JPH10291992A - Method for producing (9R) -optically active substance and intermediate thereof - Google Patents

Abstract

(57) Abstract: Perhydrothiazolo [3,2-a] in which the alkyl group at the 9-position is R-coordinate, which is effective as a prophylactic / therapeutic agent for heart failure
Provided are an efficient method for producing an azepine derivative and a novel intermediate. SOLUTION: The general formula: (Wherein R ¹ and R ² are the same or different from each other, and may be a linear or molecular lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a linear or molecular lower alkyl, A silyl group, a phenacyl group which may have a substituent, a vinyl group or an allyl group). (Wherein R ² represents the above, R ³ represents a lower alkyl group,
⁵ represents a hydrogen atom, a linear or molecular lower alkyl group which may have a substituent, a linear or molecular lower alkylsilyl group or an allyl group. ) Via the manufacturing method.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing an optically active substituted thiazolo [3,2-a] azepine derivative which is industrially useful. More specifically, the present invention relates to a novel method for producing an optically active thiazolo [3,2-a] perhydroazepine derivative having an R-coordinate substituent at the 9-position.

[0002]

2. Description of the Related Art Recently, atrial natriuretic peptide degrading enzyme (Neutral) has been newly used as a therapeutic agent for heart failure.
Endopeptidase: NEP-24, 11 Hereinafter, it is abbreviated as NEP. ) And angiotensin I converting enzyme (hereinafter abbreviated as ACE) inhibitors. Atrial natriuretic peptide (Art
rial Nutritional Peptide:
Hereinafter, it is abbreviated as ANP. ) Is a hormone present in the body that has potent water / natriuretic and vasodilatory effects, suppresses norepinephrine release by suppressing sympathetic nerves, suppresses renin secretion from the kidney, and suppresses aldosterone secretion from the adrenal gland. Further, it also shows a perfusion lowering effect by enhancing water permeability in veins. These effects of ANP are considered to be favorable for patients with congestive heart failure accompanied by an increase in preload, and are also favorable for the treatment of hypertension. But AN
Since P is a peptide, it cannot be administered orally, has low metabolic stability, and its clinical use is limited to the acute phase. It has also been reported that the effects of long-term administration are attenuated, and its use requires caution. In view of the above characteristics of ANP, the above-mentioned ANP-degrading enzyme inhibitor (hereinafter abbreviated as NEP inhibitor) has attracted attention as an orally administered ANP-related preparation. NE
It has been reported that a P inhibitor increases the blood ANP concentration when administered to a patient with heart failure and exhibits a natriuretic effect. However, the effects of existing NEP inhibitors on cardiac hemodynamics are minor, and their preload and afterload reducing effects are not clear. On the other hand, an ACE inhibitor, which is one of the vasodilators, suppresses the generation of angiotensin II (hereinafter, abbreviated as AT-II), which is an aggravating factor for heart failure, and thereby, the severity of NYHA in chronic heart failure. It shows significant improvement in exercise and exercise capacity, and its usefulness, including life-prolonging effects, has been proven. However, existing ACE
The effectiveness of inhibitors is not always high, and the variability of the effects varies from individual patient to individual. In addition, since it has side effects such as causing hypotension, its administration is restricted in patients with reduced renal function. As described above, N
Although EP inhibitors and ACE inhibitors have attracted attention as therapeutic agents for heart failure, both existing NEP inhibitors and ACE inhibitors have limited utility. Therefore, research on drugs having both advantages of both inhibitors has been actively conducted.

[0003] WO96 / 02549A1 has the merits of both inhibitors, is orally administrable, has good metabolic stability, and is expected to be extremely effective against heart failure and hypertension. The compound represented by the general formula (A)

[0004]

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(Wherein, R ²¹ represents a hydrogen atom or a thiol protecting group. R ²² represents a hydrogen atom, a lower alkyl group,
It means a heteroaryl group, a lower alkoxy group and a lower alkylthio group which may have a substituent. R ²³ ,
R ²⁴ and R ²⁵ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent Means R ²³ , R
²⁴ or R ²⁵ may be taken together with the carbon atom to which they are attached to form a ring. However, R ²³ , R ²⁴ ,
This excludes the case where R ²⁵ and R ²⁵ are both hydrogen atoms. R ²⁶ and R ²⁷ represent the same or different hydrogen atoms and lower alkyl groups. R ²⁸ represents a hydrogen atom or a carboxyl-protecting group. n and m independently mean 0 or 1, 2. ) Are disclosed. Above all, general formula (A ')

[0006]

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Wherein R ³⁰ represents a hydrogen or thiol protecting group, R ³¹ represents a lower alkyl group, and R ³² represents a hydrogen or carboxyl protecting group. Are disclosed to exhibit more excellent effects. The basic method for synthesizing the compound having the general formula (A ′) is based on the cyclic amine compound (B)

[0008]

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[0009] (wherein, R3 ¹ and R ³² denotes the.) And the general formula which corresponds to the portion of the side chain (C)

[0010]

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Wherein R ³³ represents a protecting group for a thiol group, wherein the thiol group is protected (2S, 3
S) Condensation reaction with 2-mercapto-3-methylpentanoic acid. In WO 96/02549 A1, the substituent R ³¹
The R- and S-coordinate compounds are separated into their respective optically active forms after condensation. Also, the cyclic amine compound (B)
Discloses slightly for the 9-position of the S configuration and R configuration of the optically active substance of the substituents R ³¹ in. However, in any case, the method disclosed in WO96 / 02549A1 has a higher generation ratio of the S-form than that of the R-form.
It is not an advantageous method when a body is needed. Further, a method for producing (2S, 3S) -2-mercapto-3-methylpentanoic acid (C) in which a thiol group corresponding to a side chain portion of a preferred compound is protected is disclosed in WO94 / 28901A1, Expensive D-alloy as starting material
Isoleucine is used, and the production method of this compound is not industrially advantageous.

[0012]

Accordingly, an optically active substance represented by the general formula (B) wherein the substituent R ^{31 at the} 9-position is R-coordinate can be synthesized at a high yield, with good operability and at a low cost. Establishment of industrial production method and protection of thiol group (2
An object of the present invention is to establish an inexpensive method for producing (S, 3S) -2-mercapto-3-methylpentanoic acid (C).

Means for Solving the Problems The present inventors have set forth the above situation.
In view of the above, a more important intermediate represented by the general formula (B)
Substituent R at the 9-position of the amino acid derivative³¹R-coordinate optical activity
Industrial production method of thiol represented by general formula (C)
Protected (2S, 3S) -2-mercapto-3
Method for producing methylpentanoic acid from inexpensive raw materials and
Intensive studies have been made on these condensation methods. And
Amino adipic acid or 2-piperidine carboxylic acid
(2S) -N-CO obtained_Two-R⁴⁰-6-oxo-2
-Piperidinecarboxylic acid (R⁴⁰May have a substituent
Good linear or branched lower alkyl groups, having substituents
Cycloalkyl groups, straight-chain or branched lower alkyl groups
Ryl group, phenacyl group which may have a substituent, vinyl
Or an allyl group. A) ester derivatives
A method for producing the amino acid derivative via alkylation is described below.
Substituent R at the 9-position of the amino acid derivative represented by the general formula (B)
³¹Is an efficient method for producing an R-coordinated optically active substance.
I found it. In this case, the protecting group for the NH group is an acyl group.
WO96 / 02549A1 specifically discloses
Not -CO _Two-R⁴⁰(R⁴⁰May have a substituent
Linear or branched lower alkyl group, which may have a substituent
Cycloalkyl group, linear or branched lower alkylsilyl
Group, phenacyl group which may have a substituent, vinyl group
Or an allyl group. ). In addition, thiol group
Is protected (2S, 3S) -2-mercapto-3
-Regarding the method for producing methylpentanoic acid, inexpensive L-
Low cost production using isoleucine as a starting material
I found a way to do it. That is, the present invention provides a compound represented by the general formula (VI)
I)

[0013]

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(Wherein R ¹ and R ² are the same or different and each may be a linear or branched lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, Or a branched lower alkylsilyl group, a phenacyl group, a vinyl group or an allyl group which may have a substituent, or a (2S) -6-oxo-2-piperidinecarboxylic acid derivative. , The general formula (I)

[0015]

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(Wherein R ¹ and R ² are as defined above,
³ means a linear or branched lower alkyl group. (2) -5-alkyl-6-oxo-2-piperidinecarboxylic acid derivative represented by the formula (II)

[0017]

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(Wherein R ¹ , R ² and R ³ have the same meanings as defined above), and a (2S) -5-alkyl-6-hydroxy-2-piperidinecarboxylic acid derivative represented by the formula Reacting with a cysteine optionally having a protecting group, or a compound represented by the general formula (II ″):

Embedded image (Wherein R ¹ , R ² and R ³ represent the same as above, and R ⁴ ′ represents a lower alkyl group.) (2S) -5
An alkyl-6-alkoxy-2-piperidinecarboxylic acid derivative is reacted with a cysteine in which a carboxy group may have a protecting group to obtain a compound of the general formula (III)

[0019]

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(Wherein ^, R ^{1 ,} R ² and R ³ represent the same as above, R ⁵ represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a linear or branched lower alkyl group). (2
RS, 4R) -2 - [( 1RS, 4S) -4- substituted-amino-4-carboxy-1-alkyl-butyl] a diester derivative of thiazolidine-4-carboxylic acid, and selectively release the R ¹ de generally Formula (IV)

[0021]

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(Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (2RS, 4R) -2-[(1R
(S, 4S) -carboxybutyl] thiazolidine derivative and ring closure

[0023]

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(Wherein R ² , R ³ and R ⁵ are as defined above) (3R, 6S, 9R, 9aR) -9
-Alkyl-5-oxooctahydrothiazolo [3,2
-A] a method for producing a carbamate derivative of azepine, wherein R ⁵ of the above general formula (V) is eliminated to obtain a compound of the general formula (VI)

[0025]

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(Wherein R ² and R ³ have the same meanings as defined above) (3R, 6S, 9R, 9aR) -9-
Alkyl-5-oxooctahydrothiazolo [3,2-
a] azepin-3 leads to the carbamate derivative of a carboxylic acid, then either leaving the R ^2, or previously by the R ² elimination formula (XI)

[0027]

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(Wherein R ³ and R ⁵ have the same meanings as defined above) (3R, 6S, 9R, 9aR) -6-
Leads to amino-9-alkyl-5-oxo-octahydro thiazolo [3,2-a] azepine derivatives, then as that leaving the R ⁵ or replace the elimination order of R ² and R ^5, or R ² and R ⁵ are eliminated at once to obtain a compound of the general formula (VIII)

[0029]

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(Wherein R ³ is as defined above) (3R, 6S, 9R, 9aR) -6-amino-9-
Alkyl-5-oxooctahydrothiazolo [3,2-
a] An azepine-3-carboxylic acid derivative is obtained, which has the general formula (IX)

[0031]

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Wherein R ⁶ is as defined above, and (2S, 3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid. General formula (X)

[0033]

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(Wherein R ³ and R ⁵ have the same meanings as defined above) (3R, 6S, 9R, 9aR) -6-
[[(2S, 3S) -2-acylthio-3-methyl-1
-Oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-
The present invention relates to a method for producing a carboxylic acid derivative and an intermediate thereof. Further, the compound represented by the general formula (XI) is reacted with the (2S, 3S) -2-acylthio-3-methylpentanoic acid represented by the general formula (IX) or a reactive derivative thereof represented by the general formula (XII).

[0035]

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(Wherein, R ³ , R ⁵ and R ⁶ have the same meanings as above). (3R, 6S, 9R, 9aR) -6
-[[(2S, 3S) -2-acylthio-3-methyl-
1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
A method for producing an ester of a carboxylic acid derivative, wherein R ⁵ is selectively eliminated to lead to a compound represented by the general formula (X), and R ⁵ and R ⁶ of the general formula (XII) are simultaneously eliminated to form a general formula The present invention relates to a method for producing a compound represented by the general formula (X) by converting the compound represented by the formula (XIII) and then acylating the —SH group again. Furthermore, the present invention uses inexpensive L-isoleucine as a starting material, and is represented by the general formula (IX) (2S,
The present invention relates to a method for producing 3S) -2-acylthio-3-methylpentanoic acid.

In the present invention, a novel intermediate (2)
Diester derivatives of (RS, 4R) -2-[(1RS, 4S) -4-substituted amino-4-carboxy-1-alkylbutyl] thiazolidine-4-carboxylic acid, (2RS, 4
R) -2-[(1RS, 4S) -carboxybutyl] thiazolidine derivative and (3R, 6S, 9R, 9aR)
Carbamate derivatives of -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid can form salts in the presence of acids or bases, and these salts are also included in the present invention. It goes without saying that it is included.
As those salts, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, trifluoroacetate or methanesulfonate, sulfonates such as p-toluenesulfonate, Metal salts such as sodium salt and potassium salt; alkylamine salts such as triethylamine salt and dicyclohexylamine salt; Also,
(3R, 6S, 9R, 9aR) -6-amino-9-alkyl-5-oxooctahydrothiazolo [3,2-a]
A salt of an azepine-3-carboxylic acid derivative is used (3R,
6S, 9R, 9aR) -6-[[(2S, 3S) -2-
A method for producing an acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative is also included in the present invention. Needless to say. Those mentioned above can be mentioned as their salts.

In the present invention, the term "lower alkyl group" as defined in R ³ and R ⁴ means a linear or branched alkyl group having 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl,
Examples thereof include an n-butyl group, a t-butyl group, an isobutyl group, an n-pentyl group, and an n-hexyl group.

The optionally substituted straight-chain or branched lower alkyl group defined in R ¹ , R ² , R ⁵ and R ⁴⁰ includes a methyl group, an ethyl group, an n-propyl group, Carbon number 1- such as isopropyl group, n-butyl group, t-butyl group, isobutyl group, n-pentyl group and n-hexyl group;
6, an unsubstituted lower alkyl group, a chloroethyl group, a bromoethyl group, an ethyl iodide group, a 2,2-dichloroethyl group,
2-haloethyl group such as 2,2-dibromoethyl group, 2,2,2-trichloroethyl group, 2,2,2-tribromoethyl group, benzyl group, 4-nitrobenzyl group, 4-
Bromobenzyl group, 2,4,6-trimethylbenzyl group, 4-methoxybenzyl group, 3,5-dimethoxybenzyl group, 1-methyl-1-phenylethyl group, 1-methyl-1- (3,5-dimethoxy Phenyl) ethyl group, 1
Arylalkyl groups such as -methyl-1- (4-biphenylyl) ethyl group, benzhydryl group, etc., cyclopropylmethyl group, 1-methyl-1-cyclopropylmethyl group, 9-florenylmethyl group, diisopropylmethyl group, 1,1 -Dimethylpropynyl group, 1,1-dimethyl-3- (N, N-dimethylcarboxamido) propyl group, 1,1-diphenyl-3- (N, N-diethylamino) propyl group, 1-methyl-1- (1 -Adamantyl) ethyl group, 1,1-dimethyl-2,2,2-trichloroethyl group, 1,1-dimethyl-2-cyanoethyl group, 5-benzisoxazolylmethyl group, 1-methyl-
It means a 1- (4-pyridyl) ethyl group or the like.

The cycloalkyl group which may have a substituent in the definition of R ¹ and R ² is a cyclobutyl group,
-Methylcyclobutyl group, cyclopentyl group, cyclohexyl group, 1-methylcyclohexyl group and the like. R ^1, R ² and R ⁵ linear or branched and lower alkylsilyl group a trimethylsilyl group is in the definition, triethylsilyl group, t- butyl dimethyl silyl group, refers to an isopropyl dimethyl silyl group. R ¹ , R ² , R ⁵
And substituted phenacyl groups and which may phenacyl groups found in the definition of R ^40, p- bromophenacyl group, alpha-methylphenacyl group, means such as p- methoxyphenacyl group.

The acyl group in the definition of R ⁶ includes a group derived from a saturated or unsaturated fatty acid such as a formyl group, an acetyl group, a propionyl group, an acryloyl group, a propioyl group, a cyclohexylcarbonyl group, a benzoyl group, a toluoyl group. Group, cinnamoyl group, group derived from carbocyclic carboxylic acid such as naphthoyl group, furoyl group, tenoyl group, group derived from heterocyclic carboxylic acid such as nicotinoyl group, morpholinylacetyl group, thiomorpholinyl It means an acetyl group or the like.

[0042]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, an example of the production method according to the present invention will be described in more detail.

[0043]

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(Step A) In this step, an ester derivative of (2S) -6-oxo-2-piperidinecarboxylic acid (1)
In an aprotic solvent with an alkylating agent in the presence of a base. As the alkylating agent, alkyl halides such as bromoalkyl and alkyl iodide are used. As a base, n-butyllithium (n-Bu)
Li), lithium diisopropylamide (LDA),
Lithium hexamethyldisilazane (LiHMDS),
Sodium hexamethyldisilazane (NaHMDS); lithium hexamethyldisilazane (L
iHMDS) or sodium hexamethyldisilazane (NaHMDS) is preferred. Examples of aprotic solvents include tetrahydrofuran (THF), dioxane,
3-dimethyl-2-imidazolidinone (DMI), dimethylacetamide (DMA), dimethylformamide (D
MF), dimethyl sulfoxide (DMSO) and the like. The reaction is carried out at -40 ° C to -100 ° C. (Step B) In this step, the (2S) -5 obtained in Step A is obtained.
This is a step of reducing the carbonyl group of the ester derivative (2) of alkyl-6-oxo-2-piperidinecarboxylic acid with a hydride reducing agent. Examples of the hydride reducing agent include sodium borohydride, potassium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, tri-t-butoxyaluminum hydride and the like. The reaction depends on the type of reducing agent, but methanol,
It can be widely used from alcoholic solvents such as ethanol to aprotic solvents such as tetrahydrofuran, dioxane and ethyl acetate. The compound in which R ⁴ is a lower alkyl group can be obtained by treating a hydroxy compound obtained by reducing a carbonyl group with an acid in a lower alcohol solvent. (Step C) This step is a step of reacting the compound (3) obtained in the step B with cysteine or an ester derivative thereof to obtain a thiazolidine derivative (4). When a cysteine ester salt is used, the reaction is preferably performed in the presence of sodium acetate or the like in a mixed solvent such as water-methanol-acetic acid, but is not particularly limited. The reaction can be carried out at a reaction temperature of 0 to 100 ° C., preferably around room temperature. (Step D) In this step, the protecting group R ¹ of the carboxylic acid at the terminal on the chain of the thiazolidine derivative (4) is selectively eliminated to obtain the monocarboxylic acid derivative (5). The elimination conditions include trifluoroacetic acid-anisole, methanesulfonic acid-anisole, hydrogen chloride-anisole, trimethylsilyl iodide, catalytic reduction and the like, depending on the types of R ¹ , R ² and R ⁵ and their combinations. it can. For example, in R ¹ is benzyl or t- butyl group, with R ² is benzhydryl group or a methyl group, trifluoroacetic acid when R ⁵ is a methyl group - anisole, in which R ¹ is p- nitrobenzyl group, R ² Is a t-butyl group, and when R ⁵ is a methyl group, catalytic reduction is preferred. When only R ¹ is an allyl group, it may be treated with formic acid-lower alkylamine (eg, triethylamine) in the presence of a Pd catalyst [eg, Pd (PPh ₃ ) ₄ ] to remove only R ^1. It is possible. (Step E) In this step, the monocarboxylic acid derivative (5) is closed to obtain a perhydrothiazolo [3,2-a] azepine derivative (6). For ring closure, it is preferable to use a condensing agent. As the condensing agent, a carboxylic acid group of compound (4) such as 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, ethyl chlorocarbonate, 1-hydroxybenzotriazole, or the like is used. Any reagent that can be converted to a reactive derivative can be used. The most preferred reagent is 1-ethoxycarbonyl-2-ethoxy-1,2-
Mention may be made of dihydroquinoline or ethyl chlorocarbonate. As the reaction solvent, an aprotic solvent such as ethyl acetate, tetrahydrofuran, dioxane and the like can be used.

[0045]

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(Step F) This step is a step of removing the carboxylic acid protecting group on the thiazoline ring of the perhydrothiazolo [3,2-a] azepine derivative (6). The elimination reagent may vary depending on the type of R ² and R ⁵ , but alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide can be applied to any protecting groups. When R ⁵ is an arylalkyl group such as a benzyl group or a benzhydryl group or a t-butyl group and R ² is a methyl group, trifluoroacetic acid-anisole, methanesulfonic acid-anisole, hydrogen chloride-anisole and the like can be applied. In the case of an alkyl group, it can be eliminated by catalytic reduction or the like. In addition, formic acid, boron tribromide and the like can be used. Examples of the solvent include methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and the like, a mixed solvent of these solvents and water, dichloromethane, chloroform, and an aqueous solvent. Reaction temperature is -2
It is in the range of 0 ° C to 100 ° C. When only R ⁵ is an allyl group, it is possible to remove only R ⁵ by treating with formic acid-lower alkylamine (eg, triethylamine) in the presence of a Pd catalyst [eg, Pd (PPh ₃ ) ₄ ]. It is. (Step G) In this step, perhydrothiazolo [3,2-a]
A protecting group for the amino group of the azepine carboxylic acid derivative (7),
—CO ₂ R ² , As the elimination reagent, trifluoroacetic acid-anisole, methanesulfonic acid-anisole, hydrogen chloride-anisole, trimethylsilane iodide and the like and catalytic reduction can be used. When R ² is an allyl group, it can be treated with formic acid-lower alkylamine (eg, triethylamine) in the presence of a Pd catalyst [eg, Pd (PPh ₃ ) ₄ ] to obtain an amino compound. Examples of the reaction solvent include tetrahydrofuran, ethyl acetate, acetonitrile and the like. In this step, the target amino compound can be obtained as a salt such as trifluoroacetate, methanesulfonate, hydrochloride, hydroiodide, or as a free base. (Step H) In this step, perhydrothiazolo [3, 2-a]
From the azepine derivative (6), perhydrothiazolo [3,
2-a] without going through the azepine carboxylic acid derivative (7) is a step of obtaining an amino acid (8) by elimination of the -CO ₂ R ² and R ⁵ at the same time. Depending on the type and combination of R ² and R ^5, the elimination reagent may be trifluoroacetic acid-anisole, methanesulfonic acid-anisole, hydrogen chloride-anisole, trimethylsilane iodide,
Formic acid-lower alkylamine (eg, triethylamine) and the like and catalytic reduction in the presence of a Pd catalyst [eg, Pd (PPh ₃ ) ₄ ] can be used. For example, when R ² and R ⁵ are t-butyl or benzyl, trifluoroacetic acid-anisole is used, and when both are allyl, a Pd catalyst [for example, Pd (PP
h _{3) 4]} the presence of formic acid - lower alkylamine (e.g., triethylamine), but if the are both benzyl or benzhydryl group can be utilized trimethylsilane iodide or catalytic reduction. Examples of the reaction solvent include tetrahydrofuran, ethyl acetate, acetonitrile and the like. (Step I) This step comprises the steps of (3R, 6S, 9R, 9aR)-
6-amino-9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid (7)
Is reacted with (2S, 3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid to form an amide bond, and (3R, 6S, 9R, 9aR) -6-
[[(2S, 3S) -2-acylthio-3-methyl-1
-Oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-
This is a step of obtaining a carboxylic acid derivative (9). (2S, 3
S) -2-Acylthio-3-methylthiopentanoic acid is N, N'-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 2-ethoxy-1-ethoxycarbonyl-1 , 2-dihydroquinoline, Vilsmeier reagent (N, N-dimethylchloroformiminium chloride) and the like.
Examples of the reactive derivative include acid anhydrides such as symmetric acid anhydrides and mixed acid anhydrides, acid halides, esters with N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, and the like, aralkylthiol esters, Heterocyclic thiol esters, nitrophenyl esters and the like can be mentioned. Examples of the mixed acid anhydride synthesis reagent include isopropyl chlorocarbonate, ethyl chlorocarbonate, methanesulfonic acid chloride and diethyl chlorophosphite. Examples of the acid chloride synthesis reagent include thionyl chloride, phosphorus pentachloride, Vilsmeier reagent (N, N-dimethylchloroformiminium chloride) and the like. Among these reagents, it is preferable to use the Vilsmeier reagent. This reaction is performed in dichloromethane, chloroform, tetrahydrofuran,
The reaction can be carried out in an inert solvent such as acetone, acetonitrile, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide at a reaction temperature of -50 ° C to + 50 ° C. Further, bis (trimethylacetamide) (BSA) may be added for dissolving the compound (9) in the reaction solvent and for protecting the carboxylic acid. (Step J) In this step, the protecting group -CO ₂ R ² for the amino group of the thiazolo [3,2-a] perhydroazepine derivative (6) is eliminated to give (3R, 6S, 9R, 9aR) -6- This is a step of obtaining an amino-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylate derivative (10). The reagent used depends on the type of R ² and R ⁵ , but hydrogen chloride, hydrogen bromide, hydrogen iodide, dimethylsulfide-methanesulfonic acid, trifluoroacetic acid, trimethylsilane iodide, triethylsilane, zinc powder, H ₂ / P
dC, nickel carbonyl, palladium-phosphine complex, and the like. When R ² and R ⁵ are linear lower alkyl groups, dimethyl sulfide-methanesulfonic acid is preferred.

[0047]

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(Step K) In this step, (3R, 6S, 9R,
9aR) -6-amino-9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid ester derivative (10) has (2S, 3)
(3R, 6S, 9) by reacting (S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid.
R, 9aR) -6-[[(2S, 3S) -2-acylthio-3-methyl-1-oxopentyl] amino] -9-
Alkyl-5-oxooctahydrothiazolo [3,2-
a] Azepine-3-carboxylic acid ester derivative (1
This is the step of obtaining 1). (2S, 3S) -2-acylthio-3-methylpentanoic acid is N, N′-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, 2-ethoxy-1-ethoxy. Carbonyl-1,2
The reaction may be carried out in the presence of a condensing agent such as dihydroquinoline or Vilsmeier reagent (N, N-dimethylchloroformiminium chloride). Examples of the reactive derivative include acid anhydrides such as symmetric acid anhydrides and mixed acid anhydrides, acid halides, esters with N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxybenzotriazole, and the like, aralkylthiol esters, Heterocyclic thiol esters, nitrophenyl esters and the like can be mentioned. This reaction can be carried out in an inert solvent such as dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, dimethyl sulfoxide, N, N-dimethylformamide and the like at a reaction temperature of -50 ° C to + 50 ° C. (Step L) This step is (3R, 6S, 9R, 9aR) -6
-[[(2S, 3S) -2-acylthio-3-methyl-
1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
-The acyl group of the carboxylic acid ester derivative (11) and the protecting group of the carboxylic acid are hydrolyzed and eliminated to give (3R, 6
[S, 9R, 9aR) -6-[[(2S, 3S) -3-methyl-2-mercapto-1-oxopentyl] amino]
-9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative (1
This is the step of obtaining 2). The reaction is performed using an aqueous solution or a lower alcohol solution of potassium hydroxide, sodium hydroxide, or lithium hydroxide, or a hydrated lower alcohol solution. (Step M) This step is (3R, 6S, 9R, 9aR) -6
-[[(2S, 3S) -3-methyl-2-mercapto-
1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
Acylating the -SH group of the carboxylic acid derivative (12),
(3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) Step of obtaining 2-acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative (9) It is. The reaction is performed by a commonly used method. Compound (12) and an organic acid corresponding to a desired acyl group are combined with anhydrous cobalt chloride, N, N'-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl)
The reaction may be performed in the presence of a condensing agent such as carbodiimide or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or may be reacted with a reactive derivative of the organic acid. Examples of the reactive derivative of an acid include acid anhydrides such as symmetrical acid anhydrides and mixed acid anhydrides, acid halides, N-hydroxysuccinimide, N-hydroxyphthalimide-1.
Examples thereof include esters with hydroxybenzotriazole and the like, aralkyl thiol esters, heterocyclic thiol esters, nitrophenyl esters and the like. Examples of the mixed acid anhydride synthesis reagent include isopropyl chlorocarbonate, ethyl chlorocarbonate, methanesulfonic acid chloride and diethyl chlorophosphite. Examples of the acid chloride synthesis reagent include thionyl chloride, phosphorus pentachloride, Vilsmeier reagent (N, N-dimethylchloroformiminium chloride) and the like. Among these reagents, it is preferable to use the Vilsmeier reagent. This reaction is performed in dichloromethane, chloroform, tetrahydrofuran, acetone, ethyl acetate, dimethyl sulfoxide,
The reaction can be carried out in an inert solvent such as N, N-dimethylformamide at a reaction temperature of -50 ° C to + 50 ° C. (Step N) This step is (3R, 6S, 9R, 9aR) -6
-[[(2S, 3S) -2-acylthio-3-methyl-
1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
Elimination of only R ⁵ of the ester moiety of the ester derivative of carboxylic acid (11) to give (3R, 6S, 9R, 9aR)
-6-[[(2S, 3S) -2-acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5
-Oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative (9). This step reagent used for the elimination by R ⁵ are different. For example,
When R ⁵ is a t-butyl group, hydrobromic acid, a benzyl group,
In the case of a p-nitrobenzyl group or a benzhydryl group, catalytic reduction (for example, H ₂ -Pd), and in the case of an allyl group, formic acid-lower alkylamine (for example, Pd (PPh ₃ ) ₄ ) in the presence of a phosphine complex of palladium (for example, Pd (PPh ₃ ) ₄ ) , Triethylamine)
Is used. Thiol group protected (2S, 3S)
A general method for producing -2-mercapto-3-methylpentanoic acid is as follows.

[0049]

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(Step O) In this step, L-isoleucine (1
In step 3), the amino group is converted into a hydroxyl group via a diazonium salt. This is performed by reacting sodium nitrite in a mineral acid aqueous solution. Alternatively, the reaction is carried out by reacting sodium nitrite in acetic acid to form acetate, followed by hydrolysis. (Step P) This step was obtained in Step O (2S, 3S)-
This is a step of protecting the carboxyl group of 2-hydroxy-3-methylpentanoic acid (14). For example, a lower alcohol or aralkyl alcohol is allowed to act in the presence of an acid, or benzyl bromide, diphenylbromomethane, triphenylbromomethane, trimethylsilyl bromide is acted on in the presence of a base in a solvent such as dimethylformamide, tetrahydrofuran, or acetonitrile. This is done by: (Step Q) This step is a step of converting a hydroxyl group of (2S, 3S) -2-hydroxy-3-methylpentanoic acid (15) having a carboxyl protecting group into a halogen atom while inverting the hydroxyl group to the R configuration. . Any method that is commonly used may be used as long as halogenation is performed in a stereo-inverting manner. For example, (i) a method of reacting a dialkyl azodicarboxylate, triphenylphosphine and zinc bromide or zinc iodide in an organic solvent such as tetrahydrofuran.
(ii) trialkylphosphine in an organic solvent such as acetonitrile, dimethylformamide, or dichloromethane in the presence or absence of a base such as pyridine;
A method of reacting an organic phosphorus compound such as triphenylphosphine or triphenyl phosphite and a halogen compound such as N-halosuccinimide, bromine or iodine (iii)
In an inert solvent such as dichloromethane, in the presence of a base such as pyridine or triethylamine, react with tosylic acid chloride or trifluoromethanesulfonic anhydride to form a sulfonic acid ester, and then react with a halogenating reagent such as lithium halide. Method (iv) A method in which phosphorus tribromide, phosphorus oxybromide or thionyl bromide is reacted in the presence or absence of dimethylformamide, etc., and the method (ii) is particularly preferred. However, a method using triphenylphosphine and bromine is preferable. (Step R) This step is a step of removing the protecting group of (2R, 3S) -2-bromo-3-methylpentanoic acid (16) having a carboxyl protecting group. The elimination reagent varies depending on the type of the protecting group. However, when the protecting group is a lower alkyl group, a mineral acid aqueous solution is used. When the protecting group is an arylalkyl group such as a benzyl group or a benzhydryl group or a t-butyl group, trifluoroacetic acid is used. Anisole, methanesulfonic acid-anisole, hydrogen chloride-anisole and the like can be applied. In the case of an arylalkyl group, etc., they can be eliminated by catalytic reduction or the like. In addition, formic acid, boron tribromide and the like can be used. Examples of the solvent include methanol, ethanol, acetonitrile, acetone, tetrahydrofuran and the like, a mixed solvent of these solvents and water, dichloromethane, chloroform, and an aqueous solvent. In order to carry out the production at a low cost, it is preferable that the protecting group is a methyl group in the step P, and deprotection is performed with an aqueous solution of a mineral acid such as sulfuric acid. (Step S) This step is performed using (2R, 3S) -2-bromo-3-
This is a step of acylthiolating a bromo group of methylpentanoic acid (17). The reaction is carried out according to a conventional method, for example, by reacting with a thiocarboxylate such as potassium thioacetate or sodium thioacetate in a polar solvent such as acetonitrile or acetone, or potassium carbonate,
The reaction is carried out by reacting a thiocarboxylic acid such as thioacetic acid or thiobenzoic acid in the presence of a base such as cesium carbonate.

[0051]

EXAMPLES Examples will be given below to further facilitate the understanding of the present invention, but it goes without saying that the present invention is not limited to these examples. Prior to the examples, production examples of compounds to be used as raw materials in the production method of the present invention are also shown.

Production Example 1 (2S) -6-oxo-2-piperidinecarboxylic acid

[0053]

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L-α-aminoadipic acid (50 g, 0.30 mo
l) was heated and stirred in acetic acid (250 mL) at 120 ° C. for 6 hours. After cooling, the solvent was distilled off under reduced pressure. Toluene (100 mL) and ethanol (20 mL) were added to the residue to dissolve it, and then concentrated again under reduced pressure. THF (200m
L) was added and stirred, and the precipitated crystals were collected by filtration to obtain 32 g of the title compound (colorless crystals, yield: 75%). ¹ H NMR (DMSO-d ₆ ) δ: 1.55-1.70 (2H, m), 1.70-1.8
4 (2H, m), 1.90−2.00 (2H, m), 2.08−2.20 (2H, m),
3.94−3.98 (1H, m), 7.24 (1H, s)

Production Example 2 Diphenylmethyl (2S) -6-oxo-2-piperi
Gin carboxylate

[0056]

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(2S) -6-oxo-2-piperidinecarboxylic acid (43 g, 0.30 mol) was added to DMF (215 mL).
While cooling in an ice bath while dissolving diphenyldiazomethane (61 g, 0.32 mol) in ethyl acetate (2 g).
15 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 18 hours and further at 60 ° C. for 1 hour. Ethyl acetate (400 mL) and water (400 mL) were added, the organic layer was separated, and the organic layer was further washed with water (300 mL × 2), washed with brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in butyl acetate (50 mL) with heating, isopropyl ether (150 mL) was added, and the precipitated crystals were collected by filtration to obtain 70 g of the title compound (colorless crystals, yield 76%). mp. 100-101 ° C ¹ H NMR (CDCl ₃ ) δ: 1.70-1.95 (3H, m), 2.05-2.45
(3H, m), 4.18−4.20 (1H, m), 6.17 (1H, s), 6.94 (1
H, s), 7.28−7.40 (10H, m) MS * m / z); 310 (MH +)

Production Example 3 Diphenylmethyl (S) -N- (benzyloxycar
Bonyl) -6-oxo-2-piperidinecarboxyl
G

[0059]

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Diphenylmethyl (2S) -6-oxo-2-piperidinecarboxylate (250 g, 0.81 mol
l) was dissolved in a mixture of chlorobenzene (3 L) and THF (2.5 L) and cooled in a dry ice-acetone bath. A 1M LiHMDS solution (850 mL, 0.85 mol) was added dropwise to this solution, and benzyloxycarbonyl chloride (1
41 g, 1 mol) in THF (300 mL) was added dropwise. Continue stirring for 1 hour, and add acetic acid (150 mL)
A solution of chlorobenzene (40 mL) was added. 0 ° C
After raising the temperature to 40, toluene (6 L) was added and
Heated to ° C. The organic layer was washed four times with water (5 L) and once with brine (2 L), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol (4 L) was added to the residue for crystallization. The precipitated crystals were collected by filtration to give the title compound 3
03 g (colorless crystals, yield 85%) was obtained. mp; 140-141 ° C ¹ H NMR (CDCl ₃ ) δ: 1.45-1.75 (2H, m), 1.98-2.10
(1H, m), 2.18−2.28 (1H, m), 2.42−2.58 (2H, m),
4.92−4.96 (1H, m), 5.10 (1H, d, J = 12Hz), 5.24 (1
(H, d, J = 12Hz), 6.91 (1H, s), 7.25−7.38 (15H, m) MS
(m / z); 444 (MH +)

Production Example 4 (2S) -N-methoxycarbonyl-2-piperidineca
Rubonic acid

[0062]

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In a 4-neck flask, (2S) -2-piperidinecarboxylic acid (435 g, 3.37 mol) and water (6.5 L) were added and dissolved, and NaHCO ₃ (849 g, 10.11 mol) was stirred.
l) was added slowly at room temperature. The suspension was stirred vigorously at room temperature with methyl chlorocarbonate (313 mL, 4.04 mol).
Was slowly added dropwise over 75 minutes, and the mixture was stirred overnight (18 hours) after completion of the addition. The reaction solution was washed with ethyl acetate (1 L) using a 20-L stirring extractor. The aqueous layer was separated, and ethyl acetate (2.0 L) and NaCl (1.5 kg) were added. After saturated with NaCl, concentrated hydrochloric acid (561 mL, 6.73 mol) was gradually added with stirring to make the system acidic, and the ethyl acetate layer was separated.
The aqueous layer was re-extracted with ethyl acetate (2.0 L), and the combined organic layers were washed with saturated saline (1.0 L) and dried over anhydrous magnesium sulfate (500 g). After filtration,
After concentrating the filtrate with an evaporator, a vacuum pump (40 ° C, 2h
r) and dried over a vacuum line (room temperature, 63 hr) to obtain 564.9 g (yield: 89.6%) of a crude product of the title compound as colorless crystals. mp 104-105 ° C ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.99 (0.6 H, brd, J = 4.5 Hz),
4.85 (0.4H, br), 4.12 (0.4H, brd, J = 13.5Hz), 3.99
(0.6H, brd, J = 12.0Hz), 3.74 (0.6x3H, s), 3.71 (0.4
x3H, s), 3.10−2.92 (1H, m), 2.34−2.18 (1H, m),
1.80-1.62 (3H, m), 1.52-1.24 (2H, m) HPLC RT = 7.62, purity 100% ee, condition CHIRACEL OF (4.6
x250mm, Lot.081-012-50306), hexane-iPrOH-TFA (90:10:
0.1), 1.5ml / min, UV 210nm, 40 ° C FABMS (m / e) 188 (MH +)

Production Example 5 t-butyl (2S) -N-methoxycarbonyl-2-pi
Peridine carboxylate

[0065]

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A mechanical air stirrer, a three-way cock with two 10-liter balloons, a three-way cock with a 10-liter balloon for isobutene gas introduction, and a 10-liter 4-neck flask equipped with a thermometer were obtained in Production Example 3 (2S). -N-methoxycarbonyl-2-piperidinecarboxylic acid (564.15 g, 3.01 mol
l, 1 eq.) and dehydrated CHCl3 (5.0 L) were added and dissolved. The solution was cooled in a water bath, concentrated sulfuric acid (80 ml, 1.51 mol) was added, and isobutene gas gas (excess) was continuously injected through a 10 L balloon over 30 minutes with stirring (reaction temperature was 13 ° C.-33 ° C.).
° C). When the isobutene in the 10 L balloon was consumed, the balloon was supplemented with isobutene by injecting it into the balloon (repeated three times). Five hours after the first injection, TLC analysis (CHCl ₃ / MeOH / AcOH = 90/9/1 or hexane / AcOEt = 4/1, anisaldehyde or PMA) confirmed that the reaction was almost complete. Isobutene remaining in the system was distilled off by a vacuum line (30 minutes). Using a 20 L stirring type extractor, the reaction solution was Na ₂ CO ₃ aqueous solution (480 g, 4.53 mol, 1.5 eq./
4.5L-water) for neutralization. The organic layer was separated, washed with saturated saline (2.5 L), and dried over anhydrous sodium sulfate (1.5 kg). After filtration, the filtrate was concentrated under reduced pressure at an external temperature of 25-30 ° C.
(4 hours). The residue containing the obtained crystals was purified by flash silica gel column chromatography [silica gel: 5 kg, eluent: hexane-AcOEt (6: 1)] to give the title compound as a colorless oil (which later crystallized during frozen storage). As 734.
0 g (100% yield) was obtained. mp 32-33 ° C ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.81 (0.55H, br), 4.63
(0.45H, br), 4.07 (0.45H, brd, J = 12.0Hz), 3.95 (0.
55H, brd, J = 12.0Hz), 3.71 (0.55x3H, s), 3.69 (0.45
x3H, s), 3.10−2.90 (1H, m), 2.24−2.14 (1H, m),
1.72-1.56 (3H, m), 1.46 (9H, s), 1.46-1.20 (2H,
m) HPLC RT = 4.46, purity 100% ee, condition CHIRACEL OF (4.6
x250mm, Lot.081-012-50306), hexane-iPrOH-TFA (90:10:
0.1), 1.5ml / min, UV 210nm, 40 ° C FABMS (m / e) 244 (MH +) [α] D ²⁵ −46.2 ° (C1.05, CHCl ₃ )

Production Example 6 t-butyl (2S) -N-methoxycarbonyl-6
Oxo-2-piperidine carboxylate

[0068]

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Sodium periodate (440 g, 2.06 mol) and water (3.52 L) were placed in a 10 L 4-neck flask equipped with a mechanical stirrer, a balloon, and a dropping funnel, and the system was isolated from the outside. ₂・ (H ₂ O) n (3.28g, 24.7mmol)
Was added to obtain a yellow-green (RuO ₄ ) solution. To this, t − dissolved in ethyl acetate (1.21 L; washed in advance with water) was added.
Butyl (2S) -N-methoxycarbonyl-2-piperidinecarboxylate (100 g, 411 mmol) was slowly added dropwise at room temperature with vigorous stirring over 5.3 hours.
After dropping, the mixture was stirred at room temperature overnight, and analyzed by TLC (hexane / AcOEt = 1
/ 1, anisaldehyde) almost completed the reaction. After transferring to a 20 L stirring extractor and adding water (1 L),
The ethyl acetate layer was separated, and the aqueous layer was further separated with ethyl acetate (1.17
L). The extracted organic layers (about 2 L) were combined, and hexane (1.75 L), isopropanol (65 ml), saturated saline (1.5
L) was added and the mixture was stirred at room temperature for 3.3 hours to precipitate RuO ₂ (black solid). After celite was filled in a glass filter and the above solution was filtered, the colorless filtrate was transferred to a 20 L stirred extractor to remove an aqueous layer. Saturated aqueous sodium bicarbonate (0.5L, 1Lx2)
And the aqueous layer of the washing solution was washed with ethyl acetate-hexane (250 ml-2
The organic layer was combined, washed with a saturated aqueous sodium sulfite solution (1 L) and a saturated saline solution (1 L), and dried over anhydrous sodium sulfate (1 kg). After filtration through a glass filter, the mixture was concentrated under reduced pressure at an external temperature of 40 ° C. The residue (51.6 g) was purified by flash silica gel column chromatography [silica gel: 550 g, eluent: hexane-AcOEt (2: 1)] to give the title compound as a colorless oil (which later crystallized during frozen storage). 48.52 g (45.9% yield) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.68 (1H, dd, J = 3.5, 5.5H
z), 3.86 (3H, s), 2.61 (1H, dddd, J = 1.5, 4.5, 6.0,
17.5Hz), 2.49 (1H, ddd, J = 7.0, 10.0, 17.5Hz), 2.24
−2.16 (1H, m), 2.07-1.96 (1H, m), 1.87−1.70 (2
H, m), 1.47 (9H, s) HRMS (FAB) (m / e) calcd for C ₁₂ H
₂₀ O ₅ N (MH +) 258.1341, found 258.1331 IR (neat) 2955, 1
780, 1720, 1440, 1370, 1285, 1250, 1220, 1145, 106
0, 950, 790 cm ^-1 [α] D ²⁴ + 6.69 ° (C1.075, CHCl ₃ ).

Production Example 7 t-butyl (2S) -6-oxo-2-piperidineca
Ruboxylate

[0071]

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In a 5 L 4-neck flask equipped with a mechanical air stirrer, a three-way cock with 10 L balloons (two pieces), a 10 L balloon for isobutene gas introduction, and a thermometer, (2S) -6-oxo-2- Piperidine carboxylic acid (75.5 g, 0.527 mol, 1 eq.) And dehydrated CHCl ₃ (2.5 L) were added and dissolved. The solution was cooled in a water _{bath, BF 3 · Et 2 O (} 65m
l, 0.528 mol) and isobutene gas (excess) under stirring.
Was continuously infused via a 10 L balloon. When the isobutene in the 10 L balloon was consumed, isobutene was injected into the balloon from a cylinder to make up. 3 hours after the first injection
C analysis (BuOH / AcOEt / AcOH / H2O = 1/1/1/1, ninhydrin) confirmed that the reaction was almost complete. Four hours later, isobutene remaining in the system was distilled off by a vacuum line using a 2 L eggplant flask cooled in a dry ice / ethanol bath as a trap (60 minutes). The reaction solution was poured into an aqueous solution of Na ₂ CO ₃ (106 g, 1.0 mol / 1 L water) under ice cooling to neutralize. The organic layer was separated, washed with water (500 ml) and saturated saline (500 ml), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue (26.1 g) was purified by flash silica gel column chromatography [silica gel: 380 g, eluent: hexane-AcOEt (1: 1), AcOEt] to give the title compound 21.1. g was obtained as crystals. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 6.16 (1H, br), 3.96 (1H,
m), 2.50−2.25 (2H, m), 2.25−2.10 (1H, m), 2.00
−1.70 (3H, m), 1.47 (9H, s) FABMS (m / e) 200 (MH +)

Production Example 8 t-butyl (2S) -N- (4-nitrobenzyloxy
(Cicarbonyl) -6-oxo-2-piperidinecarboxy
Silat

[0074]

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In a 2 L 4-neck flask equipped with a dropping funnel and a balloon, t-butyl (2S) -6-oxo-2- was added.
Piperidine carboxylate (21.1 g, 106 mmol) and dehydrated tetrahydrofuran (350 ml,) were added, and the external temperature was cooled to -78 ° C. To this solution, lithium bis (trimethylsilyl) amide 1.0 M in THF (LHMDS; 117 ml, 117 mmol) was added dropwise at an external temperature of −78 ° C. over 40 minutes. After dropping, keep at -78 ° C for 15
After stirring for 4 minutes, 4-nitrobenzyl chlorocarbonate (27.42 g,
127 mmol) in dehydrated tetrahydrofuran (150 ml)
Dropped over minutes. TLC analysis (AcOEt, ninhydrin) 10 minutes after the addition confirmed that the reaction was almost completed. −78
A saturated aqueous solution of ammonium chloride (300 ml) was added to the reaction solution at ℃ ° C. to stop the reaction, and the temperature was raised to around room temperature. Add water (2
After addition of ethyl acetate (300 ml) and ethyl acetate (300 ml), the ethyl acetate layer was separated, washed with saturated saline (200 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered, and the filtrate was concentrated under reduced pressure. Hexane / AcOEt = 5/1 (60m
l), CH ₂ Cl ₂ (20 ml) was added, followed by filtration, and the filtrate was subjected to flash silica gel column chromatography [silica gel:
900 g, eluent: hexane-AcOEt (5: 1), hexane-AcOEt (4:
1), 22 L of hexane-AcOEt (3: 1), pressure: 6 kg / cm ² ) to give 33.22 g (yield 83%) of the title compound as pale yellow crystals. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.23 (2H, d, J = 9.0 Hz), 7.
63 (2H, d, J = 9.0Hz), 5.43 (1H, d, J = 14.0Hz), 5.35
(1H, d, J = 14.0Hz), 4.71 (1H, dd, J = 3.5, 6.0Hz), 2.
65 (1H, dddd, J = 1.5, 4.0, 6.0, 17.5Hz), 2.53 (1H,
ddd, J = 7.0, 10.5, 17.5Hz), 2.30−2.20 (1H, m), 2.1
0-1.95 (1H, m), 1.90-1.70 (2H, m), 1.44 (9H, s) FABMS (m / e) 379 (MH +)

Production Example 9 4-Nitrobenzyl (2S) -Nt-butyloxy
Carbonyl-2-piperidine carboxylate

[0077]

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Anhydrous DM of (2S) -Nt-butyloxycarbonyl-2-piperidinecarboxylic acid (10 g, 43.6 mmol)
F (87 ml) solution, cesium carbonate (CsCO ₃ ; 7.82 g,
24.0 mmol,) was added, and the mixture was stirred under an N ₂ atmosphere for 90 minutes. 4-
Nitrobenzyl bromide (9.89 g, 45.8 mmol) was added, and the mixture was stirred at room temperature. After 63 hours, TLC analysis (hexane / AcOEt = 2 /
1, ninhydrin) confirmed the progress of the reaction. Hexan in reaction solution
e / AcOEt = 1/1 and saturated aqueous sodium bicarbonate were added and extracted. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, the filtrate is concentrated under reduced pressure, and the crude product is purified by flash silica gel column chromatography [silica gel:
100 g, eluent: hexane to hexane-AcOEt (1: 1)] to give 15.92 g (yield 100%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.22 (2H, d, J = 8.4 Hz), 7.5
2 (2H, d, J = 8.4Hz), 5.35−5.19 (2H, m,), 4.99 (0.5
9H, brs), 4.81 (0.41H, brs), 4.06 (0.41H, m), 3.94
(0.59H, m), 3.01−2.80 (1H, m), 2.29−2.17 (1H,
m), 1.77-1.13 (5H, m), 1.47 (0.59x9H, s), 1.39 (0.
41x9H, s)

Production Example 10 4-Nitrobenzyl (2S) -Nt-butoxycal
Bonyl-6-oxo-2-piperidinecarboxylate

[0080]

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4-Nitrobenzyl (2S) -Nt-
The same treatment as in Production Example 6 was performed using butyloxycarbonyl-2-piperidinecarboxylate (1.0 g, 2.74 mmol) to obtain 825 mg of a crude product, which was subjected to flash silica gel column chromatography (silica gel: 39 g, eluent:
Purification with hexane-AcOEt (2: 1)) gave 696 mg (yield 67%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.23 (2H, d, J = 6.8 Hz), 7.5
3 (2H, d, J = 8.8Hz), 5.34 (1H, d, J = 13.2Hz), 5.28
(1H, d, J = 13.2Hz), 4.79 (1H, dd, J = 3.8, 5.8Hz), 2.
62−2.46 (2H, m), 2.23−2.05 (2H, m), 1.87−1.63
(2H, m), 1.48 (9H, s)

Example 1 Diphenylmethyl (2S, 5R) -N- (benzylo
Xycarbonyl) -5-methyl-6-oxo-2-pipe
Lysine carboxylate and diphenylmethyl
(2S, 5S) -N- (benzyloxycarbonyl)-
5-methyl-6-oxo-2-piperidinecarboxyla
To

[0083]

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Diphenylmethyl (S) -N- (benzyloxycarbonyl) -6-oxo-2-piperidinecarboxylate (66 g, 148 mmol) was added to THF (2.3).
L) and 1.3-dimethyl-2-imidazolidinone (81
dissolved in a mixed solution of methyl iodide (28 mL, 444 mL).
mmol) and cooled to -60 ° C. 1MLi
An HMDS solution (193 mL, 192 mol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. Acetic acid (55 mL) was added and the temperature was raised to room temperature. Toluene (2 L) was added, and the organic layer was washed twice with water (650 mL) and saturated aqueous sodium hydrogen carbonate (650 m2).
L) and brine (300 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 55 g of a mixture of the title compounds (5R: 5S = 4: 1) was obtained as an oil (yield: 8).
1%). 5R form ¹ H NMR (CDCl ₃ ) δ: 1.16 (3H, d, J = 7 Hz), 1.37-1.46
(1H, m), 1.76-1.83 (1H, m), 2.11-2.17 (2H, m),
2.29 (1H, ddd, J = 7Hz, 7Hz, 8Hz), 4.98 (1H, dd, J = 5
Hz, 6 Hz), 5.12 (1H, d, J = 8Hz), 5.24 (1H, d, J = 8H)
z), 6.90 (1H, s), 7.20-7.40 (15H, m) 5S form ¹ H NMR (CDCl ₃ ) δ: 1.15 (3H, d, J = 7 Hz), 1.19-1.32
(1H, m), 1.73-1.80 (1H, m), 2.04-2.13 (1H, m),
2.21−2.27 (1H, m), 2.41−2.51 (1H, m), 5.10 (1H, m
d, J = 7Hz), 5.25 (1H, d, J = 7Hz), 6.92 (1H, s), 7.25
−7.34 (15H, m)

Example 2 t-butyl (2S, 5RS) -N-methoxycarbonyl
5-Methyl-6-oxo-2-piperidinecarboxy
Silat

[0086]

Embedded image

T-butyl (2S) -N-methoxycarbonyl-6-oxo-2-piperidinecarboxylate
(340.6 g, 1.32 mol) in the same manner as in Example 1 to obtain 297.7 g (yield: 82.9%) of the title compound as a pale yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 4.70 (0.66 H, dd, J = 5.0, 6.
5Hz), 4.64 (0.34H, ddd, J = 1.0, 2.5, 5.5Hz), 3.86
(0.66x3H, s), 3.85 (0.34x3H, s), 2.64−2.44 (1H,
m), 2.26-1.94 (3H, m), 1.56-1.46 (1H, m), 1.47
(9H, s), 1.27 (0.34x3H, d, J = 7.0Hz), 1.26 (0.66x3
(H, d, J = 7.0Hz) HRMS (FAB) (m / e) calcd for C ₁₃ H ₂₂ O ₅ N (MH +) 272.1496,
found 272.1497IR (neat) 2950, 1785, 1720, 1440, 137
0, 1285, 1260, 1160, 1150, 1005, 845,790 cm ^-1

Example 3 4-Nitrobenzyl (2S, 5RS) -5-methyl-
Nt-butoxycarbonyl-6-oxo-2-piperi
Gin carboxylate

[0089]

Embedded image

[0090] 4-nitrobenzyl (2S) -Nt-
Butoxycarbonyl-6-oxo-2-piperidinecalcium
As in Example 1 using boxylate (695 mg, 1.84 mol)
740 mg of the crude product obtained by flash
Chromatography [silica gel: 39 g, eluent: hexan
e-AcOEt (3: 1)] to give 511 mg (yield) of the title compound.
71%).

Example 4 t-butyl (2S, 5R) -5-methyl-N- (4-
Nitrobenzyloxycarbonyl) -6-oxo-2-
Piperidine carboxylate and t-butyl
(2S, 5S) -5-methyl-N- (4-nitrobenzyl)
Ruoxycarbonyl) -6-oxo-2-piperidineca
Ruboxylate

[0092]

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Obtained in the same manner as in Example 1 using t-butyl (2S) -N- (4-nitrobenzyloxycarbonyl) -6-oxo-2-piperidinecarboxylate (32.78 g, 86.6 mmol). The yellow oily residue (46.08 g) was repeatedly purified by flash silica gel column chromatography [eluent: hexane-AcOEt (3: 1)].
12.12 g of the title compound (5R form) as a yellow oil (HPL
C; chemical purity 97.4%, 5R: 5S = 98.5: 1.5) (yield 35.7%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.23 (2H, d, J = 9.0 Hz), 7.6
3 (2H, d, J = 9.0Hz), 5.42 (1H, d, J = 14.0Hz), 5.35
(1H, d, J = 14.0Hz), 4.74 (1H, dd, J = 5.5, 6.5Hz), 2.
61 (1H, m), 2.26-1.96 (3H, m), 1.63-1.50 (1H,
m), 1.44 (9H, s), 1.28 (3H, d, J = 7.0Hz) FABMS (m / e) 379 (MH +) Also, the title compound (5S form) was obtained as a yellow oil (7.33 g).
(HPLC; chemical purity 95.8%, 5R: 5S = 1.0: 99.
0) (21.6% yield). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.23 (2H, d, J = 9.0 Hz), 7.6
2 (2H, d, J = 9.0Hz), 5.43 (1H, d, J = 14.0Hz), 5.31
(1H, d, J = 14.0Hz), 4.66 (1H, ddd, J = 1.0, 2.5,5.5H
z), 2.52 (1H, m), 2.24 (1H, m), 2.10 (1H, m), 1.94
(1H, m), 1.86 (1H, m), 1.44 (9H, s), 1.28 (3H, d,
J = 6.5Hz) FABMS (m / e) 379 (MH +)

Example 5 t-butyl (2S, 5RS, 6RS) -6-hydroxy
C-N-methoxycarbonyl-5-methyl-2-piperi
Gin carboxylate

[0095]

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In a 10 L 4-neck flask equipped with a mechanical stirrer and a balloon, t-butyl (2S, 5RS)-
N-methoxycarbonyl-5-methyl-6-oxo-2
-Piperidine carboxylate (296.3 g, 1.09 mol), dehydrated
THF (4 L) was added for dissolution, and the external temperature was cooled to -78 ° C. Under a nitrogen atmosphere, diisobutylaluminum hydride 0.95M in hexane (DIBAH; 1.70 L, 1.62 mol) was added dropwise at −78 ° C. over 50 minutes using a cannula. 70 minutes TLC after dropping
DIBAH (100 ml, 95 mmol) because the reaction was not completed by analysis
Was added dropwise over 10 minutes. Since the reaction was not completed again by TLC analysis, DIBAH (100 ml, 95 mmol) was added dropwise over 10 minutes. 160 minutes after the first addition, a saturated ammonium chloride solution (200 ml) was poured into the reaction solution at -78 ° C. Sodium potassium tartrate tetrahydrate (Rochelle salt, Seignette sal
t; 5 kg) was dissolved in water (8 L), and the above reaction solution and ethyl acetate (4 L) were added thereto, and the mixture was vigorously stirred at room temperature with a mechanical stirrer. Two hours later, when both the aqueous layer and the organic layer became transparent, the mixture was transferred to a 20 L stirring type extractor and the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (1 L), and the combined organic layers were washed with saturated saline (1.5 L) and dried over anhydrous magnesium sulfate (1 L).
kg). After filtration through a glass filter, the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C to give the title compound as a colorless oil.
7.1 g were obtained.

Example 6 4-Nitrobenzyl (2S, 5RS, 6RS) -6
Hydroxy-Nt-butoxycarbonyl-5-methyl
-2-piperidine carboxylate

[0098]

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4-nitrobenzyl (2S, 5RS)-
5-Methyl-Nt-butoxycarbonyl-6-oxo-2-piperidinecarboxylate (510 mg, 1.30 mmol) was treated with diisopropylaluminum hydride 1.0 M in hexane (D
IBAH; 1.43 ml, 1.43 mmol, 1.1 eq.) Was added dropwise. 45 minutes later, methanol (0.11 ml, 2 eq.) Was added to the reaction solution at -78 ° C, and the mixture was stirred for 10 minutes. Further, saturated aqueous ammonia (0.1 ml) was added to the reaction solution at −78 ° C., and the temperature was raised to room temperature. An aqueous solution of sodium potassium tartrate tetrahydrate (Rochelle salt) and ethyl acetate were added, and the mixture was vigorously stirred at room temperature. After 1.3 hours, the layers were separated, and the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration through a glass filter, the filtrate was concentrated under reduced pressure to obtain 504 mg of the title compound.

Example 7 t-butyl (2S, 5RS, 6RS) -6-methoxy
-N-methoxycarbonyl-5-methyl-2-piperidi
Carboxylate

[0101]

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T-butyl (2S, 5RS, 6RS)-
6-hydroxy-N-methoxycarbonyl-5-methyl-2-piperidinecarboxylate (0.188 g, 0.689 mmol
l) was dissolved in methanol (10 ml) and the external temperature was cooled to 0 ° C under a nitrogen atmosphere. 10% HCl / methanol (0.02ml)
Was added. Five minutes later, a saturated aqueous sodium hydrogen carbonate solution (0.1 ml) was added to the reaction solution, and the mixture was concentrated under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was partitioned. The ethyl acetate layer was separated, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was concentrated under reduced pressure to obtain 0.177 g of the title compound as an oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.20-4.15 (2H, m), 3.80-
3.67 (3H, m), 3.41−3.28 (3H, m), 2.32-1.11 (5H,
m), 1.41-1.46 (9H, m), 1.01-0.88 (3H, m)

Example 8 Methyl (2RS, 4R) -2-[(1RS, 4S)-
4-t-butoxycarbonyl-4-methoxycarbonyl
Amino-1-methylbutyl] thiazolidine-4-carbo
Xylate

[0104]

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H ₂ O (1.56 L) was added to a 10 L 4-neck flask, and the mixture was degassed under reduced pressure with stirring and replaced with nitrogen. Then, the t-butyl obtained in Example 5 dissolved in methanol (6.24 L)
(2S, 5RS, 6RS) -6-hydroxy-N-methoxycarbonyl-5-methylpipecolate (277.1 g, 1.09
mol) was added and the atmosphere was replaced with nitrogen. To this were simultaneously added L-cysteine methyl hydrochloride (L-Cys-OMe.HCl; 187.5 g, 1.09 mol) and sodium acetate (89.6 g, 1.09 mol).
(105.3 ml, 1.86 mol), and the mixture was stirred at room temperature under a nitrogen atmosphere. TLC analysis after 12.5 hours (hexane / AcOEt = 2/1
The reaction was completed twice with anisaldehyde), and the mixture was concentrated under reduced pressure at an external temperature of 30 ° C. until methanol was not distilled off. After concentration, the residue was transferred to a 20 L stirred extractor and extracted with ethyl acetate (3 L). The organic layer was washed with a 5% aqueous citric acid solution (2 L), a saturated aqueous sodium bicarbonate solution (1 L), and a saturated saline solution (1 L), and then dried over anhydrous sodium sulfate (500 g). After filtration through a glass filter, the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. to obtain 334.7 g of a brown oil. This was subjected to flash silica gel column chromatography [silica gel: 10 kg, eluent: hexa
ne-AcOEt (3: 1), hexane-AcOEt (2: 1), hexane-AcOEt (1:
1)] to give 178.6 g of the title compound (two-step yield from Example 5: 42.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.27 (0.55 H, brd, J = 6.5 H
z), 4.53 (0.45H, d, J = 7.0Hz), 4.44-4.04 (2H, m),
3.79 (0.55x3H, s), 3.77 (0.45x3H, s), 3.68 (3H,
s), 3.28 (0.55H, dd, J = 7.0, 10.0Hz), 3.18 (0.45H,
dd, J = 7.0, 11.0Hz), 3.00 (0.45H, dd, J = 6.5, 11.0H
z), 2.77 (0.55H, t, J = 10.0Hz), 1.96−1.22 (6H, m),
1.48 (0.55x9H, s), 1.47 (0.45x9H, s), 1.11 (0.55x
3H, d, J = 7.0Hz), 0.96 (0.45x3H, d, J = 7.0Hz) HRMS (FAB) (m / e) calcd for C ₁₇ H ₃₁ O ₆ N ₂ S (MH +) 391.189
5, found 391.1899IR (neat) 3325, 2950, 1720, 1520,
1450, 1365, 1240, 1150, 1050, 840, 780cm ^-1

Example 9 Methyl (2RS, 4R) -2-[(1RS, 4S)-
4-t-butoxycarbonylamino-4- (4-nitro
[Benzyloxycarbonyl) -1-methylbutyl] thia
Zolidine-4-carboxylate

[0107]

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4-Nitrobenzyl obtained in Example 6
(2S, 5RS, 6RS) -6-hydroxy-Nt-
579 mg of the crude product obtained in the same manner as in Example 7 using butoxycarbonyl-5-methyl-2-piperidinecarboxylate (504 mg, 1.30 mmol) [flash silica gel column chromatography [silica gel: 34 g, eluent: hexane] -AcOEt (2: 1)] to give 349 mg of the title compound.
(Two-stage yield from Example 6: 52.0%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 8.23 (2H, d, J = 8.8 Hz), 7.5
4 (2H, d, J = 7.6Hz), 5.32-5.23 (2H, m), 5.07-4.03
(3H, m), 3.79 (0.60x3H, s), 3.77 (0.40x3H, s), 3.2
8 (0.60H, dd, J = 7.2, 10.0Hz), 3.17 (0.40H, dd, J =
6.4,10.6Hz), 2.99 (0.40H, dd, J = 6.8, 10.6Hz), 2.75
(0.60H, t, J = 10.0Hz), 2.20-1.30 (6H, m), 1.44 (9
H, s), 1.09 (0.60x3H, d, J = 6.8Hz), 0.95 (0.40x3H,
d, J = 6.4Hz)

Example 10 Methyl (2RS, 4R) -2-[(1RS, 4S)-
4-diphenylmethyloxycarbonyl-4-benzyl
Oxycarbonylamino-1-methylbutyl] thiazoly
Gin-4-carboxylate and methyl (2R
S, 4R) -2-[(1S, 4S) -4-diphenylmeth
Tyloxycarbonyl-4-benzyloxycarbonyl
Amino-1-methylbutyl] thiazolidine-4-carbo
Xylate

[0110]

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The compound of Example 1 (92 g, 0.2 mmol) was dissolved in anhydrous tetrahydrofuran (920 mL) and cooled in an ice bath. A solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran (220 mL of a 1 M solution, 0.22 mol) was added dropwise while maintaining the temperature of the reaction solution at -5 ° C to 0 ° C. After stirring at this temperature for 2 hours, acetone (92 mL) was added and the mixture was stirred for 20 minutes. An aqueous solution containing acetic acid (92 mL) (3
The reaction solution was added to a mixture of L) and ethyl acetate (3 L), and the organic layer was separated. Subsequently, the organic layer was washed with water, a phosphate buffer having a pH of 6.8, and a saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The thus obtained diphenylmethyl (2S, 5R) -N- (benzyloxycarbonyl) -5-methyl-6-hydroxy-2-piperidinecarboxylate and diphenylmethyl (2S, 5
A mixture of S) -N- (benzyloxycarbonyl) -5-methyl-6-hydroxy-2-piperidinecarboxylate was dissolved in ethanol (1.1 L) and L-cysteinemethyl hydrochloride (0.34 g, 0.2 mol) was added. Combine with a solution of sodium acetate (16 g, 0.2 mol) in water (150 mL). Next, acetic acid (19 mL) was added thereto, and the mixture was stirred for 18 hours. Ethyl acetate (3 L) was added to the reaction solution, and the organic layer was separated.
L), washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (hexane: AcOEt = 1: 1) to obtain 67 g (yield 59%) of a mixture of the title compounds as an oil. _{^{1 H NMR (CDCl 3) δ}} : 0.88 (1.5H, d, J = 6Hz), 1.01 (1.
5H, d, J = 6Hz), 1.10−2.20 (5H, m), 2.74 (0.5H, dd,
(J = 10Hz, 10Hz), 2.96 (0.5H, dd, J = 10Hz, 8Hz), 3.12
(0.5H, dd, J = 6Hz, 10Hz), 3.26 (0.5H, dd, J = 10Hz,
7Hz), 3.74 (1.5H, s), 3.78 (1.5H, s), 3.98 (0.5H,
(dd, J = 6Hz, 8Hz), 4.12 (0.5H, dd, J = 7Hz, 10Hz), 4.2
9 (0.5H, d, J = 6Hz), 4.37 (0.5H, d, J = 6Hz), 4.42−
4.58 (1H, m), 5.10 (2H, s), 5.31−5.40 (1H, m), 6.
91 (1H, s), 7.24−7.40 (15H, m) MASS (m / e); 577 (MH +)

Example 11 Methyl (3R, 6S, 9R, 9aR) -6-t-butene
Xycarbonylamino-9-methyl-5-oxoocta
Hydroazepine [2,1-b] thiazolo-3-carboxy
Silat

[0113]

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Methyl (2RS, 4R) -2-[(1
R, 4S) -4-t-butoxycarbonylamino-4-
(4-Nitrobenzyloxycarbonyl) -1-methylbutyl] thiazolidine-4-carboxylate (84 mg, 0.
164 mmol), ethanol (8.2 ml), 10% Pd / C (50 wt% wet, 25 m
g) and hydrogenated (H ₂ , 3 kgf / cm ² ) with pearl at room temperature. After 8.25 hours, the mixture was concentrated under reduced pressure, and methyl
76 mg of (S, 4R) -2-[(1R, 4S) -4-t-butoxycarbonylamino-4-carboxy-1-methylbutyl] thiazolidine-4-carboxylate were obtained as a yellow oil. To this, dehydrated tetrahydrofuran (3.3 ml) and N-methylmorpholine (0.018 ml, 0.164 mmol
l), 1-ethoxycarbonyl-2-ethoxy-1,2-
Dihydroquinoline (EEDQ; 49 mg, 0.20 mmol) was added continuously and stirred. After 65.5 hours, the reaction solution was concentrated under reduced pressure at an external temperature of 40 ° C, a 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 67 mg of a residue, which was subjected to flash silica gel column chromatography [silica gel: 16 g, eluent: hexane-AcOE
t (4: 1)] to give 19.2 mg (yield 33%) of the title compound.

Example 12 Methyl (3R, 6S, 9R, 9aR) -6-methoxy
Carbonylamino-9-methyl-5-oxooctahydride
Rothiazolo [3,2-a] azepine-3-carboxyla
To

[0116]

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Methyl (2RS, 4R) -2-[(1R
[S, 4S) -4-tert-butoxycarbonyl-4-methoxycarbonylamino-1-methylbutyl] thiazolidine-4-carboxylate (178.4 g, 457 mmol) was added with trifluoroacetic acid (351 ml, 4.57 mol) at room temperature. The mixture was stirred for 44.5 hours under a nitrogen atmosphere, and methyl (2RS, 4R) -2 was added.
-[(1RS, 4S) -4-carboxy-4-methoxycarbonylamino-1-methylbutyl] thiazolidine-
It was 4-carboxylate. Next, dehydrated tetrahydrofuran (4.57 L) and N-methylmorpholine (602 ml, 5.
48 mol), 1-ethoxycarbonyl-2-ethoxy-1,
After 2-dihydroquinoline (EEDQ; 141.2 g, 572 mmol) was continuously added, ice cooling was stopped and the mixture was stirred at room temperature. After 63.5 hours, the reaction solution was concentrated under reduced pressure at an external temperature of 35 ° C., the residue was dissolved in ethyl acetate (2 L), transferred to a 20 L stirred extractor, and treated with water (1
L), and washed with 1N-hydrochloric acid (1 L × 2). The aqueous layer of the washing solution was re-extracted with ethyl acetate (1 L) and washed with 1N-hydrochloric acid (1 L). The extracted ethyl acetate layers were combined, washed with saturated aqueous sodium hydrogen carbonate (1.5 L) and saturated saline (1 L), and dried over anhydrous magnesium sulfate (250 g). After filtration, the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. to obtain a brown oily residue (112 g) as a brown oily substance. This was subjected to flash silica gel column chromatography [silica gel: 1.7 kg, eluent: hexane-AcOEt (2: 1), hexane-AcOEt (3: 2), hexane
-AcOEt (1: 1), hexane-AcOEt (2: 3)] to give 74.9 g (yield 51.8%) of the title compound as a pale yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.97 (1H, brd, J = 8.0 Hz),
5.21 (1H, s), 4.99 (1H, t, J = 7.0Hz), 4.31 (1H, m),
3.78 (3H, s), 3.67 (3H, s), 3.32 (1H, dd, J = 6.0,
11.5Hz), 3.13 (1H, dd, J = 7.0, 11.5Hz), 2.14-1.78
(5H, m), 1.12 (3H, d, J = 7.5Hz) HRMS (FAB) (m / e) calcd for C ₁₃ H ₂₁ O ₅ N ₂ S (MH +) 317.117
1, found 317.1171IR (neat) 3350, 2925, 1720, 1650, 1
500, 1440, 1400, 1350, 1220, 1170, 1050, 780 cm ^-1

Example 13 Methyl (3R, 6S, 9R, 9aR) -6-amino-
9-methyl-5-oxooctahydrothiazolo [3,2
-A] azepine-3-carboxylate

[0119]

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In a 3 L flask at room temperature under a nitrogen atmosphere, methyl (3R, 6S, 9R, 9aR) -6-methoxycarbonyl-9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3 was added. -Carboxylate (74.7
g, 236 mmol) and methanesulfonic acid (460 ml, 7.08 mol) were added and dissolved, and the external temperature was set to 0 ° C. Dimethyl sulfide (86.7 ml, 1.18 mol) was added thereto, the external bath at 0 ° C. was removed, and the mixture was stirred while warming to room temperature. After 4 hours, the completion of the reaction was confirmed. 29% ammonia water (831
g, 14.2 mol), ice water (1.5 L), ethyl acetate (2 L), salt (about 300
g) was added and stirred, and the reaction solution was gradually added thereto. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate (1 L × 2) and dichloromethane (1 L). Combine organic layers and saturated saline
(500 ml), and dried over anhydrous magnesium sulfate (1 kg). After filtration, the filtrate was concentrated under reduced pressure.
mlx4) was added thereto, and the mixture was repeatedly concentrated. Finally, the residue was vacuum-pump-dried at an external temperature of 40 ° C to obtain 45.3 g (yield 74%) of the title compound as a yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 5.17 (1H, s,), 5.00 (1H,
t, J = 6.5Hz), 3.78 (3H, s), 3.48 (1H, dd, J = 2.0, 10.
5Hz), 3.30 (1H, dd, J = 6.5, 11.5Hz), 3.11 (1H, dd,
J = 7.0, 11.5Hz), 2.14 ~ 1.66 (7H, m), 1.12 (3H, d, J =
(7.0Hz) HRMS (FAB) (m / e) calcd for C ₁₁ H ₁₉ O ₃ N ₂ S (MH +) 259.111
6, found 259.1136

Example 14 Methyl (3R, 6S, 9R, 9aR) -6-[[(2
S, 3S) -2-Acetylthio-3-methyl-1-oxo
Sopentyl] amino] -9-methyl-5-oxoocta
Hydrothiazolo [3,2-a] azepine-3-carboxy
Silat

[0122]

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The methyl (3R, 6S,
9R, 9aR) -6-amino-9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylate (35.3 g, 137 mmol) was dissolved in dehydrated tetrahydrofuran (1.00 L), External temperature at 0 ° C (2S, 3S)
A solution of -2-acetylthiopentanoic acid (31.2 g, 164 mmol) in dehydrated tetrahydrofuran (370 ml) was added. In addition, N
-Methylmorpholine (18.0 ml, 164 mmol), 1-hydroxybenzotriazole monohydrate (25.1 g, 164 mmol), 1-
After addition of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC; 31.4 g, 164 mmol), the mixture was stirred under a nitrogen atmosphere while cooling was stopped and gradually returned to room temperature.
After 34 hours, the reaction solution was concentrated under reduced pressure at an external temperature of 40 ° C. After concentration, ethyl acetate (1.3 L) and 0.5N-hydrochloric acid (500 ml) were added to the residue, the ethyl acetate layer was separated, and the aqueous layer was extracted again with ethyl acetate (100 ml). The combined organic layers were combined with water (500 ml) and saturated aqueous sodium bicarbonate (20
After washing with 0 ml × 2), it was dried over anhydrous magnesium sulfate (200 g). After filtration, the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C., and finally dried by a vacuum pump to obtain 58.4 g of a residue as crystals. This was subjected to flash silica gel column chromatography [silica gel: 2.6 kg, eluent: hexane-AcOEt (3: 1), AcOE
t]. The obtained crude crystals were further recrystallized from ethyl acetate to give the title compound as colorless crystals 30.06 g
(51.1% yield). mp 144-145 ° C ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.34 (1 H, d, J = 5.5 Hz), 5.2
1 (1H, s), 5.00 (1H, t, J = 6.5Hz), 4.48 (1H, m), 3.
96 (1H, d, J = 7.0Hz), 3.79 (3H, s), 3.33 (1H, dd, J =
5.5, 11.5Hz), 3.14 (1H, dd, J = 6.5, 11.5Hz), 2.37
(3H, s), 2.18-1.50 (7H, m), 1.15 (1H, m), 1.10 (3
H, d, J = 7.5Hz), 0.98 (3H, d, J = 7.0Hz), 0.88 (3H, t,
J = 7.0Hz) [α] D ²⁵ −138.1 ° (C0.935, CHCl ₃ ) FABMS (m / e) 431 (MH +)

Example 15 (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -3-Methyl-1-oxa-2-mercapto pliers
[Amino] -9-methyl-5-oxaoctahydroti
Azolo [3,2-a] azepine-3-carboxylic acid

[0125]

Embedded image

In a nitrogen atmosphere, methyl (3R, 6S, 9
R, 9Ra) -6-[[(2S, 3S) -2-acetylthio-3-methyl-1-oxopentyl] amino] -9
-Methyl-5-oxooctahydrothiazolo [3,2-
a] Azepine-3-carboxylate (28.67 g, 66.6 mmol
l) was added to degassed 99.5% ethanol (774 ml) to form a suspension, and then the external temperature was set to 0 ° C. To this was added a degassed 1N-lithium hydroxide aqueous solution (333 ml, 333 mmol) dropwise over 15 minutes,
The external bath was removed, and the mixture was stirred under a nitrogen atmosphere while heating to room temperature. After 2 hours, the reaction solution was cooled to an external temperature of 0 ° C., and 2N-hydrochloric acid (233 ml, 466 mmol) was added to make the reaction solution acidic. After stirring for 30 minutes, ethyl acetate (1 L), water (400 ml) and sodium chloride (to a saturated amount) were added, and the mixture was extracted under saline saturation, and the aqueous layer was extracted once more with ethyl acetate (200 ml). The combined organic layers were washed with saturated saline (250 ml), and then anhydrous magnesium sulfate (300 g)
, And the filtrate after filtration was concentrated under reduced pressure at an external temperature of 40 ° C. After concentration to some extent, the remaining water was removed by azeotropic distillation several times with ethyl acetate-ether-hexane in order to remove the remaining water, and the resulting amorphous residue was dried with a vacuum pump. After drying, ethyl acetate (200 ml) was added at 50 ° C. in order to remove inorganic salts mixed in the amorphous. After filtration, the filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. and dried under vacuum. 27.45 g of a crude product of the title compound was obtained as a colorless amorphous. Ethyl acetate (20 ml) was added thereto to dissolve the mixture at an external temperature of 60 ° C., and then ether (250 ml) was gradually added with stirring under heating. Further, hexane (125 ml), which had been preliminarily heated, was gradually added under heating and stirring, and the precipitated crystals were collected by filtration, and 23.7 g of the title compound was obtained.
(95% yield, 97.9% purity by HPLC) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.60 (1 H, d, J = 6.5 Hz), 5.3
0 (1H, s), 5.06 (1H, dd, J = 4.0, 7.0Hz), 4.60 (1H,
m), 3.46 (1H, dd, J = 3.5, 12.0Hz), 3.25 (1H, dd, J =
6.5, 8.5Hz), 3.14 (1H, dd, J = 7.0, 12.0Hz), 2.18−
1.52 (7H, m), 1.86 (1H, d, J = 9.0Hz), 1.23 (1H, m),
1.04 (3H, d, J = 7.0Hz), 1.01 (3H, d, J = 7.0Hz), 0.9
0 (3H, t, J = 7.5Hz) [α] D ²⁷ −104.7 ° (C1.025, CHCl ₃ )

Example 16 (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acetylthio-3-methyl-1-oxopen
[Tyl] amino] -9-methyl-5-oxooctahydro
Thiazolo [3,2-a] azepine-3-carboxylic acid

[0128]

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In a nitrogen atmosphere, dehydrated tetrahydrofuran (3
15 ml) and acetic acid (5.05 ml, 88.2 mmol) were mixed, and the external temperature was cooled to 0 ° C. To this solution was added 1,1'-carbonylbis-1H
-Imidazole (CDI; 12.3 g, 75.6 mmol) was added at once,
The mixture was immediately warmed to room temperature and stirred for 2.5 hours. 0 outside temperature again
And cooled to (3R, 6S, 9R, 9aR) -6.
-[[(2S, 3S) -3-methyl-1-oxa-2-
Mercaptopentyl] amino] -9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-
Dehydrated tetrahydrofuran of carboxylic acid (23.6 g, 63.0 mmol)
(315 ml) solution was added dropwise over 1 hour, and then stirred while warming to room temperature. After 19 hours, the reaction solution was concentrated under reduced pressure at an external temperature of 40 ° C. The concentrated residue was dissolved in ethyl acetate (500 ml), 1N hydrochloric acid (100 ml x 2), water (100 ml x 2), saturated saline (100 m
After washing in the order of l) and drying over anhydrous magnesium sulfate (100 g),
The filtrate was concentrated under reduced pressure at an external temperature of 40 ° C. To 26.77 g of the obtained colorless crystalline residue, methanol (1.
50 ml) was gradually added with stirring, and completely dissolved over 40 minutes. Subsequently, water (75 ml) was gradually added while heating at 50 ° C., and the precipitated crystals were collected by filtration to obtain 23.14 g (yield: 88.2%) of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.30-7.20 (1H, m), 5.28
(1H, s), 5.06 (1H, dd, J = 3.0, 7.0Hz), 4.59 (1H, m),
3.95 (1H, d, J = 7.0Hz), 3.46 (1H, dd, J = 3.0,11.5H
z), 3.13 (1H, dd, J = 7.0, 11.5Hz), 2.39 (3H, s), 2.
16−1.52 (7H, m), 1.18 (1H, m), 1.01 (3H, d, J = 7.0
Hz), 1.00 (3H, d, J = 7.0Hz), 0.89 (3H, t, J = 7.5Hz) [α] D ²⁷ −160.3 ° (C1.175, CHCl ₃ )

Example 17 Methyl (3R, 6S, 9R, 9aR) -6-benzyl
Oxycarbonylamino-9-methyl-5-oxooctane
Tahydrothiazolo [3,2-a] azepine-3-carbo
Xylate

[0131]

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67 g of the oil obtained in Example 10 was dissolved in anisole (54 mL), cooled in an ice bath, trifluoroacetic acid (92 mL) was added, and the mixture was stirred for 3 hours. Ethyl acetate (500 mL) was added to the reaction solution, and N-methylmorpholine (1
54 mL, 1.4 mol) was added dropwise, and 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (5
9g, 0.24mol) and stirred for 24 hours. The reaction solution was diluted with ethyl acetate (3 L) and once with aqueous sodium bicarbonate (2 L).
The extract was washed three times with water (2 L) and once with brine (1 L), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-AcOEt = 2: 1) to give the title compound as an oil (26 g, yield 57%).
Obtained. ¹ H NMR (CDCl ₃ ) δ: 1.11 (3H, d, J = 7 Hz), 1.80−2.18
(5H, m), 3.12 (1H, dd, J = 7Hz, 11Hz), 3.32 (1H, d
d, J = 6Hz, 11Hz), 3.77 (3H, s), 4.32 (1H, dd, J = 6Hz,
10Hz), 4.99 (1H, dd, J = 6Hz, 7Hz), 5.10 (2H, s),
5.20 (1H, s), 6.06 (1H, d, J = 6Hz), 7.30−7.45 (5H,
m) Mass (m / z); 415 (M + Na)

Example 18 Methyl (2RS, 4R) -2-[(1R, 4S) -4
-Benzyloxycarbonylamino-4-carboxy-
1-Methylbutyl] thiazolidine-4-carboxylate
G and methyl (2RS, 4R) -2-[(1
S, 4S) -4-benzyloxycarbonylamino-4
-Carboxy-1-methylbutyl] thiazolidine-4-
Carboxylate

[0134]

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Methyl separately obtained in the same manner as in Example 2.
(2RS, 4R) -2-[(1R, 4S) -4-diphenylmethyloxycarbonyl-4-benzyloxycarbonylamino-1-methylbutyl] thiazolidine-4-
Carboxylate and methyl (2RS, 4R) -2-
A mixture of [(1S, 4S) -4-diphenylmethyloxycarbonyl-4-benzyloxycarbonylamino-1-methylbutyl] thiazolidine-4-carboxylate (67 g, 0.11 mol) was dissolved in anisole (67 mL), and the solution was dissolved in an ice bath. After cooling, trifluoroacetic acid (67 mL) was added dropwise. After dropping, the bath was removed and the mixture was stirred at room temperature for 2 hours.
It was cooled again in an ice bath and a 1.2N hydrochloric acid solution was added. Diisopropyl ether (700 mL) was added to remove the organic layer, and the aqueous layer was made alkaline with sodium bicarbonate. After washing the aqueous layer with diisopropyl ether (700 mL), the aqueous layer is diluted with diluted hydrochloric acid to pH.
Adjusted to 3.26. Toluene (700 mL) was added thereto for extraction, and the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether (120 mL) was added to the residue, and the precipitated crystals were collected by filtration to obtain 17 g (colorless crystals) of the title compound as a mixture. ¹ H NMR (CDCl ₃ ) d: 0.97 (1.5H, d, J = 7Hz), 1.09 (1.5
H, d, J = 7Hz), 1.20−2.10 (5H, m), 2.82 (0.5H, dd,
J = 10Hz, 10Hz), 3.05 (0.5H, dd, J = 5Hz, 11Hz), 3.19
(0.5H, dd, J = 6Hz, 11Hz), 3.28 (0.5H, dd, J = 4Hz, 10
Hz), 3.75 (1.5Hs), 3.78 (1.5H, s), 3.89 (0.5H, dd,
(J = 4Hz, 10Hz), 4.19 (0.5H, dd, J = 5Hz, 6Hz), 4.35−
4.50 (2H, m), 5.11 (2H, s), 5.44−5.52 (1H, m), 7.
30−7.40 (5H, m)

Example 19 Methyl (3R, 6S, 9R, 9aR) -6-benzyl
Oxycarbonylamino-9-methyl-5-oxooctane
Tahydrothiazolo [3,2-a] azepine-3-carbo
Xylate

[0137]

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The methyl (2RS, 4) obtained in Example 18
R) -2-[(1R, 4S) -4-diphenylmethyloxycarbonyl-4-benzyloxycarbonylamino-1-methylbutyl] thiazolidine-4-carboxylate and methyl (2RS, 4R) -2-[(1S,
4S) -4-Diphenylmethyloxycarbonyl-4-
Benzyloxycarbonylamino-1-methylbutyl]
Mixture of thiazolidine-4-carboxylate 2.0
g (4.9 mmol) was dissolved in THF (20 mL), cooled in an ice bath, and added in the order of 1.0 mL (9.9 mmol) of triethylamine and 0.56 mL of ethyl chlorocarbonate. After stirring for 2 hours, 10 mL of 1N aqueous hydrochloric acid solution was added, and ethyl acetate 5 mL was added.
Extracted with 0 mL. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1.46 g (yield 76%) of the title compound as a yellow oil.

Example 20 (3R, 6S, 9R, 9aR) -6-Bendioxycal
Bonylamino-9-methyl-5-oxooctahydroti
Azolo [3,2-a] azepine-3-carboxylic acid

[0140]

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The methyl (3R, 6S,
9R, 9aR) -6-benzyloxycarbonylamino-9-methyl-5-oxooctahydrothiazolo [3,
2-a] azepine-3-carboxylate 1.41 g
(3.6 mmol) was dissolved in THF, cooled in an ice bath, 4.3 mL of 1N lithium hydroxide was added, and the mixture was stirred for 1 hour. After raising the reaction temperature to room temperature and stirring for 6 hours, 21 mL of water and 7 mL of ethyl acetate were added, and the mixture was separated. First, the ethyl acetate layer was washed with 2 mL of a 1N aqueous lithium hydroxide solution, combined with the previous aqueous layer, and the aqueous layer was acidified by adding 6.3 mL of a 1N aqueous hydrochloric acid solution. This was extracted with 21 mL of ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. After adding 5 mL of ethyl acetate to the residue and dissolving by heating,
50 mL of isopropyl ether was added, the mixture was cooled on ice, and the precipitated crystals (colorless) were collected by filtration to obtain 710 mg (yield 53%) of the title compound. mp = 146-147 ° C ¹ H NMR (CDCl ₃ ) δ: 1.01 (3H, d, J = 7 Hz), 1.70-2.15
(5H, m), 3.10 (1H, dd, J = 7Hz, 12Hz), 3.45 (1H, d
d, J = 8Hz, 12Hz), 4.38−4.44 (1H, m), 5.01−5.08 (1
H, m), 5.11 (2H, s), 5.26 (1H, s), 5.96 (1H, d, J =
6Hz), 7.20-7.40 (5H, m)

Example 21 (3R, 6S, 9R, 9aR) -6-amino-9-methyl
Ru-5-oxooctahydrothiazolo [3,2-a] a
Zepin-3-carboxylic acid hydroiodide

[0143]

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Separately obtained in the same manner as in Example 20 (3R,
6S, 9R, 9aR) -6-Bendioxycarbonylamino-9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid 1 g (2.6 mmo
l) was dissolved in 5 mL of acetonitrile, 0.66 mL of trimethylsilyl iodide was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Next, after stirring at room temperature for 20 minutes, 0.32 mL of methanol was added and the mixture was stirred for 30 minutes. 10 mL of isopropyl ether was added, and the precipitated solid was filtered to obtain 0.92 g (yield 93%) of a pale yellow title compound. ¹ H NMR (CD ₃ OD) δ: 1.11 (3H, d, J = 6 Hz), 1.70-1.80
(1H, m), 1.90−2.10 (4H, m), 3.22 (1H, dd, J = 7Hz,
11Hz), 3.30−3.38 (1H, m), 4.17 (1H, d, J = 9Hz),
4.81 (1H, dd, J = 7Hz, 7Hz), 5.33 (1H, s)

Example 22 (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acetylthio-3-methyl-1-oxopen
[Tyl] amino] -9-methyl-5-oxooctahydro
Thiazolo [3,2-a] azepine-3-carboxylic acid

[0146]

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0.14 mL of DMF was dissolved in 2 mL of THF and cooled with ice. 0.25 mL of phosphorus oxychloride was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. (2S, 3S)
251 mg of -2-acetylthio-3-methylpentanoic acid
(1.3 mmol). After stirring for further 20 minutes,
(3R, 6S, 9R, 9aR) -6-amino-9 obtained in
-Methyl-5-oxooctahydrothiazolo [3,2-
a] Azepine-3-carboxylic acid hydroiodide 0.4
8 g (1.32 mmol) and N, O-bis (trimethylsilyl)
Acetamide 1.3 mL, N-methylmorpholine 0.14 m
L was added to a solution of 10 mL of THF dissolved therein. After reacting for 1 hour, 1N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 2 mL of methanol was added to the residue and heated to 40 ° C. 1 mL of water was added, and the mixture was stirred at room temperature for 12 hours.
The precipitated crystals were collected by filtration, and 308 mg of the title compound was obtained (yield 5).
6%).

Example 23 (3R, 6S, 9R, 9aR) -6-amino-9-methyl
Ru-5-oxooctahydrothiazolo [3,2-a] a
Zepin-3-carboxylic acid

[0149]

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Separately obtained in the same manner as in Example 20 (3R,
6S, 9R, 9aR) -6-Bendioxycarbonylamino-9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid 500 mg
(1.32 mmol) was dissolved in 2.5 mL of acetonitrile, 0.37 mL of trimethylsilyl iodide was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Then at room temperature 20
After stirring for 2.5 minutes, 2.5 mL of methanol was added, followed by 2.5 mL of a methanol solution in which 200 mg of sodium acetate was dissolved.
mL was added and stirred for 1 hour. The precipitated solid was filtered to obtain 0.27 g of the colorless title compound (yield: 84%). mp = 258-259 ° C ¹ H NMR (DMSO-d ₆ ) δ: 1.08 (3H, d, J = 7 Hz), 1.60-1.
80 (3H, m), 1.85−2.00 (2H, m), 3.06−3.20 (2H, m),
3.90 (1H, d, J = 7Hz, 7Hz), 5.31 (1H, s)

Example 24 (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acetylthio-3-methyl-1-oxopen
[Tyl] amino] -9-methyl-5-oxooctahydro
Thiazolo [3,2-a] azepine-3-carboxylic acid

[0152]

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[0153] 0.12 mL of DMF was dissolved in 4 mL of THF and cooled with ice. 0.13 mL of phosphorus oxychloride was added dropwise, and the mixture was stirred at the same temperature for 20 minutes. (2S, 3S)
214 mg of -2-acetylthio-3-methylpentanoic acid
(1.1 mmol) was added. After stirring for another 20 minutes, (3R, 6
S, 9R, 9aR) -6-Amino-9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
T in which 0.25 g (1.0 mmol) of carboxylic acid and 0.76 mL of N, O-bis (trimethylsilyl) acetamide are dissolved
Added to 4 mL of HF solution. After reacting for 1 hour, 1N aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 1 mL of methanol was added to the residue, and the mixture was heated to 40 ° C. 0.5 mL of water was added, and the mixture was stirred at room temperature for 12 hours. The precipitated crystals were collected by filtration to give 254 mg (yield 61%) of the title compound.
Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.30-7.20 (1H, m), 5.28
(1H, s), 5.06 (1H, dd, J = 3.0, 7.0Hz), 4.59 (1H, m),
3.95 (1H, d, J = 7.0Hz), 3.46 (1H, dd, J = 3.0,11.5H
z), 3.13 (1H, dd, J = 7.0, 11.5Hz), 2.39 (3H, s), 2.
16−1.52 (7H, m), 1.18 (1H, m), 1.01 (3H, d, J = 7.0
Hz), 1.00 (3H, d, J = 7.0Hz), 0.89 (3H, t, J = 7.5Hz)

Example 25 (2S, 3S) -2-Hydroxy-3-methylpentane
acid

[0155]

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L-isoleucine (100 g, 0.762 mol)
To a 3M sulfuric acid (700 ml, 0.914 mol) solution was added a solution of sodium nitrite (105 g, 1.52 mol) in water (147 ml) at -5 ° C over about 20 minutes, and the mixture was stirred at 0 ° C for 2 hours and at room temperature for 22 hours. did. After adding sodium chloride (100 g) and stirring at room temperature for 30 minutes, the mixture was extracted with ethyl acetate (400 ml × 4). The combined organic layer was distilled off under reduced pressure to obtain 72.4 g (yield: 72%) of the title compound as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.5 Hz), 1.03 (3
H, d, J = 7.0Hz), 1.30 (1H, m), 1.43 (1H, m), 1.89
(1H, m), 4.18 (1H, d, J = 3.5Hz) MS (FAB) m / z: 133 [M + 1] ⁺

Example 26 Methyl (2S, 3S) -2-hydroxy-3-methyl
Pentanate

[0158]

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(2S, 3S) -2-Hydroxy-3-methylpentanoic acid (136 g, 1.03 mol) in methanol (2.0
4 L) The solution was added with concentrated sulfuric acid (2.7 ml, 0.053 mol) and refluxed for 4 hours. After cooling to room temperature, sodium hydrogen carbonate (10.4
g, 0.124 mol), and the mixture was stirred at room temperature for 10 minutes, and then the solvent was distilled off under reduced pressure. Ethyl acetate (500ml) was added and water (300m
l), washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate (300 ml) and a saturated saline solution (300 ml). The organic layer was dried over magnesium sulfate, filtered and the solvent was distilled off under reduced pressure.
126 g (yield: 84%) was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ: 0.90 (3H, t, J = 7.5 Hz), 0.99 (3
H, d, J = 7.0Hz), 1.25 (1H, m), 1.35 (1H, m), 1.80
(1H, br m), 2.69 (1H, d, J = 6.0Hz), 3.79 (3H, s),
4.09 (1H, dd, J = 3.7, 6.0Hz)

Example 27 Methyl (2R, 3S) -2-bromo-3-methylpen
Tanat

[0161]

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Triphenylphosphine (100 g, 0.383 m
ol) in acetonitrile (0.48 L) solution (19.7 ml,
(0.383 mol) was added dropwise at -10 ° C, and the mixture was stirred at 0 ° C for 2 hours. To this solution was added methyl (2S, 3S) -2-hydroxy-3-methylpentanate (40 g, 0.274 mol) at room temperature, and the mixture was stirred for 25 hours. A saturated aqueous sodium hydrogen carbonate solution (600 ml) was added, and the mixture was extracted three times with ethyl acetate (100 ml). The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a mixture of the title compound and triphenylphosphine oxide as a white solid oily mixture. Hexane (300 ml) was added to this mixture, and the mixture was stirred at 0 ° C. for 2 hours. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel: 80 g,
Eluent: Purified with hexane: AcOEt = 4: 1) to give the title compound 53.
0 g (yield: 93%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.05 (3
H, d, J = 6.8Hz), 1.28 (1H, m), 1.46 (1H, m), 1.97
(1H, m), 3.77 (3H, s), 4.24 (1H, dd, J = 6.6Hz) Elemental analysis: calcd for C ₇ H ₁₃ BrO ₂ ; C 40.21, H 6.27; Fo
und C 40.21, H 6.27

Example 28 (2R, 3S) -2-bromo-3-methylpentanoic acid

[0164]

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Methyl (2R, 3S) -2-bromo-3
-Methylpentanate (15.0 g, 71.7 mmol) in acetic acid (1
1M sulfuric acid (150 ml, 150 mmol) was added to the solution (95 ml), and the mixture was refluxed for 9 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. Saturated saline (100 ml) was added, and the mixture was extracted three times with toluene (50 ml). The organic layer was washed with water (100 ml), dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure.
(Yield: 81%) was obtained as a colorless oil. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.5 Hz), 1.07 (3
H, d, J = 6.6Hz), 1.35 (1H, m), 1.52 (1H, m), 2.00
(1H, m), 4.28 (1H, d, J = 6.4Hz)

Example 29 (2S, 3S) -2-acetylthio-3-methylpenta
Acid

[0167]

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(2R, 3S) -2-bromo-3-methylpentanoic acid (80.0 g, 0.41 mol) in acetonitrile (40
0 ml) to the solution, potassium thioacetate (49.2 g, 0.431 mol)
Was added and stirred at 40 ° C. for 3 hours. The solvent was distilled off under reduced pressure, ethyl acetate (415 ml) was added, and the mixture was washed twice with water (356 ml).
The organic layer was dried over magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure. The crude product of the title compound (60.4 g, yield: 77%)
Was obtained as a pale yellow oil. The above crude product (60.0
g, 0.41 mol) in acetonitrile (720 ml) while stirring at room temperature with dicyclohexylamine (62.8 ml, 0.3
15 mol) was added. After the crystals were precipitated, the mixture was stirred in an ice bath for 1 hour, and the precipitate was collected by filtration to obtain 93.8 g of pale yellow crystals. 91.0 g of these crystals were dissolved in ethyl acetate (273 ml) while heating, followed by addition of hexane (273 ml) and stirring in an ice bath for 1 hour. The precipitate was collected by filtration to obtain 62.8 g of pale red crystals. Ethyl acetate (188 ml), 1M potassium hydrogen sulfate (288 ml) and water (70 ml) were added to the crystals and extracted. 1 organic layer
M Washed sequentially with potassium hydrogen sulfate (188 ml) and water (310 ml), and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain 32.5 g (yield: 54%) of the title compound as a brown oil. ¹ H-NMR (CDCl ₃ ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.03 (3
H, d, J = 6.8Hz), 1.24 (1H, m), 1.59 (1H, m), 2.02
(1H, m), 2.38 (3H, s), 4.20 (1H, d, J = 6.2Hz) MS (FAB) m / z: 191 [M + 1] ⁺

The effects of the present invention will be compared with those of the prior art.
First of all, protection of the NH group of piperidine-2-carboxylic acid.
Protecting group is converted from acyl group to R ^TwoConvert to oxycarbonyl group
To obtain perhydrothiazolo [3,2-a] azepine
High yield of R-coordinated optically active substance at substituent 9 at the ring
Improved. That is, a synthesis example of WO96 / 02549A1
NH group of piperidine-2-carboxylic acid shown in 6
Wherein the protecting group is an acetyl group

[0169]

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The following compounds derived from

[0171]

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The yield of 1 was 1 as shown in Synthesis Example 7.
3% (2: 1 isomer ratio of the mixture), but as shown in Examples 10, 11 and 16 of the present invention, the protecting group for the NH group of piperidine-2-carboxylic acid is changed to a methyloxycarbonyl group. (Example 10) A perhydrothiazolo [3,2-a] azepine derivative derived from a compound converted to a t-butyloxycarbonyl group (Example 11) or a benzyloxycarbonyl group (Example 16).

[0173]

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The yield was greatly improved to 33 to 57%.
Second, by using inexpensive L-isoleucine as a starting material, mass production of (2S, 3S) -2-acylthio-3-methylpentanoic acid has become possible. This makes it useful as a therapeutic agent for heart failure (3R, 6S, 9R, 9a).
R) -6-[[(2S, 3S) -2-acylthio-3-
Methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid, especially (3R, 6S, 9R, 9a
R) -6-[[(2S, 3S) -2-acetylthio-3
A more inexpensive industrial process for the production of -methyl-1-oxopentyl] amino] -9-methyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid has been completed.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 277/60 C07D 277/60 // C07M 7:00 (72) Inventor Shinji Suda 2-2 Nishi, Toride-shi, Ibaraki G-1006 (72) Inventor Naoki Yoneda 1-906-306 Takezono, Tsukuba City, Ibaraki Prefecture (72) Inventor Makoto Kotake 144-3 Abiko, Abiko City, Chiba Prefecture 25-9 Arc Flat 205 (72) Inventor Yoshio Fukuda 5th Wakamiya Office, Shinjuku-ku, Tokyo Room 502, Takano Hane, Room 502 (72) Inventor Naoyuki Shimomura 3-32-6, Sakuradai, Ushiku-shi, Ibaraki Prefecture (72) Invention Person Hiroyuki Naka 3-5-9 Matsushiro, Matsushiro, Tsukuba, Ibaraki 103 (72) Inventor Keiji Akamatsu 2-23-5, Akubo, Tsukuba, Ibaraki Maison Gakuen 201 (72) Inventor Juichi Shimizu 3-7-17 Matsushiro Parkside High, Tsukuba-shi, Ibaraki 405 (72) Inventor Toshihiko Naito 616-54 Koshiro, Koshiro, Tsukuba-shi, Ibaraki (72) Inventor Hironori Ikuta 2-35- 12 (72) Inventor Kozo Akasaka 1-47-5 Kamikashida, Ibaraki Prefecture

Claims (24)

[Claims] 1. A compound of the general formula (I) (Wherein, R ¹ and R ² are the same or different from each other, and may be a linear or branched lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, a linear or branched A branched lower alkylsilyl group, a phenacyl group which may have a substituent, a vinyl group or an allyl group, and R ³ represents a linear or branched lower alkyl group.) 5-alkyl-6-oxo-2-piperidinecarboxylic acid derivatives. 2. A compound of the general formula (II) (Wherein, R ¹ , R ² and R ³ represent the same as above, and R ⁴ represents a hydrogen atom or a lower alkyl group).
S) -5-Alkyl-2-piperidinecarboxylic acid derivatives. 3. A compound of the general formula (III) (Wherein, R ¹ , R ² and R ³ represent the same as above, and R ⁵ represents a hydrogen atom, a linear or branched lower alkyl group which may have a substituent, a linear or branched lower alkylsilyl group, (2RS, 4R) -2- which means a group or an allyl group.)
[(1RS, 4S) -butyl] thiazolidine derivative or salt thereof. 4. A compound of the general formula (IV) (Wherein R ² , R ³ and R ⁵ have the same meanings as described above). (2RS, 4R) -2-[(1RS, 4S) -4
[Carboxybutyl] thiazolidine derivative or a salt thereof. 5. A compound of the general formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
5-oxooctahydrothiazolo [3,2-a] azepine derivatives. 6. A compound of the general formula (VI) (Wherein R ² and R ³ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-5-
Oxooctahydrothiazolo [3,2-a] azepine-
3-carboxylic acid derivatives or salts thereof. 7. A compound of the general formula (VII)(Where R¹And R^TwoMeans the above. ) Is an alkyl
Into a compound of the general formula (I)(Where R¹, R^TwoAnd R^ThreeMeans the above. )
(2S) -5-alkyl-6-oxo-2-pipe
A lysine carboxylic acid derivative is obtained and reduced
(II)(Where R¹, R^TwoAnd R^ThreeMeans the above. )so
(2S) -5-alkyl-6-hydroxy-2 shown
-A piperidine carboxylic acid derivative,
Reacting with a cysteine, wherein the group may have a protecting group
And the general formula (III)(Where R¹, R^Two, R^ThreeAnd R^FiveMeans the above. )
(2RS, 4R) -2-[(1RS, 4S)
-Butyl] thiazolidine derivative, and selectively R ¹Escape
By separating, the compound represented by the general formula (IV)(Where R^Two, R^ThreeAnd R^FiveMeans the above. )
(2RS, 4R) -2-[(1RS, 4S) -4
-Carboxybutyl] thiazolidine derivative to obtain a ring-closed
And the general formula (V)(Where R^Two, R^ThreeAnd R^FiveMeans the above. )
(3R, 6S, 9R, 9aR) -9-alkyl-
5-oxooctahydrothiazolo [3,2-a] azepi
Derivative, where R^FiveAnd the compound of the general formula (VI)(Where R^TwoAnd R^ThreeMeans the above. )
(3R, 6S, 9R, 9aR) -9-alkyl-5-o
Oxooctahydrothiazolo [3,2-a] azepine-3
-A carboxylic acid derivative, followed by a protecting group for the amino group.
-CO_TwoR^TwoIs removed to give a compound of the general formula (VIII)(Where R^ThreeMeans the above. ) (3R,
6S, 9R, 9aR) -6-amino-9-alkyl-5
-Oxooctahydrothiazolo [3,2-a] azepine
A -3-carboxylic acid derivative is obtained, which has the general formula (IX):(Where R⁶Represents an acyl group. (2)
(S, 3S) -2-acylthio-3-methylpentanoic acid or
Reacts with a reactive derivative of the acid.
General formula (X)(Where R^ThreeAnd R⁶Means the above. )
(3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopenti
[Amino] -9-alkyl-5-oxooctahydro
Preparation of thiazolo [3,2-a] azepine-3-carboxylic acid
Construction method. 8. A compound of the general formula (I) (Wherein R ¹ , R ² and R ³ have the same meanings as defined above), and the (2S) -5-alkyl-6-oxo-2-piperidinecarboxylic acid derivative represented by the general formula (II): Formula 18 (Wherein, R ¹ , R ² and R ³ have the same meanings as defined above). (2S) -5-Alkyl-6-hydroxy-2-
A piperidine carboxylic acid derivative is obtained, which is then reacted with a cysteine in which a carboxy group may have a protecting group to obtain a compound of the general formula (III) (Wherein, R ¹ , R ² , R ^3, and R ⁴ mean the above). (2RS, 4R) -2-[(1RS, 4S)-
[Butyl] thiazolidine derivative, and R ¹ is selectively eliminated to obtain a compound represented by the general formula (IV): (Wherein, R ² , R ³ and R ⁴ have the same meanings as described above). (2RS, 4R) -2-[(1RS, 4S) -4
[Carboxybutyl] thiazolidine derivative, and ring-closing; (Wherein R ² , R ³ and R ⁴ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
A method for producing a 5-oxooctahydrothiazolo [3,2-a] azepine derivative. 9. A compound of the general formula (II ″)(Where R¹, R^TwoAnd R^ThreeRepresents the above, and R^Four’Is straight
A chain or branched lower alkyl group is meant. )
(2S) -5-alkyl-6-alkoxypiperidine induction
A system in which a carboxy group may have a protecting group on the conductor
And reacting with a compound of the general formula (III)(Where R¹, R^Two, R^ThreeAnd R^FiveMeans the above. )
(2RS, 4R) -2-[(1RS, 4S)
-Butyl] thiazolidine derivative, and selectively R ¹Escape
When separated, the compound represented by the general formula (IV)(Where R^Two, R^ThreeAnd R^FiveMeans the above. )
(2RS, 4R) -2-[(1RS, 4S) -4
-Carboxybutyl] thiazolidine derivative, and ring closure
General formula (V) characterized by the following:(Where R^Two, R^ThreeAnd R^FiveMeans the above. )
(3R, 6S, 9R, 9aR) -9-alkyl-
5-oxooctahydrothiazolo [3,2-a] azepi
A method for producing a derivative. 10. A compound of the general formula (VII) (Wherein R ¹ and R ² have the same meanings as defined above), and are alkylated to obtain a compound of the general formula (I). (Wherein, R ¹ , R ² and R ³ have the same meanings as described above). (2S) -5-alkyl-6-oxo-2-piperidinecarboxylic acid derivative represented by the following formula: 11. A compound of the general formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
R ⁵ of the ⁵ -oxooctahydrothiazolo [3,2-a] azepine derivative is eliminated to give a compound of the general formula (VI). (Wherein R ² and R ³ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
-Carboxylic acid derivative, and then a protecting group for amino group -C
O ₂ R ² is eliminated to give a compound of the general formula (VIII) (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-amino-9-alkyl-5
-Oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative was obtained, which had the general formula (IX) (Wherein, R ⁶ has the same meaning as described above).
3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid is reacted with a general formula (X) (Wherein, R ³ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 12. A compound of the general formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
R ⁵ of the ⁵ -oxooctahydrothiazolo [3,2-a] azepine derivative is eliminated to give a compound of the general formula (VI). (Wherein R ² and R ³ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3
-Carboxylic acid derivative, and then a protecting group for amino group -C
Wherein O ₂ R ² is eliminated.
I) (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-amino-9-alkyl-5
-A process for producing oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 13. A compound of the general formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
R ^{5 of the 5} -oxooctahydrothiazolo [3,2-a] azepine derivative and the protecting group for the amino group —CO ₂ R ² are simultaneously eliminated to obtain a compound of the general formula (VIII). (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-amino-9-alkyl-5
-Oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative was obtained, which had the general formula (IX) (Wherein, R ⁶ has the same meaning as described above).
3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid is reacted with a general formula (X) (Wherein, R ³ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative production method 14. A compound of the formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
Wherein R ^{5 of the} 5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative and an amino-protecting group —CO ₂ R ² are simultaneously eliminated. ) (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-amino-9-alkyl-5
-A process for producing oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 15. A compound of the general formula (VIII) (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-amino-9-alkyl-5
-Oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative and a compound of the general formula (IX) (Wherein, R ⁶ has the same meaning as described above).
3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid is reacted with a compound represented by the general formula (X): (Wherein, R ³ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 16. A compound of the formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
The protecting group -CO ₂ R ² for the amino group of the 5-oxooctahydrothiazolo [3,2-a] azepine derivative is eliminated to give a compound of the general formula (XI). (Wherein, R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-6-amino-5-oxooctahydrothiazolo [3,2-a ]
An ester derivative of azepine-3-carboxylic acid is obtained, which has the general formula (IX) (Wherein, R ⁶ has the same meaning as described above).
3S) -2-Acylthio-3-methylpentanoic acid or a reactive derivative of the acid is reacted with a compound of the general formula (XIII). (Wherein, R ³ , R ⁵ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2
(S, 3S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine derivatives are obtained, followed by R ⁵ and R ^{5 6} is removed to give a compound of the general formula (XIII) (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -6-[[(2S, 3S) -3-
Methyl-2-mercapto-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid and then acylating the -SH group. Characteristic general formula (X) (Wherein, R ³ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 17. A compound of the general formula (V) (Wherein R ² , R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-
The protecting group -CO ₂ R ² for the amino group of the 5-oxooctahydrothiazolo [3,2-a] azepine derivative is eliminated to give a compound of the general formula (XII): (Wherein, R ³ and R ⁵ have the same meanings as defined above). (3R, 6S, 9R, 9aR) -9-alkyl-6-amino-5-oxooctahydrothiazolo [3,2-a ]
An azepine derivative is obtained, which then has the general formula (IX) (Wherein, R ⁶ represents an acyl group.)
General formula (XII) characterized by reacting with (S, 3S) -2-acylthio-3-methylpentanoic acid or a reactive derivative of the acid. (Wherein, R ³ , R ⁵ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2
(S, 3S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine derivatives. 18. A compound of the general formula (V ') (Wherein, R ³ and R ⁵ represent the same as above, and R ² ′ represents a linear or branched lower alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, (3R, 6S, 9R, 9aR) -9-alkyl-5 represented by a linear or branched lower alkylsilyl group, a phenacyl group, a vinyl group or an allyl group which may have a substituent.
-The protecting group for the amino group of -oxooctahydrothiazolo [3,2-a] azepine derivative -CO ₂ R ² 'is selectively eliminated to obtain a compound of the general formula (XI'). (Wherein, R ³ represents the same as described above).
6S, 9R, 9aR) -9-Alkyl-6-amino-5
-Oxooctahydrothiazolo [3,2-a] azepine derivative having the general formula (IX) (Wherein, R ⁶ represents an acyl group.)
Reaction with (S, 3S) -2-acylthio-3-methylpentanoic acid gives a compound of the general formula (XII ′) (Wherein, R ³ and R ⁶ represent the same as above, and R ⁵ ′ represents a linear or branched lower alkyl group which may have a substituent, a linear or branched lower alkylsilyl group, or an allyl group. (3R, 6S, 9R, 9aR) -6-
[[(2S, 3S) -2-acylthio-3-methyl-1
-Oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-
A carboxylic acid derivative is obtained, and then R ⁵ ′ is eliminated. (Wherein, R ³ and R ⁶ have the same meanings as above.) (3R, 6S, 9R, 9aR) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 19. A compound of the general formula (XI ″) (Wherein, R ³ represents the above, and R ⁵ ″ represents a t-butyl group.) (3R, 6S, 9R, 9aR) —
A 9-alkyl-6-amino-5-oxooctahydrothiazolo [3,2-a] azepine derivative has the general formula (IX): (Wherein, R ⁶ has the same meaning as described above).
3S) -2-Acylthio-3-methylpentanoic acid is reacted with a compound of the general formula (XII ″). (Wherein, R ³ and R ⁶ represent the same as described above, and R ^{5 ″} represents a t-butyl group.) (3R, 6S, 9R, 9)
aR) -6-[[(2S, 3S) -2-acylthio-3
-Methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative, followed by selective elimination of R5 ^" Having the general formula (X): (Wherein, R ³ and R ⁶ have the same meanings as described above). (3R, 6S, 9R, 9Ra) -6-[[(2S, 3
S) -2-Acylthio-3-methyl-1-oxopentyl] amino] -9-alkyl-5-oxooctahydrothiazolo [3,2-a] azepine-3-carboxylic acid derivative. 20. L-isoleucine Is converted to a hydroxyl group to obtain (2S, 3S)
-2-Hydroxy-3-methylpentanoic acid And then convert the hydroxyl group to a bromo atom,
The ester moiety is hydrolyzed to give (2S, 3S) -2-bromo-3-methylpentanoic acid And acylthiolating the compound to obtain a compound of the general formula (XIV): (Wherein, R 6 means the same as above) (2S,
3S) A method for producing 2-acylthio-3-methylpentanoic acid. 21. The compound according to any one of claims 1 to 6 or the production method according to any one of claims 7 to 18, wherein R ³ is a methyl group. 22. R ¹ is a benzhydryl group, t-butyl group or 4-nitrophenylmethyl group, and R ² is a linear or branched lower alkyl group, a benzhydryl group or
A nitrophenylmethyl group, R ³ is a methyl group, R ⁵ is a methyl group or an ethyl group, and R ⁶ is an acetyl group, The compound according to any one of claims 1 to 6,
Or the manufacturing method according to any one of claims 7 to 19. 23. The compound according to claim 1, wherein R ¹ is a benzhydryl group, R ² is a benzyl group, R ³ and R ⁵ are methyl groups, and R ⁶ is an acetyl group. Or the method according to any one of claims 7 to 18. 24. The method according to claim 20, wherein R ⁶ is an acetyl group.