dropwise at the same temperature. After stirring for about 1 hour, the reaction suspension was heated to 0 and added to 1N hydrochloric acid (50 ml), which had been cooled to 0 beforehand, with stirring. The organic layer was separated, the aqueous layer extracted with methylene chloride was combined, the organic layer was washed with water and a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulfate, and the solvent was distilled off. Benzylamine (47.7 g) was added to the dimethanesulfonic acid ester with stirring, and the reaction was carried out at 30 to 35 ^ C for 3 days. Water and methylene chloride are added to the reaction suspension, the organic layer is separated, concentrated, and a water-acetonitrile mixed solution is added to the residue to form a non-crystal (cis: trans = 3: l, 50% de) (3 65 g). Recrystallized from n-heptane, colorless crystals of (3S, 4S) -111-benzyl-3-tert-butoxycarbonylamino-4-methylbirolidine (1.35 g) were obtained as a diastereomer mixture (74 % de).

_{NMR (CDC1 3, δ):} 0.93 (3H, d, J = 6.6Hz), 1-44 (9H, s), 2.06-2.49 (

3H, m), 2.57-2.92 (2H, m), 3.57 (2H, s), 4.13 (lH, m), 4.75 (1H, br), 7.25 (5H, s)

Example 4

(3 S, 4 S) 1-1-benzyl-3-tert-butoxycarbonylamino-4-methylbi-lysine (74% de) (1.0 g) in methanol (1 Otnl) was added to a solution of ammonium formate (13. 76 g) and water (1.0 ml) were added, and the mixture was stirred at room temperature. Further, a suspension of 10% palladium-carbon (0.1 g) in 1: 1 aqueous methanol (5.0 ml) was added at the same temperature. Addition The reaction was carried out at room temperature for 2 hours and at 30 to 4 CTC for another 3 hours. The reaction mixture was concentrated by filtration, the residue was dissolved in methylene chloride (1.0 ml), and diisobutyryl ether (20 ml) was added under stirring at room temperature to give colorless crystals of (3S, 4S) -3-3-tertiary. Butoxycarbonylamino-4-methylpyrrolidinate formate (74% de) was obtained quantitatively.

NR (CDCla, δ): 1.07 (3Η, d, J = 6.8Hz), 1.45 (9H, s), 2.20-2.70 (lH, m), 2.83 (IH, t, J = ll.2Hz), 3.10- 3.50 (3H, m), 4.20-4.50 (lH, m), 6.20-6.38 (lH, br), 8.52 (lH, m) ^h

Example 5

3 To a mixed solution of 3-tert-butoxycarbonylamino-4-methylpyrrolidine formate (74% de) (0.79 g) in ethyl acetate (50 ml) and methanol (5. Oral) While stirring, 3.9 N hydrogen chloride / ethyl acetate solution (1 2. Oml) was added, and the mixture was reacted at the same temperature for 2 hours, and further reacted at 35 T) for 2 hours. The precipitated crude crystals are filtered and dried, and then recrystallized from methanol and isopropyl alcohol to obtain crude crystals (0.30 g). The crude crystal (0.20 g) was recrystallized to obtain a purified crystal of (3S, 4S) -1-amino-4-methylpyrrolidine (0.10 g). Melting point: 195-203 ° C

(a 3 ^{21 at} D = -10.0 (C = 0.2, Me0H)

NMR (DMS0-d ₆ , δ): 1.08 (3Η, d, J = 7.OHz), 2.36-2.66 (IH, m), 3.12 (IH, t, J = 10 Hz), 3.20-3.44 (2H, m ), 3.55 (IH, dd, J = 14, 8. OHz), 3.76-3.90 (lH, m), 8.91 (3H, br)

Example 6

A solution of hexamethyldisilazane (18, 54 g) in tetrahydrofuran (55 ml) was cooled to 130 ° C., and stirred while stirring a 1.62 M n-butyllithium hexane solution (52. 30 ml) was added dropwise. A solution of (S) -N-dimethyl tert-butoxycarborylaspartate (10.0 g) in tetrahydrofuran (15 m1) was prepared at 19-13. After dropwise addition, a solution of methyl iodide (6.52 g) in tetrahydrofuran (20 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour. After adding water acetic acid (6.90 g) to the reaction solution, water (20 ml) was added dropwise at 5 to 15 and the pH was adjusted to 7 to 8 with glacial acetic acid. After liquid separation, the organic layer was reduced to remove the solvent, dissolved in ethyl acetate (50 ml), washed with 5% saline (10 ml) and saturated saline, and then collapsed (2). S) —N—Tertiary butoxycarbonyl 3-methyl-3-aspartate (10:64 g) in the form of a triethyl: erythro (1: 6) dimethyl trisulfate (10:64 g) was obtained.

_{NR (CDC1 3, δ):} 1.22 (0.43Η, d, J = 8.7Hz), 1.25 (2.57H, d,

J = 8.8Hz), 1.44 (0.14H, s), 1.46 (0.86H, s), 2.80-3.10 (

0.14H, ro), 3.10-3.40 (Q.86H, m), 3.69 (0.43H, s), 3.71 (

2.57H, s), 3.74 (0.43H, s), 3.76 (2.57H, s), 4.52 (0.14H, dd, J = 9.6, 3.8Hz), 4.58-4.72 (0.86H, in), 5.10-5.30 (0.14H, br-d), 5.30-5.50 (0.86H, br-d)

Example 7

The compound of Example 3 was recrystallized from isopropyl alcohol monohydrate (1: 1) to obtain the same compound with improved optical purity (92% de) in a yield of 81 • 2%.

Example 8

The compound of Example 4 was recrystallized three times from acetonitrile to give the compound having improved optical purity (99.3% de) in a yield of 46.8%.

Claims

The scope of the claims

(a) Expression:

(Wherein, R ² _a is Amino protecting group, R ⁴ and R ⁵ each means a carboxy protecting group) in the compound represented by the formula:

R ¹ -X

(Wherein, R ¹ represents a lower alkyl group, and X represents a leaving group).

Expression:

^{^{_{(Wherein, R 1, R 2 a,}}} R 4 and R s are each as defined) to produce the indicated compounds,

(b) Then, the resulting compound is subjected to a reduction reaction to obtain a compound represented by the formula:

Rf-HN R,

H 0 0 H

(Wherein, R ¹ and R ² each have the same meaning as before)

New paper Generate things,

(C) Then the resulting compound or its reactive derivative at the hydroxy group has the formula:

H z N-R ³ a

(Wherein R represents an amino protecting group) or a salt thereof, and reacted with a compound represented by the formula:

(Wherein, R ^1, R ² _a and R ³ _a are each the same meaning as before) compound Ru indicated by or to produce a salt thereof,

(d) then, if desired, subjecting the ring and Z or a side chain amino-protecting group to elimination reaction.

(In the formula, R ¹ has the same meaning as before, R ² t, and R ³ _b denotes each hydrogen atom or an Amino protecting group, but at the same time Amino protective 'not a group) pyro lysine compound represented by or How to make that salt.

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