FI81089C - 4-PIPERIDYL-SUBSTITUERADE KARBOXYLSYRADERIVAT OCH FOERFARANDE FOER DERAS FRAMSTAELLNING. - Google Patents

Description

1,81089 4-Piperidyl-substituted carboxylic acid derivatives and process for their preparation 4-Piperidyl-substituted carboxylic acid derivatives and a process for their preparation This application is divided into FI patent application 851154.

The invention relates to novel 4-piperidyl-substituted carboxylic acid derivatives which can be used as intermediates in the preparation of medically useful condensed seven-membered ring compounds. The invention also relates to methods for preparing novel derivatives.

The invention relates to a compound of formula R 6 - A - E-COOR 3 (L) wherein R 3 is hydrogen or C 1-4 alkyl; R 6 is 1-benzyloxycarbonyl-4-piperidyl; A is C 2-4 alkylene and E is ^ C = O or a group represented by the formula ^: CH-Wa wherein Wa is halogen or a group represented by the formula RaSC> 2-O-, wherein Ra is C 1-4 alkyl, trifluoromethyl , phenyl or p-tolyl, or a pharmaceutically acceptable salt thereof.

2 81089

The final compounds (I) show an inhibitory effect on the angiotensin converting enzyme and are useful as medicinal substances in circulatory diseases such as hypertension, heart disease and stroke.

The final product compounds are represented by the formula:

C 11-1 n -COOR * wherein R 1 and are independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both together form tri- or tetramethylene; R 1 is independently hydrogen, lower alkyl or aralkyl; R 4 is hydrogen or lower alkyl; n is 1 or 2; and R3, R® and A have the same meaning as above, and their salts. The final product compounds and methods for their preparation are set out in the parent application FI 851154 of this application.

The lower alkyl group represented by R 3 or Ra comprises alkyl groups containing about 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

The alkylene chain represented by A comprises, for example, straight-chain or branched alkylene chains containing about 2 to 6 carbon atoms, examples of which are divalent groups such as ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or propylene, ethylmethylene. Said alkylene chains may have an unsaturated bond or unsaturated bonds in the chain (e.g. a double bond, a triple bond).

Il 3 81089

Particularly preferred compounds of formula (L) are ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyloxyhexanoate, ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorohexanoate and ethyl 6- (1-benzyl-lioksikarbonyyli-4-piperidyl) -2-oxohexanoate.

The compounds of the invention and their salts can be prepared by a) a compound of the formula R 6 -A-COOR 3 'wherein R 1 and A are as defined above and R 3' is lower alkyl or aralkyl, and a compound of the formula COOR 3 ' 'COOR3' 'wherein R3' 'is lower alkyl or aralkyl is reacted in the presence of a base, followed by heating, and if desired b) a compound of formula (L) wherein E is ^ C = O is subjected to a reduction reaction followed by halogenation. or a sulfonylation reaction, and if desired c) a compound of formula (L) wherein R 3 is lower alkyl or aralkyl is hydrolysed to give a compound of formula (L) wherein R 3 is hydrogen, and if desired 4,81089 d) a compound of formula The compound of (L) is converted to its bog-lax i.

The preparation of compounds (L), i.e. compounds of formulas (IV) and (VIII), is described in the following reaction formula.

R6-A-COOR3 '-1 r6-acco-r3 "(xxxvni) ® ° (ΥΠΙ ·) _r R6-A-CH-COOR3" - * hm (IL) R6-A-CH-COOR3' -> R6- A = H-COOR 3

Wa Ka (IV *) (IV)

In the above reaction scheme, R 3 'and R 3' * are independently lower alkyl corresponding to R 3; other symbols are as previously defined.

Compound (VIII ') can be prepared by subjecting compounds (XXXVIII) and (XXXIX) to a condensation reaction in the presence of a base such as sodium ethoxide, followed by heating in the presence of aqueous dimethyl sulfoxide, lithium chloride, etc. Compound (IV ') can be prepared by subjecting compound (VIII') as such to a known reduction reaction and then subjecting the resulting compound (IL) as such to a known halogenation or sulfonylation reaction.

The starting compound (XXXVIII) can be easily prepared, for example, by reacting a compound of formula: I! 5 81 089 r6-A'-CH-COOR3 '

Wh (where Wh is halogen; A 'represents A as A'-CH2; other symbols are as previously defined) to a reduction reaction known per se.

When R 6 has a group which may interfere with the reaction, the reaction may be carried out by protecting said group with a protecting group such as lower (C 1-5) alkanoyl (e.g. acetyl), benzoyl, phenyl-lower (C 1-4) alkoxycarbonyl (e.g. Bent -syloxycarbonyl), lower (C 1-4) alkoxycarbonyl (e.g. tert-butoxycarbonyl), etc.

Compounds of formulas (VIII '), (IL) and (IV') in which R 1 is hydrogen can be readily prepared by subjecting compounds (VIII '), (IL) and (IV') to a hydrolysis reaction, respectively.

The compounds of formulas (VIII) and (IV) are novel compounds and are industrially preferred as an intermediate in the synthesis of a novel compound (I) useful as a medicament.

The desired condensed seven-membered ring compounds (I) as final products can be prepared from intermediates of formula (L) by giving a compound of formula:

CnE2n-COOR5 6 81089 (wherein each of the symbols is as previously defined) reacts with a compound of formula: R6-A-CH-COOR3 (IV)

Wa (wherein Wa is halogen or a group represented by the formula RaSO2-O- (wherein Ra is lower (C1-4) alkyl, trifluoromethyl, phenyl or p-tolyl); other symbols are as previously defined). The reaction can be allowed to proceed by normally keeping both compounds without solvent or in the presence of water or another organic solvent (e.g., acetonitrile, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, benzene, toluene) alone or as a mixture thereof at a temperature in the range of about -20 to + 150 ° C. In this case, for the purpose of accelerating the reaction rate, it is possible to allow a base such as potassium carbonate, sodium hydroxide, sodium hydrogencarbonate, pyridine or triethylamine to be present in the reaction systems at the same time.

A compound of formula (I) wherein R 4 is hydrogen may be prepared, for example, by reacting a compound of formula: li 7 81089 ‘Prt“

CnH2n-COOR5 (wherein each of the symbols is as previously defined) and a compound of formula: R3-O-C-C-A-R6 (VIII)

Il H O o (where each of the symbols is as previously defined) to a condensation reaction under reducing conditions.

Said reducing conditions include catalytic reduction reaction conditions using a metal such as platinum, palladium or rhodium or a mixture thereof with an arbitrary support as a catalyst; reduction with a metal hydride compound such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride or sodium cyanoborohydride; reduction with sodium metal, magnesium metal, etc. and alcohols; reduction with a metal such as iron or zinc and an acid such as hydrochloric acid or acetic acid; electrolytic reduction; reduction with a reducing enzyme and so on. The above reaction is normally carried out in the presence of water or an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide) and the reaction temperature generally depends on the solvent used. 20 ... + 100 ° C. The reaction can be carried out at atmospheric pressure to obtain the desired result satisfactorily, but can also be carried out under pressure or under reduced pressure, depending on the conditions.

The compound (I) thus obtained can be isolated from the reaction mixture by conventional separation and purification means, for example, β 81089 such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin layer chromatography.

compound (I) may exist as at least four stereoisomers. These independent isomers and mixtures thereof can be prepared independently. For example, a single optical isomer of compound (I) can be obtained by carrying out the above reaction using a single isomer of each of the starting compounds (III), (IV) and (VII), and when the product is a mixture of at least two isomers, it can also be separated into individual isomers by separation methods such as methods. to form salts with optically active acids (e.g. camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.) or optically active bases (e.g. cinchonine, cinchonidine, quinine, quinidine, methylbenzylamine, dehydroabietylamine, etc.) in large quantities, by fractional recrystallization.

The fused seven-membered ring compounds represented by the formula (I) and their salts show an inhibitory effect on angiotensin converting enzyme and bradykinin degrading enzyme (kininase), etc., in animals, certain mammals (e.g. human, dog, rabbit, cat, cat). and are useful, for example, as drugs in the diagnosis, prevention and treatment of hypertension, and circulatory diseases induced by hypertension, such as heart disease and stroke. Compound (I) has low toxicity, is well adsorbed when administered orally, has excellent longevity and is very stable, and when used as the above drugs, can therefore be safely administered orally or parenterally as such or in admixture with suitable pharmaceutically acceptable carriers, excipients or diluents. in pharmaceutical forms such as powders, granules, tablets, capsules and injectable solutions.

The starting compounds (III) and (VII) can be easily prepared, for example, by the methods described in the following reaction formulas.

COOH - (XXVI); WSC ^ CH ^ J E

R2 zvxmT> ΧΛϊ02 <* »Η 0 (XXH) & (XXI)

VrSCH2f "VO - fo ^ y / n

COOHO

(XXX) (XXX) ifc-CnHo n — COOR5 / τπΛ —5— © CVOO - »r2 | 0 Tcxx2)

CnHan — CCQR5 «> - jDC ^ ·

CnH-n-COOR5 s * I 13

CaBjjn-COOR 5

In the process for preparing compounds (III) and (VII), the amino group of compound (XXVI) is primarily protected with a suitable amino-protecting group (e.g., a phthaloyl group) to prepare compound (XXVIII). This reaction is allowed to proceed easily by condensation of compound (XXVI) with compound (XXVII) in the presence of a base (e.g. sodium carbonate, potassium carbonate, potassium hydrogen carbonate) normally at a temperature between 0 ... + 100 <> C. Reaction (XXVIII) -> (XXIX) is a reduction reaction of a nitro group to an amino group 10 81 089 and conventionally known reduction techniques can be used. Reduction techniques include catalytic reduction using, for example, palladium on carbon, palladium with a barium sulfate support, sulfated palladium, platinum, etc., reduction with a metal such as zinc, tin, stannous chloride or iron, and acid or alkali, and so on. The dehydrating ring closure reaction of the resulting compound (XXIX) to the compound (XXX) can be carried out preferably by a conventionally known dehydrating coupling agent. Such dehydrating coupling agents include, for example, dicyclohexylcarbodiimide, carbonyldiimidazole, diethylphosphorus cyanidate, etc. As the solvent, for example, dioxane, methylene chloride, acetonitrile, N, N-dimethylformamide, etc., tetrahydrofuran are used. normally at a temperature between -10 ... + 100 ° C. In order to advantageously proceed with the reaction in such a case, it may also be possible to add a base such as triethylamine or pyridine to the reaction solution as a catalyst. The preparation of compound (XXXI) via a condensation reaction between compounds (XXX) and (VI) can be carried out normally by condensation in a solvent such as Ν, Ν-dimethylformamide, dimethyl sulfoxide or acetonitrile in the presence of a base such as sodium hydride or potassium carbonate at a temperature between -10. + 100 ° C. The reaction (XXXI) -> (VII) can then be carried out by treatment with hydrazine hydrate in a solvent such as methanol, ethanol or dioxane at a temperature between -10 ° C and + 100 ° C to prepare compound (VII).

Reaction (VII) -> (III) is a conventional alkylation reaction, and such an alkylation process includes, for example, a process in which the reaction occurs with a lower alkyl aldehyde corresponding to the group R * under reducing conditions and a process in which the reaction takes place with a compound (XX) in a suitable solvent.

In the above processes for the preparation of the compound (I) and its intermediate 81089, the compounds used in the reactions can be used in the form of salts such as salts of an inorganic acid such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., organic acid salts such as as examples of acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, etc., as metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt, etc., and as salts with bases such as triyl guanidine salt, ammonium salt, hydrazine salt, quinine salt, quinone salt, etc., as long as they do not interfere with these reactions.

The following reference examples illustrate the preparation of starting materials, the examples illustrate the preparation of novel compounds, and the use examples illustrate the use of novel compounds to prepare preferred end products. The examples in no way limit the present invention.

Reference Example 1

To an aqueous solution (200 ml) of 1.4 g of sodium carbonate is dissolved 2.9 g of S- (o-nitrophenyl) -L-cysteine and 3.5 g of N-ethoxycarbonylphthalimide are added to the solution with stirring. After the mixture is stirred for 5 h at room temperature, the insoluble matter is removed by filtration, and the filtrate is made weakly acidic with concentrated hydrochloric acid. The crystals which separate are collected by filtration and recrystallized from 30 ml of ethanol to give 3.6 g of 3- (o-nitrophenyl) thio-2 (R) -phthalidopropionic acid as pale yellow needles, m.p. 220-222 ° C.

Elemental analysis, C 17 H 12 N 2 O 6 S Calculated: C, 54.84; H, 3.35; N, 7.53 Found: C, 54.46; H, 3.26; N, 7.46 (oi) 24-790 (C = or9 in methanol) δ u 81089

Reference Example 2,3 To 300 ml of methanol is added 10 g of 3- (o-nitroenyl) thio-2 (R) -phthalimidopropionic acid, which is catalytically reduced at ordinary temperature under atmospheric pressure using 5% palladium on carbon as a catalyst. After the calculated amount of hydrogen has been absorbed, the catalyst is removed and the methanol is evaporated off under reduced pressure. Ether and petroleum ether are added to the residue, and the precipitated yellowish crystalline powder is collected by filtration to give 8.4 g of 3- (o-aminophenyl) thio-2 (R) -phthalimidopropionic acid. This product (8.4 g) is dissolved in 50 ml of dimethylformamide and 5.5 g of diethylphosphorocyanidate are added dropwise to the solution under ice-cooling with stirring. When the addition is complete, the mixture is stirred for 5 min and 2.28 g of triethylamine are added dropwise under ice-cooling. The mixture is stirred under ice-cooling for 30 minutes and then at room temperature for 1 h. Water (200 ml) is added to the reaction solution and the mixture is allowed to stand overnight. The precipitated solid is collected by filtration and dried. This product is purified by silica gel chromatography (dichloromethane: ethyl acetate = 2: 1) to give 5.4 g of 3 (R) -imidido-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one as colorless prisms, m.p. 202-205 ° C.

Elemental analysis, C 17 H 12 N 2 O 3 S Calculated: C, 62.95; H, 3.73; N, 8.64 Found: C, 63.15; H, 4.02; N, 8.49 (o () 21-164 ° (c = 0.9 in methanol)

O

Reference Example 3 To 50 ml of dimethylformamide is added 0.5 g of sodium hydride (60% in oil) and the mixture is stirred under ice-cooling. 3 (R) -Phthalimido-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one (4 g) obtained in Reference Example 2 is added to the mixture under ice-cooling, followed by stirring for 5 min. To the mixture is further added tert-butyl chloroacetate (2 g) under ice-cooling, and after stirring for 15 minutes under ice-cooling, ice-cold water (200 ml) is added to the reaction solution. The precipitated crystals are collected by filtration, dried and purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 4 g of tert-butyl-4-oxo-3 (R) -phthalimido-2,3,4,5-tetrahydro 1,5-benzothiazepine-5-acetate as colorless crystals. Recrystallization of part of the compound from ethyl ether gives colorless prisms, m.p. 181-184 ° C. Elemental analysis, C 23 H 22 N 2 O 5 S Calculated: C, 63.01; H, 5.06; N, 6.39 Found: C, 62.95; H, 5.10; N, 6.34 (o () E 0 - 156 ° (c = 0.9 in chloroform)

Reference Example 4 To 100 ml of ethanol is added 4 g of the tert-butyl-4-oxo-3 (R) -phthalimido-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-t obtained in Reference Example 3. acetate and 1.4 g of hydrazine hydrate and the mixture is heated to reflux with stirring for 1 h. The reaction solution is concentrated under reduced pressure, and 300 ml of ethyl acetate and 100 ml of water are added to the residue, followed by shaking thoroughly. The ethyl acetate layer is washed successively with dilute aqueous sodium hydroxide solution and water, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is crystallized from a mixture of ether and petroleum ether to give 2 g of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as colorless prisms. , sp 86-89 ° C.

Elemental analysis, C 15 H 20 N 2 O 3 S Calculated: C, 58.42; H, 6.54; N, 9.08 Found: C, 58.73; H, 6.48; N, 9.13 (K) 20-238 ° (c = 1 in methanol)

Reference Examples 5 to 9 Using substituted o-nitroaniline derivatives as a starting material, the reaction is carried out in the same manner as in the synthesis of unsubstituted tower derivatives (R = H) to give the compounds shown in Table 1.

Table 1 NH2

* 1, S v COOH

Reference.

eg R Config. m.p., C ° [α] D IN salt.

No .__ I * 1 ___ in acid__ 5 4-CH3 R 156-158 + 44 · 6 4-OCH3 R 166-168 + 24 ° 7 4,5- (CH2) 3 ”R 157-158 + 33 ° 8 4-Cl R 169 -171 + 46 * 9 4-CF3 R 181-183 + 53 ·

Reference Examples 10 ... 13

In the same manner as in Reference Example 1, the S- (2-nitrophenyl) -L-cysteine derivatives obtained in Reference Examples 5 to 8 are reacted with N-ethoxycarbonylphthalimide to give the compounds shown in Table 2.

Il 15 81 089

Table 2 .. j »°

5 ---- ii ^ COOH

4 W-VnO 2

Reference, e.g., Config. m.p., C ° lalp

Ko ._____ in methanol i 10 4-CH3 R Used (in the following reaction) without purification 11 4-OCH3 R 157-159 -120 ° 12 4,5- (CK2) 3 ”R 219-222 -149» 13 4-Cl R 183 -185 -116 »

Reference Examples 14 ... 17

The phthalimide derivatives obtained in Reference Examples 10 to 13 are subjected to a reaction similar to that described in Reference Example 2 to give the compounds shown in Table 3.

Table 3

Reference ^ e.g. j Config. m.p., ° C

Well. 1_2_ »1 [<Od 14 7-CH3 R 222-225 -180» (in methanol) 15 7-OCH3 R 255-258 -34 »(in chloroform) 16 7.8- (CH2) 3- R 240-243-136 »(In methanol) 17 7-C1 R 256-258 -169» (in methanol)

Reference Examples 18 ... 21 16 81 089

The phthalimidobenzothiazepine derivatives obtained in Reference Examples 14 to 17 are subjected to a reaction similar to that described in Reference Example 3 to give the compounds shown in Table 4.

Table 4 ΐφΟτφο CHoCOOC (CH3) 3

Reference 2 J J o r,

e.g. n Config. B.p., C [ajD

Well. ____ »1 ^ __ (in methanol) 18 7-CH3 R 140-143 -151 ° 19 7-OCH3 R 155-157 -139 ° 20 7.8- (CH2) 3- R 195-198 -114 * 21 7- Cl R 182-184 -148 ·

Reference Examples 22 ... 25

The tert-butyl phthalaidobenzothiazepine acetate derivatives obtained in Reference Examples 18 to 21 are subjected to a reaction similar to that described in Reference Example 4 to give the compounds shown in Table 5.

Il it 81089

Table 5

Reference R CK2COOC (CH3) 3

e.g., R Config.p., C ° [e] D

Well. _ * 1 ___ (in methanol) _ 22 7-CH3 R 159-160 -146 ° (oxalate) 23 7-OCH3 R 175-178 -147 ° (hydrochloric acid) 24 7.8- (CH2) 3 “R is reacted in the next reaction without purification 25 7-C1 R 158-160 I -102e (Oxalate) *

Reference Example 26 To 67 ml of 0.25 N aqueous sodium hydroxide solution was added 5.3 g of S- (2-nitro-4-trifluoromethylphenyl) -L-cysteine obtained in Reference Example 9, and after stirring for 30 minutes at room temperature, 2.7 ml of benzyloxycarbonyl chloride and 19 ml of 1N aqueous sodium hydroxide solution are simultaneously added dropwise under ice-cooling over 30 minutes, followed by stirring at room temperature for 2.5 h. The reaction solution is extracted with ethyl ether and the aqueous layer is slightly acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and ethyl ether is added to the resulting residue to precipitate 5.5 g of S- (2-nitro-4-trifluoromethylphenyl) -N-benzyloxycarbonyl-L-cysteine as pale yellow crystals. 150-153 ° C.

(oOd + 20 ° (in methanol)

Elemental analysis, C 18 H 15 F 3 N 2 O 6 S Calculated: C, 48.65; H, 3.40; N, 6.30 Found: C, 48.68; H, 3.41; N, 6.27

Reference Example 27 IE 81089

To a mixture of 50 ml of acetic acid and 50 ml of water are added 4.3 g of S- (2-nitro-4-trifluoromethylphenyl) -N-benzyloxycarbonyl-L-cysteine obtained in Reference Example 26 and 4 g of zinc powder, followed by stirred at room temperature for 50 min. Water (150 ml) and 150 ml of ethyl acetate are added to the mixture, and the insoluble matter is filtered off. The aqueous layer is further extracted twice with 100 ml of ethyl acetate, and the ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in 50 ml of ethyl ether and 5 ml of hydrochloric acid-ethyl acetate solution (5N) are added to give 3.4 g of S- (2-amino-4-trifluoromethylphenyl) -N-benzyloxycarbonyl-L-cysteine hydrochloride as a yellowish powder. . This product is dissolved in 30 ml of dimethylformamide and a solution of 0.78 g of triethylamine in 5 ml of dimethylformamide is added dropwise with stirring under ice-cooling over 10 minutes, followed by dropwise addition of a solution of 1 over 5 minutes. 83 g of diethyl phosphorus cyanidate in 5 ml of dimethylformamide and a solution of 0.78 g of triethylamine in 5 ml of dimethylformamide is added. The reaction solution is stirred for 30 min under ice-cooling and then at room temperature for 2.5 h, after which 200 ml of water are added. The mixture is extracted with ethyl acetate, and the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 to 2: 1) to give 1.3 g of 3 (R) -benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one as a colorless crystalline powder, m.p.

120 ... 123 <> C.

(<X) d ”161 ° (in methanol)

Elemental analysis, C 18 H 15 F 3 N 2 O 3 S Calculated: C, 54.54; H, 3.81; N, 7.07 Found: C, 54.79; H, 3.90; N, 7.09

Reference Example 28 19 81 81 089 1.1 g of 3 (R) -benzyloxycarbonylamino-7-trifluoromethyl-2,3-dihydro-1,5 (5H) -benzothiazepine obtained in Reference Example 27 are dissolved in 20 ml of dimethylformamide. 4-one and 0.46 g of tert-butyl chloroacetate, 0.42 g of potassium carbonate and 0.1 g of potassium iodide are added to the solution, followed by stirring at room temperature for 4.5 h. Water (100 ml) is added to the reaction solution, and the mixture is extracted with 100 ml of ethyl acetate. . The extract was washed successively with 0.1N hydrochloric acid, aqueous sodium hydrogencarbonate solution and water, and the mixture was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.4 g of tert-butyl-3 (R) -benzyloxycarbonylamino-4-oxo-7 trifluoromethyl 2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless viscous substance.

IR nujol cm-1; 1680 (amide), 1710 (urethane), 1740 (ester) v max * IR: (means infrared absorption spectrum; the same is used hereinafter).

Reference Example 29 1.4 g of tert-butyl-3 (R) -benzyloxycarbonylamino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-acetic acid are dissolved in 5 ml of acetic acid. -benzothiazepine-5-acetate and 10 ml of 30% hydrobromic acid solution are added to the solution, then the mixture is allowed to stand at room temperature for 4 h. Petroleum ether (100 ml) is added to the reaction solution and the mixture is shaken thoroughly, after which the supernatant is decanted. After re-addition of petroleum ether to repeat the same procedure, the residue is dissolved in a mixture of ethyl acetate and benzene, and the mixture is concentrated to dryness under reduced pressure. Petroleum ether is added to the residue to give 0.75 g of 3 (R) -amino-4-oxo-7-trifluoromethyl-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrobromide as crystals.

20 81 089

mp: 176-180 ° C

Initial analysis, C12H11F3N2O3S · HBr · H2O Calculated: C, 34.38; H, 3.37; N, 6.68 Found: C, 34.40; H, 3.60; N, 6.66

Reference Example 30 Any dimethylformamide is dissolved in 6.48 g of 3 (R) -phthalimido-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one obtained in Reference Example 2, and 6.27 g is added to the solution. g of tert-butyl 2-bromopropionate, 5.5 g of potassium carbonate and 0.5 g of potassium iodide, followed by stirring at room temperature overnight. Water (200 ml) is added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is washed successively with 200 ml of 0.5N hydrochloric acid and 100 ml of saturated aqueous sodium hydrogencarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silica gel chromatography (hexane: ethyl acetate = 3: 1 to 2: 1) to give 7.8 g of tert-butyl-3 (R) -phthalimido-4-oxo-2,3,4 .5-Tetrahydro-1,5-benzothiazepin-5-o (-ethyl acetate) as a colorless powder.

IR .neat cm-1: 1770, 1730, 1720, 1680 (C = O)

K

max

Elemental analysis, C 24 H 24 N 2 O 5 S * 1 / 2H 2 O Calculated: C, 62.46; H, 5.46; N, 6.07 Found: C, 62.62; H, 5.14; N, 6.13

Reference Example 31

In the same manner as in Reference Example 4, 7.6 g of the tert-butyl 3 (R) -phthalimido-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5- obtained in Reference Example 30 were obtained. -methyl acetate is treated with hydrazine hydrate to give 5.4 g of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-c-ethyl acetate as a pale yellow as an oil.

il 2i 81089 IR neat cm-1: 1735, 1670 (C = 0)

P

max (oOd "223 ° (c = 0.5 in methanol)

Mass spectrum (m / e): 322 (M +)

Reference Example 32 A mixture of 3 (R) -phthalimido-2,3-dihydro-1,5- (5H) -benzothiazepin-4-one (10 g), ethanol (500 ml) and hydrazine hydrate (6.2 g) is refluxed. 1 h. After the ethanol is removed by evaporation under reduced pressure, water (300 ml) is added and the mixture is extracted with ethyl acetate (400 ml). The extract is washed successively with 0.1 N sodium hydroxide solution (100 ml x 2) and water (100 ml), dried over anhydrous magnesium sulfate and concentrated in vacuo; to give 3 (R) -amino-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one (3.75 g) as colorless leaves, m.p. 170-173 ° C (i? <) D - 367 ° (in methanol)

Elemental analysis, C 9 H 10 N 2 OS Calculated: C, 55.65; H, 5.19; N, 14.42 Found: C, 55.73; H, 5.09; N, 14.51

Example 1 0.43 g of sodium is dissolved in 10 ml of ethanol and 5 g of ethyl 3- (1-benzyloxycarbonyl-4-piperidyl) propionate and 2.75 g of diethyl oxalate are added to the solution. The solvent is evaporated off under reduced pressure while heating in a hot water bath at 60-70 ° C for 45 min. After cooling, the resulting brown viscous substance is treated with 200 ml of water and the mixture is weakly acidified with concentrated hydrochloric acid. The mixture is extracted with 300 ml of ethyl acetate, and the extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ten (10)% aqueous dimethylformamide (50 ml) and 0.73 g of lithium chloride are added to the resulting 22 81 089 yellow oily substance, followed by stirring at 100 ° C for 30 min, 120-130 ° C for 30 min and then at 140 ° C for 45 min. After cooling, 300 ml of water are added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-oxobutyrate as a pale yellow oil.

IR neat cm-1: 1730, 1700 (C = O)

P

max

Mass spectrum (m / e): 347 (M +)

Example 2

A mixture of 25 g of isonicotinic aldehyde, 82 g of ethyl (triphenylphosphoranilidene) acetate and 300 ml of toluene is stirred at 100 [deg.] C. for 3 h. After cooling, the precipitated crystals are filtered off and the filtrate is concentrated under reduced pressure. A mixture of ethyl acetate and petroleum ether (1: 1, 400 ml) is added to the residue, and the mixture is extracted with 500 ml of 5% hydrochloric acid. The aqueous solution is extracted with 50 ml of ethyl acetate, then neutralized with potassium carbonate and cooled. The precipitated crystals are collected by filtration and dried to give 34 g of 3- (4-pyridyl) acrylate as colorless prisms, m.p. 64-66 ° C.

Example 3 28 g of ethyl 3- (4-pyridyl) acrylate are dissolved in 300 ml of acetic acid and a catalytic reduction reaction is carried out at medium temperature and atmospheric pressure using 1 g of platinum oxide as catalyst. When the absorption of hydrogen stops, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. Water (500 ml) and 300 ml of ethyl acetate are added to the residue and sodium hydrogen carbonate is added to the mixture with stirring until no foam is detectable.

II

23 81 089 from. To the resulting mixture is added benzyloxycarbonyl chloride (5 ml), followed by stirring for 1 h at room temperature, and a further 20 ml of benzyloxycarbonyl chloride are added. Sodium hydrogen carbonate (30 mg) was added portionwise to the reaction solution under stirring at room temperature, and after stirring at room temperature for 2 h, the ethyl acetate layer was separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 37 g of ethyl 3- (1-benzyloxycarbonyl-4-piperidyl) propionate as a colorless oily substance.

IR neat cm-1: 1730, 1700 (C = O) l> max

Example 4 17 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-oxobutyrate are dissolved in 30 ml of ethanol and 4.5 g of acetic acid are added to the solution. Sodium cyanoborohydride (3 g) is added to the mixture with stirring at room temperature, followed by stirring at room temperature for 3 h and 500 ml of water are added to the reaction mixture, which is extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give 11.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl). ) -2-hydroxybutyrate as a colorless oily substance.

IR neat cm-1: 3430 (OH), 1730, 1690 (OO) max NMR spectrum (CDCl 3 + D 2 O) δ: 7.3 (5H), 5.1 (2H), 3.9 ..., 4 (5H), 2.5 ... 3.1 (2H), 1.0 ... 2.0 (12H)

Example 5

To a mixture of 200 ml of ethyl acetate and 12 g of pyridine.

24 81 089 11.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxybutyrate are dissolved and 5 ml of thionyl chloride are added to the solution, followed by refluxing with stirring for 1 h.

After cooling, 500 ml of water and 100 ml of ethyl acetate are added to the reaction solution, followed by extraction. The extract is washed successively with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and treated with activated carbon.

The ethyl acetate is evaporated to give 10.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorobutyrate as a pale yellow oil.

IR neat cm-1: 1740, 1690 (C = O) \> max

Example 6 10.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorobutyrate are dissolved in 20 ml of ethanol and a catalytic reduction reaction is carried out at medium temperature and atmospheric pressure using 5 g of 10% palladium on carbon (50% in water). as a catalyst. When the absorption of hydrogen has stopped, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give ethyl 4- (4-piperidyl) butyrate. This product is dissolved in a mixture of 200 ml of ethyl acetate and 100 ml of water, 6 g of sodium hydrogen carbonate are added to the solution, followed by stirring at room temperature. Benzyloxycarbonyl chloride (6 ml) is added dropwise to the mixture, and after the addition is complete, the mixture is stirred at room temperature for 1.5 h. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 5.3 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidylbutyrate as a colorless oily substance.

IR neat cm-1: 1730, 1700 (C = O) λ max 25 81 089

Example 7 0.48 g of sodium is dissolved in any ethanol and 5.3 g of ethyl 4- (1-beyloxycarbonyl-4-piperidyl) butyrate and 2.8 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure of 60 to 70 g. At ° C to remove the substance below. After cooling, the resulting brown viscous substance is treated with 300 ml of water and the mixture is acidified with 1N hydrochloric acid and extracted twice with 100 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting oily substance are added dimethyl sulfoxide (45 ml), 5 ml of water and 0.8 g of lithium chloride, and the solution is stirred at 135-140 ° C for 30 minutes. After cooling, 500 ml of water are added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) -2-oxovalerate as an oily substance.

IR neat cm-1t 1730, 1700 (C = 0) V> max

Mass spectrum (m / e) t 361 (m +)

Example 8

A solution of 84 g of 3- (4-piperidyl) propanol and 65 g of triethylamine in 100 ml of methylene chloride is added dropwise over 45 minutes at room temperature while stirring with 100 g of tn benzyloxycarbonyl chloride to a mixture of 400 ml of methylene chloride and 40 ml of water. After the addition is complete, the reaction solution is stirred at room temperature for 1 h. The methylene chloride layer is separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is distilled in vacuo to remove a fraction having a b.p. is 50-60 ° C / 5 mmHg to give 110 g of 3- (1-benzyloxycarbonyl-4-piperidyl) phenyl as a pale yellow oil.

26 81 089 IR neat cm-1: 3400 (OH), 1680 (C = O) ^ max

Example 9

A mixture of 110 g of 3- (1-benzyloxycarbonyl-4-piperidyl) propanol and 500 ml of pyridine is stirred under ice-cooling, and 100 g of tosyl chloride are added portionwise over 2 hours. The reaction solution is further stirred under ice-cooling for 1 h, and 1 L of ice-cold water is added dropwise to the solution.

In succession, 500 ml conc. hydrochloric acid is added dropwise to the reaction mixture under ice-cooling, followed by extraction with 1 L of ethyl acetate. The extract is washed successively with dilute hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethanol is added to the resulting oily substance and the mixture is allowed to stand to give 99 g of 3- (1-benzyloxycarbonyl-4-piperidyl) propyl p-toluenesulfonate as colorless crystals, m.p. 59-60 ° C.

Elemental analysis, C23H29NO5S Calculated: C, 64.01; H, 6.77; N, 3.25 Found: C, 64.25; H, 6.78; N, 3.26

Example 10 5.8 g of sodium are dissolved in 300 ml of ethanol and 40 g of diethyl malonate are added to the solution, followed by stirring. To this mixture is added 3- (1-benzyloxycarbonyl-4-piperidyl) propyl p-toluenesulfonate (90.5 g), followed by refluxing with stirring for 2 h. After cooling, 1 l of water is added to the reaction solution, which is then extracted with 500 ml: 11a ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 5- (1-benzyloxycarbonyl-4-piperidine) -2-ethoxycarbonylvalerate as an oily substance. This product is dissolved in l! 27 81 089 to 200 ml of ethanol and a solution of 34 g of sodium hydroxide in 200 ml of water is added dropwise to the stirred solution. After the addition is complete, 300 ml of water are added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1: 1, 300 ml). The aqueous layer is acidified with conc. hydrochloric acid, followed by extraction with 500 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5- (1-benzyloxycarbonyl-4-piperidyl) -2-carboxyvaleric acid as an oily substance. This product is heated at 160-170 ° C with stirring for 45 min to give 50 g of 5- (1-benzyloxycarbonyl-4-piperidyl) valeric acid as an oily substance.

IR neat cm-1: 1730, 1700 (C = O) λ max

Example 11

A mixture of 54.8 g of 5- (1-benzyloxycarbonyl-4-piperidyl) valeric acid, 29 g of sodium hydrogen carbonate, 21 ml of ethyl iodide and 150 ml of Ν, Ν-dimethylformamide is heated at 70-80 ° C with stirring. h. Ethyl iodide (10 ml) is further added to the reaction solution, followed by heating at 90 to 100 ° C for 3 h. After cooling, 1 l of water is added to the reaction solution, and the mixture is extracted with 1 L of ethyl acetate. The extract is washed successively with water, 1N hydrochloric acid and dilute aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 58 g of ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) valerate as a pale yellow oil.

IR .neat cm -1: 1730, 1700 (C = O)

V

max NMR spectrum (CDCl 3) δ: 7.3 (5H), 5.1 (2H), 3.9-4 (4H), 2.5..3.1 (2H), 2.1-2, Δ (2H), 1.0 ... 1.9 (14H) 28 81 089

Example 12 2.2 g of sodium are dissolved in 50 ml of ethanol and 30 g of ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) valerate and 14 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure at 60 ° C for 1 h. and at 60-70 ° C for 30 min to remove the low boiling agent. After cooling, 500 ml of water are added to the resulting brown viscous substance, and the mixture is acidified with hydrochloric acid and extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting oily substance are added dimethyl sulfoxide (150 ml), 15 ml of water and 5 g of lithium chloride, followed by stirring at 150-155 ° C for 35 min. After cooling, 500 ml of water are added to the reaction, and the mixture is extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 26 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate as an oily substance.

IR neat cm-1: 1730, 1690 (C = 0) v max

Mass spectrum (m / e): 375 (M +)

Example 13 26 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate are dissolved in 40 ml of ethanol and 6.2 g of acetic acid are added to the solution. Sodium cyanoborohydride (4.4 g) was added to the mixture under ice-cooling, and the mixture was stirred for 1 h and allowed to stand at room temperature overnight. Water (500 ml) is added to the reaction solution, followed by extraction with methylene chloride. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown viscous substance is purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 16 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate as a colorless oily substance.

li 29 81 089 IR neat cm-1: 3450 (OH), 1730, 1690 (C = O) \> max

Example 14

To a mixture of 120 ml of ethyl acetate and 13 g of pyridine are dissolved 12.8 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate and 5.1 ml of thionyl chloride are added to the solution, followed by refluxing with stirring. min. After cooling, 500 ml of water and 200 ml of ethyl acetate are added to the reaction solution, and extraction is performed. The extract is washed successively with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give 10 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorohexanoate as a colorless oily substance.

IR neat cm-1: 1740, 1690 (C = O) \> max

Example 15 In 200 ml of ethanol, 10 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorohexanoate are dissolved and a catalytic reduction reaction is carried out at medium temperature and atmospheric pressure using 5 g of 10% palladium on carbon (50% in water) as a catalyst. . After the hydrogen absorption is stopped, the catalyst is removed by filtration and the filtrate is concentrated under reduced pressure to give ethyl 6- (4-piperidyl) hexanoate. To this product are added water (100 ml) and 200 ml of ethyl acetate, and 10 g of sodium hydrogencarbonate is added to the mixture, followed by stirring. Benzyloxycarbonyl chloride (7.2 ml) is added dropwise to the mixture at room temperature, followed by stirring overnight. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane-ethyl acetate = 4: 1) to give 7.7 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) hexanoate as a colorless oily substance.

IR ^ neat cm-1: 1730, 1690 (C = O) max

Example 16 0.56 g of sodium are dissolved in 20 ml of ethanol and 7.3 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) hexanoate and 3.5 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure at 60 ° C. .70 ° C for 20 min and 75 ° C for 20 min to remove low boiling point. After cooling, 100 ml of water are added to the resulting brown viscous substance, and the mixture is acidified with hydrochloric acid and extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting oily substance are added dimethyl sulfoxide (50 ml), 5 ml of water and 1.5 g of lithium chloride, followed by stirring at 140-160 ° C for 40 min. After cooling, 300 ml of water are added to the reaction solution, which is then extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6.5 g of ethyl 7- (1-benzyloxycarbonyl-4-piperidyl) -2-oxoheptanoate as an oily substance.

IR neat cm - * -: 1720, 1690 (OD)

V

T max

Mass spectrum (m / e): 389 (M +)

Example 17 26.8 g of ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) valerate are dissolved in 200 ml of tetrahydrofuran and 13.4 g of sodium cyanoborohydride are added to the solution. Methanol is added dropwise to the mixture over 1.5 h at 70-80 ° C with stirring

II

3i 81089 (40 ml) and after the addition is complete, reflux for a further 2 h. The reaction solution is concentrated under reduced pressure and 300 ml of water are added to the residue, followed by extraction with 300 ml of ethyl acetate. The extract is washed successively with 50 ml of 1N hydrochloric acid and 50 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 23 g of 5- (1-benzyloxycarbonyl-4-piperidyl) pentanol as a colorless oily substance.

IR neat cm-1: 3400 (OH), 1690 (C = O) max NMR spectrum (CDCl 3): 7.3 (5H), 5.1 (2H), 3.9-4.4 (2H) , 3.5 ... 3.8 (2H), 2.4 ... 3.0 (3H), 1.0 ... 1.9 (13H)

Example 18

A mixture of 18 g of 5- (1-benzyloxycarbonyl-4-piperidyl) pentanol and 150 ml of pyridine is stirred under ice-cooling, and 14.6 g of tosyl chloride are added portionwise over 30 minutes. After stirring for another 1 h under ice-cooling, 2 ml of ice-cold water are added dropwise. Ethyl acetate (500 ml) is added to the reaction solution, which is then washed successively with 500 ml of 2N hydrochloric acid and 500 ml of 1N hydrochloric acid, further successively with dilute aqueous sodium hydrogencarbonate solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is purified by silica gel chromatography to give 18 g of 5- (1-benzyloxycarbonyl-4-piperidyl) pentyl p-toluenesulfonate as an oily substance.

IR neat cnT ^: 1700 (C = 0) V> max

Example 19 0.95 g of sodium is dissolved in 80 ml of ethanol and 7.2 g of diethyl malonate are added to the solution, followed by stirring. To the mixture is added 5- (1-benzyloxycarbonyl-4-piperidyl) -3281,089 pentyl p-toluenesulfonate (13.7 g), followed by refluxing with stirring for 2 h. A further mixture of 0.25 g of sodium is added. 25 ml of ethanol and 1.8 g of diethyl malonate and the reaction solution are refluxed with stirring for 2 h. The ethanol is evaporated off under reduced pressure and 200 ml of water are added to the residue, which is then extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 7- (1-benzyloxycarbonyl-4-piperidyl) -2-ethoxycarbonylheptanoate as an oily substance. This product is dissolved in 30 ml of ethanol and a solution of 6 g of sodium hydroxide in 50 ml of water is added dropwise with stirring. After the addition is complete, 150 ml of water are added to the reaction solution, which is then extracted with a mixture of ether and petroleum ether (1: 1, 150 ml). The aqueous layer is acidified with conc. hydrochloric acid and extracted with 300 ml of ethyl acetate, and the extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 7- (1-benzyloxycarbonyl-4-piperidyl) -2-ethoxycarbonylheptanoate. This product is heated at 160-165 ° C with stirring for 1 h and the resulting oily substance is purified by silica gel chromatography (hexane-ethyl acetate = 3: 1 ... 1: 1) to give 6.4 g of 7- (1-benzyloxycarbonyl). -li-4-piperidyl) heptanoic acid as an oily substance.

IR neat cm-1: 1730, 1710 (OD)

V

max

Example 20

A mixture of 6.4 g of 7- (1-benzyloxycarbonyl-4-piperidyl) heptanoic acid, 3.1 g of sodium hydrogen carbonate, 8.6 g of ethyl iodide and 20 ml of Ν, Ν-dimethylformamide is heated at 100 ° C with stirring. h. Further, 2.9 g of ethyl iodide and 1 g of sodium hydrogencarbonate are added to the reaction solution, followed by heating at 100 ° C for 2.5 h. After cooling, 200 ml of water are added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract was washed successively with brother 33 81 089, 0.1 N hydrochloric acid and dilute aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5 g of ethyl 7- (1-benzyloxycarbonyl-4-piperidyl) heptanoate as an oil.

IR neat cm -1: 1730, 1700 (OD)

V

max NMR spectrum (CDCl 3) (δ: 7.3 (5H), 5.1 (2H), 4.0 ... 4.3 (4H), 2.5 ... 3.0 (2H), 2 , 1 ... 2.4 (2H), 1.0 ... 1.9 (18H)

Example 21 0.48 g of sodium is dissolved in 30 ml of ethanol and 6.5 g of ethyl 7- (1-benzyloxycarbonyl-4-piperidyl) heptanoate and 3 g of diethyl oxalate are added to the solution, followed by evaporation under reduced pressure of 60 to 70 g. At 1 ° C for 1 h to remove low boiling point. After cooling, 150 ml of water are added to the resulting viscous substance, and the mixture is acidified with hydrochloric acid and extracted with 300 ml of ethyl acetate. The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting oily substance are added dimethyl sulfoxide (54 ml), 6 ml of water and 1 g of lithium chloride, followed by stirring at 140 ° C for 1 h. After cooling, 150 ml of water are added to the reaction solution, and the mixture is extracted with 300 ml of ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 6 g of ethyl 8- (1-benzyloxycarbonyl-4-piperidyl) -2-oxooctanoate as an oily substance.

IR neat cm-1: 1730, 1700 (C = O) rmax

Mass spectrum (m / e): 403 (M +)

Example 22

To a stirred solution of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (5 g) in methanol (81 ml) was added dropwise a solution of sodium hydroxide (2.6 ml) at room temperature. g) in water (20 ml). After the addition is complete, the mixture is stirred for 30 min, diluted with water (300 mL) and extracted with ethyl ether (50 mL). The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ethyl acetate (200 mL). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid (3.5 g) as a colorless oil.

IR neat cm-1: 3400 (OH), 1670 (C = O)

V

max

Example 23

To a stirred solution of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (1.0 g) in pyridine (10 ml) is added dropwise methanesulfonyl chloride (0.92 g) at ice bath temperature. After stirring for 1 h at ice bath temperature, the mixture is stirred for 30 min at room temperature and then cooled. After adding water (1 mL), the mixture is stirred for 30 min at ice bath temperature and the ice bath is removed. The mixture is stirred for 30 min at room temperature, diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract is washed successively with 10% hydrochloric acid, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 6- (1-benzylocycarbonyl-4-piperidyl) -2-methanesulfonylhexanoate (1.1 g). as an oil.

IR neat cm-1: 1750, 1690 (C = O) rmax NMR spectrum (CDCl 3) δ: 7.3 (5H), 4.9 ... 5.1 (3H), 3.9 ... 4, Δ (4h), 3.1 (3H), 1.0 ... 3.1 (18H) li

Example 24 81089 To 1.2 l of Ο, ΐΜ phosphate buffer (Ο, ΙΜ KH2PO4 600 ml and 0.1 IM K2HPO4 600 ml) is added ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (40 g ) and Lipase PN (200 mg: Wako Pure Chemicals, Japan), and the mixture is stirred vigorously at room temperature for 3.5 h. The mixture is acidified with conc. hydrochloric acid and extracted twice with a mixture of ethyl acetate and petroleum ether (2: 1). The ethyl acetate layer was washed with saturated sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (14.6 g) as a colorless oil. The aqueous sodium hydrogen carbonate layer is extracted with ethyl ether, acidified with conc. hydrochloric acid and extracted with ethyl acetate (500 ml). The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give S-isomer-rich 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid (23.5 g). Ethyl 6- (1-Benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (7 g) rich in R-isomer is dissolved in pyridine (30 ml) and added methanesulfonyl chloride (2.9 ml) dropwise with stirring under ice-cooling over 5 minutes. . The mixture is stirred under ice-cooling for 1.5 h and water (5 ml) is added dropwise to the mixture. The reaction mixture is stirred for 30 min, diluted with ethyl acetate (300 mL) and washed with 1N hydrochloric acid, saturated sodium bicarbonate solution and water. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the R-isomer-rich ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonylhexanoate (8.2 g) as a pale yellow oil.

(o () d + 15 ° (in methanol)

Example 25 36 81 089

Dissolve 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid (3.6 g) rich in S-isomer in toluene (50 ml) and add ethanol (10 ml) and p-toluenesulfonic acid (0.2 ml) to the solution. g), followed by vigorous stirring at 90 ° C for 1.5 h. The mixture is diluted with ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (100 mL) and water (100 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give S isomeric ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate (3.7 g) as an oil. This product (1.0 g) is dissolved in pyridine (5 ml) and methanesulfonyl chloride (0.4 ml) is added dropwise to the solution over 5 minutes under ice-cooling with stirring. After stirring for 15 min under ice-cooling, water (3 ml) is added to the mixture, followed by stirring for 30 min. Ethyl acetate (150 ml) is added to the mixture, and the resulting mixture is washed with 1N hydrochloric acid (50 ml x 2), saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml). The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give S- isomer-rich 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonylhexanoate (1.2 g: (^) p - 16.6 ° (in methanol)). as a pale yellow oil. This product (1.2 g) and cesium propionate (prepared from cesium carbonate (0.47 g) and propionic acid (0.32 g)) are added to N, N-dimethylformamide (30 ml) and the mixture is stirred at 90 ° C for 1 h. then ethyl acetate (150 ml) is added to the mixture, and the mixture is washed with 0.1N hydrochloric acid (50 ml x 2), sodium hydrogencarbonate solution (50 ml) and water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product is purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give R-isomer-rich ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-propionyloxyhexanoate (1.07 g) as a colorless oil. This product (1.05 g) is dissolved in ethanol (10 ml) and li 3? 81089 over 1 min dropwise 1N aqueous sodium hydroxide solution (10 ml), followed by vigorous stirring for 30 min. The mixture is acidified with conc. hydrochloric acid and extracted with ethyl acetate (100 ml). The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the R-isomer-rich 6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid as an oily product. This product is dissolved in toluene (30 ml) and ethanol (5 ml) and p-toluenesulphonic acid (0.1 g) are added to the solution, followed by stirring at 90 ° C for 1.5 h. Ethyl acetate (150 ml) and the resulting mixture was washed with saturated sodium hydrogen carbonate solution (50 ml) and water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the R-isomer-rich ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2- hydroxyhexanoate (0.84 g) as a colorless oil. This product (0.3 g) is dissolved in pyridine (3 ml) and methanesulfonyl chloride (0.15 ml) is added dropwise to the solution under ice-cooling over 2 minutes with stirring. The mixture is stirred for 1 h under ice-cooling, and ethyl acetate (70 ml) is added to the mixture. The resulting mixture is washed with 1N hydrochloric acid (30 ml x 2), saturated sodium hydrogen carbonate solution (30 ml) and water (30 ml). The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-ethanesulfonylhexanoate (0.35 g: (<x-) q + 16, 6 ° (in methanol) as a colorless oil.

Use Example 1 2 g of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate are dissolved in 50 ml of ethanol and 0.43 ml of g of acetic acid, 4.5 g of ethyl 4- (1-benzyloxycarbonyl-4-piperidyl) -2-oxobutyrate obtained in Example 1 and 10 g of molecular sieve 3A. The mixture is stirred at room temperature for 1 h and a solution of 0.4 g of sodium cyanoborohydride in 30 ml of ethanol is added dropwise to the mixture over 2.5 h at room temperature with stirring. A solution of 0.5 g of sodium cyanoborohydride in 20 ml of ethanol is further added dropwise over 3 h to the mixture. The reaction solution is allowed to stand overnight and concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is filtered off, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To a residue to which is added a solution of 1 g of oxalic acid in 50 ml of ethyl ether is added ethyl ether (50 ml). Add petroleum ether (200 ml), then shake well and allow the mixture to stand. The supernatant is decanted and 100 ml of petroleum ether are added again to the precipitate, which is then shaken. The petroleum ether layer is removed by decantation, and 50 ml of water and 200 ml of ethyl acetate are added to the precipitate, followed by the addition of excess sodium hydrogencarbonate to the mixture with stirring to effect neutralization. The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily substance. This product is separated and purified by silica gel chromatography (hexane: ethyl acetate = 2: 1 to 4: 3) to give 0.6 g of tert-butyl-3 (R) - (3- (1-benzyloxycarbonyl) as a first fraction. -4-Piperidyl) -1 (R) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR δ neat cm-1: 3320 (NH), 1740, 1700, 1680 (C = O) max

Mass spectrum (m / e): 639 (M +)

The following fraction gives 1.3 g of tert-butyl-3 (R) - (3- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4, 5-Tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR ^ neat cm-1: 3320 (NH), 1740, 1700, 1690, 1670 (OO) x max

Mass spectrum (m / e): 639 (M +)

II

39 81 089 Use Example 2 20 g of a 5N hydrochloric acid-ethyl acetate solution are dissolved in 0.3 g of the tert-butyl 3 (R) - (3- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) - obtained in Example 1. ethoxycarbonylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and the solution is allowed to stand at room temperature for 3 h. To the reaction solution is added petroleum ether (200 ml) 3 (R) - ( 3- (1-Benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid to precipitate hydrochloride . The supernatant is decanted and then dried to give 0.22 g of a colorless powder.

Elemental analysis, C3qH37N3O7S * HCl * H2O Calcd: C, 56.46; H, 6.32; N, 6.58 Found: C, 56.29; H, 6.31; N, 6.57 (<? Od ~ 91 ° (c = 0.6 in methanol). Use Example 3 In 2 ml of acetic acid is dissolved 0.6 g of the tert-butyl-3 (R) - (3- (1- benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2 ml of 30% hydrobromic acid solution are added to the solution. The mixture was allowed to stand at room temperature for 1 h, ethyl ether (150 ml) was added to the reaction solution and the mixture was allowed to stand, then the supernatant was decanted and the precipitate was washed with ethyl ether and dried to give 0.5 g of 3 (R) - (1 (r)). -ethoxycarbonyl-3- (4-piperidyl) propyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

Elemental analysis, C22H31N3O5S · 2HBrΉ2Ο Calculated: C, 41.98; H, 5.60; N, 6.68 Found: C, 41.43; H, 5.39; N, 6.30 (<^) ^ 2 _ 106 ° (c = 0.6 in methanol) Application Example 4 40 81 089

In the same manner as in Use Example 3, 0.4 g of the tert-butyl 3 (R) - (3- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo obtained in Use Example 1 was obtained. - 2,3,4,5-Tetrahydro-1,5-benzothiazepine-5-acetate is treated with hydrogen bromide to give 0.35 g of 3 (R) - (1 (S) -ethoxycarbonyl-3- (4-Piper idyl) propyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

Onset analysis, C 22 H 31 N 3 O 5 S * 2HBr * H 2 O Calcd: C, 40.81; H, 5.76; N, 6.49 Found: C, 40.47; H, 5.32; N, 6.28 (δ) d “β6 ° (c = 0.6 in methanol) Use Example 5 4 Any 0.1 N aqueous sodium hydroxide solution is dissolved in 0.15 g of the 3 (R) - (1 (S) -ethoxycarbonyl) obtained in Use Example 4. -3- (4-Piperidyl) -propyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide and the solution is allowed to stand at room temperature for 2 h. The solution is made slightly acidic 1 ml of acetic acid and purified by column chromatography on Amberlite XAD-2 (methanol water = 1: 1).

The eluate is concentrated under reduced pressure and the residue is lyophilized to give 0.06 g of 3 (R) - (1 (S) -carboxy-3- (4-piperidyl) propyl) -amino-4-oxo-2,3 , 4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder. Elemental analysis, C20H27N3O5S * H2O Calculated: C, 54.65; H, 6.65; N, 9.56 Found: C, 54.05; H, 6.17; N, 9.21 Mass spectrum (m / e): 422 (MH +): KI addition, 460 (M + K) + () d - 128 ° (c = 0.1 in methanol-water) 11 Application Example 6 4i 81089 10 0.25 g of the 3 (R) - (1- (S) -ethoxycarbonyl-3- (4-piperidyl) propyl) amino-4-oxo-2,3,4,5- obtained in Example 4 is dissolved in 1 ml of ethanol. tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide and 67 mg of sodium acetate and 52 mg of benzaldehyde are added to the solution. A solution of 31 mg of sodium cyanoborohydride in 10 ml of ethanol is added dropwise over 30 minutes. The ethanol is evaporated off under reduced pressure and 50 ml of water are added to the residue. The mixture is weakly acidified with acetic acid and extracted three times with 50 ml of dichloromethane. The extract is washed with a small amount of water and concentrated under reduced pressure. The resulting oily substance is dissolved in 1 ml of dichloromethane and 0.5 ml of 5N hydrochloric acid-acetic acid solution is added to the solution. The precipitated colorless powder was washed with ethyl ether and dried to give 157 mg of 3 (R) - (3- (1-benzyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride.

Elemental analysis, C 29 H 37 N 3 O 5 S · 2HCl * H 2 O Calcd: C, 55.23; N, 6.55; N, 6.66 Found: C, 54.92; H, 6.74; N, 6.14 (<tOd 76 76 ° (c = 0.4 in methanol) Use Example 7 0.1 g of the 3 (R) - (1 (S) -ethoxycarbonyl-3- (4- piperidyl) propyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide and 66.2 mg of triethylamine are added to the solution. A solution of 23 mg of benzoyl chloride in 2 ml of ethyl acetate is added dropwise with cooling, the reaction solution is stirred at room temperature for 50 minutes and 20 ml of petroleum ether are added, followed by extraction 6 times with 20 ml of saturated aqueous sodium hydrogen carbonate solution. times with 30 ml of dichloromethane 42 81 089. The extract is dried over anhydrous magnesium sulphate and concentrated under reduced pressure, the resulting oily substance is dissolved in 1 ml of ethyl acetate and 0.3 ml of 5N hydrochloric acid-ethyl acetate solution is added. to a solution which is then diluted with ethyl ether. The precipitate was washed with ethyl ether and dried to give 28 mg of 3 (R) - (3 (1-Benzoyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.

Elemental analysis, C 29 H 35 N 3 O 8 S * HCl * H 2 O Calcd: C, 57.27; H, 6.30; N, 6.91 Found: C, 56.98; H, 5.99; N, 7.01 Application example 8

In the same manner as in Use Example 7, 0.12 g of 3 (R) - (1 (S) -ethoxycarbonyl-3- (4-piperidyl) propyl) amino-4-oxo-2,3,4,5- Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide is reacted with acetyl chloride to give 77 mg of 3 (R) - (3- (1-acetyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4 -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.

{cJ) - 97 ° (c = 0.8 in methanol) Application Example 9

A mixture of 0.4 g of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, 1 g of ethyl 4- ( 1-Benzyloxycarbonyl-4-piperidyl) -2-chlorobutyrate, 0.2 g of triethylamine, 0.9 g of potassium iodide and 50 ml of acetonitrile are heated at reflux for 2 days. After cooling, the reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to give 0.15 g of tert-butyl-3 (R) - (3- (1-benzyloxycarbonyl-4-piperidyl) -1 (R ) -ethoxycarbonylpropyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzo. ages

II

43 81 089 Silicon 5-acetate and 0.25 g of tert-butyl 3 (R) - (3- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpropyl) amino-4-oxo, respectively -2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

Use Example 10 2.1 ml of ethanol are dissolved in 2.1 g of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0, 4 g of acetic acid, 2.5 g of ethyl 5- (1-benzyloxycarbonyl-4-piperidyl) -2-oxovalerate and 10 g of molecular sieve 3A. The mixture is stirred at room temperature for 20 minutes and a solution of 0.4 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture over 3 hours at room temperature with stirring. The reaction solution is allowed to stand at room temperature overnight and is concentrated under reduced pressure, and 300 ml of water and 300 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl acetate (20 ml) and 2 g of oxalic acid are added to the residue, and the mixture is shaken thoroughly and 300 ml of petroleum ether are added, followed by allowing the mixture to stand. The solution portion is removed by decantation, and 100 ml of water and 200 ml of ethyl acetate are added to the precipitate portion, followed by the addition of excess sodium hydrogencarbonate to neutralize. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oily substance. This product is separated and purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to give 0.4 g of tert-butyl-3 (R) - (4- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylbutyl from the first fraction. ) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR ^ neat cm ”1: 3310 (NH), 1730, 1680 (OO) max 44 81 089

Mass spectrum (m / e): 653 (M +)

The following fraction gives 0 # 8 g of tert-butyl-3 (R) - (4- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylbutyl) amino-4-oxo-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR «.neat cm-1: 3320 (NH), 1730, 1690 (C = O)

V

'max

Mass spectrum (m / e): 653 (M +) Use Example 11 0.4 g of tert-butyl-3 (R) - (4- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) is dissolved in 2 ml of acetic acid. (ethoxycarbonyl-butyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2 ml of a 30% hydrogen bromide-acetic acid solution are added to the solution, followed by allowing the mixture to stand. at room temperature for 1.5 h. Ethyl ether (50 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is washed with ethyl ether and dried to give 0.4 g of 3 (R) - (1 (R) -ethoxycarbonyl-4- (4-piperidyl) butyl) amino-4-oxo-2,3, 4,5-Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

Initial analysis, C23H33N3O5S · 2HBr · 2H2O Calculated: C, 41.76; H, 5.94; N, 6.35 Found: C, 42.07; H, 6.16; N, 6.09 (¢ /) D ~ 111 ° (in methanol)

Mass spectrum (m / e): 463 (M +) Use Example 12 0.8 g of tert-butyl-3 (R) - (4- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) - is dissolved in 2 ml of acetic acid. ethoxycarbonyl-butyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 3 ml of a 30% hydrogen bromide-acetic acid solution are added to the solution, followed by allowing the mixture to stand at room temperature. 1.5 h. Ethyl ether (50 ml) is added to the reaction solution 45 81 089, which is then allowed to stand. The supernatant is decanted and the precipitate is washed with ethyl ether and dried to give 0.75 g of 3 (R) - (1 (S) -ethoxycarbonyl-4- (4-piperidyl) butyl) amino-4-oxo-2,3, 4,5-Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

Elemental analysis, C23H33N3O5S · 2HBr · 3 / 2H2O Calculated: C, 42.34; H, 5.87; N, 6.44 Found: C, 42.35; H, 6.03; N, 6.12 (Cl 2) d ”(in methanol)

Mass spectrum (m / e): 436 (MH +) Use Example 13 0.5 g of 3 (R) - (1 (S) -ethoxycarbonyl-4- (4-piperidyl) butyl) amino-4 is dissolved in 12 ml of aqueous sodium hydroxide solution. -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide and the solution is allowed to stand at room temperature for 30 min. The solution is neutralized with 2 ml of acetic acid and purified on an MCI gel (CHP 20P, 150-300 yu, Mitsubishi

Chemical Industries, Japan) by column chromatography (aqueous methanol = 2: 1). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.3 g of 3 (R) - (1 (S) -carboxy-4- (4-piperidyl) butyl) amino-4-oxo-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder. Elemental analysis, C 21 H 29 N 3 O 5 S · 2H 2 O Calculated: C, 53.49; H, 7.05; N, 8.91 Found: C, 53.77; H, 7.11; N, 8.96 ° C (Jd - 117 ° (methanol-water) SIMS spectrum (m / e): 436 (MH +) Use Example 14 3 g of tert-butyl-3 (R) -amino- are dissolved in 30 ml of ethanol. 4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.58 g of acetic acid, 4.4 g of ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) - 2-Oxohexanoate and 46 81 089 10 g of molecular sieve 3 A. The mixture is stirred at room temperature for 15 min and a solution of 0.61 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise to the mixture over 3 h at room temperature with stirring.

The reaction is allowed to stand at room temperature overnight and then concentrated under reduced pressure, and 100 ml of water and 200 ml of ethyl acetate are added to the residue, followed by shaking thoroughly. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed successively with 10% aqueous phosphoric acid solution, 0.1 N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica gel chromatography (hexane-ethyl acetate = 2: 1) to give 0.45 g of the first fraction, tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl). ) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR neat cm -1: 3330 (NH), 1740, 1700 (00) max

Mass spectrum (m / e): 667 (M +)

The following fraction gives 0.8 g of tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonyl-pentyl) -amino-4-oxo-2,3,4 , 5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR neat cm -1: 3320 (NH), 1740, 1690 (00) max

Mass spectrum (m / e): 667 (M +) Application Example 15 0.45 g of tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) - is dissolved in 1 ml of acetic acid. ethoxycarbonyl-lipentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 1 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand.

II

47 81 089 at room temperature for 1/5 h; Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is washed with ethyl ether and dried to give 0.3 g of 3 (R) - (1 (R) -ethoxycarbonyl-5- (4-piperidyl) pentyl) amino-4-oxo-2,3, 4,5-Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

Elemental analysis, C24H35N3O5S · 2HBrΉ2Ο Calculated: C, 43.85; H, 5.98; N, 6.39 Found: C, 43.95; H, 6.29; N, 6.47 (<Odd 108 ° (in methanol))

Mass spectrum (m / e): 477 (M +) Use Example 16 1 l of any acetic acid is dissolved in 0.75 g of tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonyl- lipentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2 ml of 30% hydrobromic acetic acid solution are added to the solution, after which the mixture is allowed to stand at room temperature for 1.5 h. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is washed with ethyl ether and dried to give 0.6 g of 3 (R) - (1 (S) -ethoxycarbonyl-5- (4-piperidyl) pentyl) amino-4-oxo-2,3,4 , 5-Tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide as a colorless powder.

(c <) d “89 ° (in methanol)

Mass spectrum (m / e): 477 (M +) Application Example 17 In 10 ml of 1N aqueous sodium hydroxide solution is dissolved 0.45 g of 3 (R) - (1 (S) -ethoxycarbonyl-5- (4-piperidyl) pentyl) amino-4 -oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrobromide and the solution is allowed to stand at room temperature for 30 min. The reaction solution is neutralized with 2 ml of acetic acid <81089 and purified on an MC1 gel by column chromatography (water: methanol = 2: 1). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.3 g of 3 (R) - (1 (S) -carboxy-5- (4-piperidyl) pentyl) amino-4-oxo-2,3,4, 5-Tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder. Elemental analysis, C22H31N3O5S · 2H2O Calculated: C, 54.42; H, 7.27; N, 8.66 Found: C, 54.84; H, 7.38; N, 8.61 (<? Od ~ 131 ° (methanol-water) SIMS spectrum (m / e): 450 (MH +) Application Example 18 2.5 g of tert-butyl-3 (R) - are dissolved in 30 ml of ethanol. amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.5 g of acetic acid, 3.2 g of ethyl 7- (1-benzoate) are added to the solution. syloxycarbonyl-4-piperidyl) -2-oxoheptanoate and 10 g of molecular sieve 3 A. The mixture is stirred at room temperature for 10 min and a solution of 0.51 g of sodium cyanoborohydride in 50 ml of ethanol is added dropwise over 3 h at room temperature with stirring. .

The reaction solution is allowed to stand at room temperature overnight and concentrated under reduced pressure, and 50 ml of water and 200 ml of ethyl acetate are added to the residue, followed by shaking well. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed successively with 0.1N hydrochloric acid, 0.1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 0.5 g of the first fraction of tert-butyl-3 (R) - (6- (1-benzyloxycarbonyl-4-piperidyl) -1 (R ) -ethoxycarbonylhexyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

IR neat cm -1: 3320 (NH), 1730, 1680 (C = O)

V

max a 49 81 089

Mass spectrum (m / e): 681 (M +)

The following fraction gives 0.9 g of tert-butyl-3 (R) - (6- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonyl-hexylamino-4-oxo-2,3,4, 5-Tetrahydro-1,5-benzothiazine-5-acetate as a colorless oily substance.

IR δ neat cm-1: 3330 (NH), 1730, 1690 (C = O) max

Mass spectrum (m / e): 681 (M +) Application Example 19 0.5 g of tert-butyl-3 (R) - (6- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) - is dissolved in 1 ml of acetic acid. ethoxycarbonylhexyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2 ml of 30% hydrobromic acetic acid solution are added to the solution, followed by allowing the mixture to stand at room temperature for 1 h. Ethyl ether (200 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is dissolved in 20 ml of 1N aqueous sodium hydroxide solution, after which the solution is allowed to stand at room temperature for 30 minutes. The solution is neutralized by adding 2 ml of acetic acid and purified by MCI gel column chromatography (water: methanol = 1: 2). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.23 g of 3 (R) -1 (R) -carboxy-6- (4-piperidyl) hexyl) amino-4-oxo-2,3,4,5-tetrahydro- 1,5-Benzothiazepine-5-acetic acid as a colorless powder.

(^) d ~ 144 ° (in water) Use Example 20 0.9 g of tert-butyl-3 (R) - (6- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonyl) are dissolved in 1 ml of acetic acid. -hexyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 2 ml of 30% hydrobromic acetic acid solution are added to the solution, followed by allowing the mixture to stand at room temperature for 1.5 h. Ethyl ether (200 mL) is added to the 81089 reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is dissolved in 30 ml of 1N aqueous sodium hydroxide solution, after which the solution is allowed to stand at room temperature for 30 minutes. The solution is neutralized by adding 3 ml of acetic acid and purified by chromatography on MCI gel (aqueous methanol = 1: 2). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.43 g of 3 (R) - (1 (S) -carboxy-6- (4-piperidyl) hexyl) amino-4-oxo-2,3,4,5- tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless powder.

(C ^) d - 121 ° (in water) SIMS spectrum (m / e): 464 (MH +) Application Example 21 2 g of tert-butyl-3 (R) -amino-4-oxo-2,3 are dissolved in 30 ml of ethanol, 4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 0.47 g of acetic acid, 3 g of ethyl 8- (1-benzyloxycarbonyl-4-piperidyl) -2-oxooctanoate and 10 g of molecular sieve 3A. The mixture is stirred at room temperature for 10 minutes and a solution of 0.45 g of sodium cyanoborohydride in 40 ml of ethanol is added to the mixture over 3 hours at room temperature with stirring.

The reaction solution is allowed to stand at room temperature overnight and then concentrated under reduced pressure, and 100 ml of water and 200 ml of ethyl acetate are added to the residue, followed by shaking. The insoluble matter is removed by filtration, and the ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is separated and purified by silica gel chromatography (hexane: ethyl acetate = 3: 1 to 2: 1) to give 0.3 g of tert-butyl-3 (R) - (7- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -Ethoxycarbonylheptyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oily substance.

si 81089 IR neat cm-1: 3320 (N-H), 1730, 1690 (C = 0) max

Mass spectrum (m / e): 695 (M +) Use Example 22 0.3 g of tert-butyl-3 (R) - (7- (1-benzyloxycarbonyl-4-piperidyl) -1 (1.5 g) is dissolved in 1.5 ml of acetic acid. S) -ethoxycarbonylheptyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 1 ml of 30% hydrogen bromide-acetic acid solution is added to the solution, followed by allowing the mixture to stand. at room temperature for 0.5 h. Ethyl ether (80 ml) is added to the reaction solution, which is then allowed to stand. The supernatant is decanted and the precipitate is dissolved in 10 ml of 1N aqueous sodium hydroxide solution, after which the solution is allowed to stand at room temperature for 30 minutes. The solution is neutralized with 2 ml of acetic acid and purified by XAD-2 column chromatography (aqueous methanol = 1: 1). The eluent is concentrated under reduced pressure and the residue is lyophilized to give 0.1 g of 3 (R) - (1 (S) -carboxy-7- (4-piperidyl) heptyl) amino-4-oxo-2,3,4,5-tetrahydro 1,5-Benzothiazepine-5-acetic acid as a colorless powder.

(c? 0d ~ 116 ° (in water) SIMS spectrum (m / e): 478 (MH +) Application Example 23

A mixture of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (3.0 g), acetonitrile (100 g) ml), ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorohexanoate (4.0 g), triethylamine (1.0 g) and potassium iodide (1.6 g) are stirred for 3 days at 80 ° C . Ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-chlorohexanoate (2.0 g) and potassium iodide (0.8 g) are added and stirring is continued for 1 day at 80 ° C. The mixture is concentrated in vacuo, diluted with water (100 mL) and extracted with ethyl acetate (300 mL). The extract is washed with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. Purification of the residual oil by silica gel column chromatography (hexane: ethyl acetate = 2: 1) gives tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl) amino. 4-Oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (3.1 g) as a colorless oil and tert-butyl 3 (R) - (5- (1-benzyloxycarbonyl) 1- (4-piperidyl) -1 (S) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (2.1 g) as a colorless oil.

Application example 24

A mixture of tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (2.05 g) and ethyl 6 - (1-Benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyl oxyhexanoate (1.5 g) is heated at 90 ° C for 1 day. After cooling, ethyl acetate (300 ml) is added to the mixture, and the resulting solution is washed successively with 5% phosphorus solution (30 ml x 2) and water (20 ml). The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oily residue which is purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl-4-piperidyl-4-piperidyl). ) -1 (R) -Ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.7 g) as a colorless oil. The following fraction gives tert-butyl 3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro- 1,5-Benzothiazepine-5-acetate (0.55 g) as a colorless oil.

Use Example 25 6- (1-Benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid (4.7 g) and quinine (4.4 g) are dissolved in hot acetone (150 ml). After the insoluble matter has been removed by filtration, the solution is allowed to stand in the refrigerator. The precipitated crystals are collected by filtration and recrystallized three times from acetone to give the quinine salt (1.9 g) as colorless crystals. This salt (1.2 g) is added to a mixture of ethyl acetate (200 ml) and 1N hydrochloric acid (50 ml) and the resulting mixture is stirred vigorously. The ethyl acetate layer is washed successively with 1N hydrochloric acid (30 ml, 20 ml) and water, dried over anhydrous magnesium sulfate and evaporated in vacuo. To the oily residue (0.6 g) are added toluene (50 ml), ethanol (10 ml) and p-toluenesulfonic acid (0.05 g). The resulting mixture was stirred at 100 ° C for 3 h, cooled, diluted with ethyl acetate, washed with water (50 mL x 2) and dried over anhydrous magnesium sulfate. Evaporation of the solvent gives the ethyl ester (0.6 g) as a colorless oil which is dissolved in pyridine (5 ml). To the stirred solution is added dropwise methanesulfonyl chloride (0.5 mL) at ice bath temperature. After stirring for 2 h at ice bath temperature, the mixture is stirred at room temperature for 30 min and cooled again in an ice bath. Water (0.5 ml) is added and the mixture is stirred in an ice bath for 30 min and then at room temperature for 30 min. The mixture is diluted with water (20 ml) and extracted with ethyl acetate (50 ml). The extract is washed successively with 10% hydrochloric acid, water, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and evaporated in vacuo to give ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyloxyhexahexahexa 6 g: (cX) jj - 12.8 ° in methanol) as a colorless oil. A mixture of this sulfonate (0.5 g) and tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.71 g) heated at 80-100 ° C for 1 day. After cooling, ethyl acetate (200 ml) is added and the resulting solution is washed successively with 5% phosphoric acid solution (30 ml, 20 ml) and water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give a yellow oil which is purified by silica gel chromatography (silica gel chromatography). 2: 1). The first fraction yields tert-butyl 3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5 -tetrahydro-1,5-benzothiazepine-5-acetate (0.45 g) as a colorless oil. The second fraction gives tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro- 1,5-Benzothiazepine-5-acetate (0.09 g) as a colorless oil.

Use Example 26 6- (1-Benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoic acid (5 g) and cinchonidine (4.2 g) are dissolved in hot acetone (50 ml). After cooling, the solution is diluted with ethyl ether (50 mL) and allowed to stand in the refrigerator. The precipitates are removed by filtration and the filtrate is concentrated in vacuo. The residue is dissolved in acetone (5 ml) and the resulting solution is diluted with ethyl ether (35 ml). After standing in the refrigerator, the resulting precipitates were collected by filtration to give the cinchonidine salt (1.4 g). This salt (1.3 g) is added to a mixture of ethyl acetate (200 ml) and 1N hydrochloric acid (50 ml) and the resulting mixture is shaken well. The ethyl acetate layer was washed successively with 1N hydrochloric acid (50 ml) and water (50 ml), dried over anhydrous magnesium sulphate and evaporated in vacuo to give an oily residue which was dissolved in toluene (30 ml), ethanol (3 ml) and p-toluenesulphonic acid (0 ml). .05 g) to a mixture. The solution is stirred for 1 h at 90-100 ° C, cooled, diluted with ethyl acetate (200 mL) and washed with water (50 mL x 2). The organic layer is dried over anhydrous magnesium sulfate and evaporated in vacuo to give the ethyl ester as a colorless oil which is dissolved in pyridine (5 mL). Methanesulfonyl chloride (0.4 ml) is added dropwise to the stirred solution at ice bath temperature. After stirring for 30 min, water (1 mL) is added to the mixture and the resulting mixture is stirred for 30 min at ice bath temperature and diluted with ethyl acetate (150 mL). The organic layer is washed successively with 1N hydrochloric acid

II

55 81 089 (50 ml x 2), sodium bicarbonate solution (50 ml) and water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulphonylhexanoate (0, 8 g: (cK) d + 13.7 ° in methanol) as a colorless oil. A mixture of this mesylate (0.72 g) and tert-butyl 3 (R) -amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (1.46 g) stirred overnight at 90-100 ° C. After cooling, the reaction mixture is dissolved in ethyl acetate (200 ml) and the solution is washed successively with 5% phosphoric acid solution (30 ml x 2) and water, dried over anhydrous magnesium sulphate and evaporated in vacuo to give a yellow oil which is purified by silica gel chromatography: 1). t-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine -5-acetate (0.12 g) is obtained as a colorless oil from the first fraction. The second fraction gives t-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine- 5-acetate (0.52 g) as a colorless oil.

Use Example 27 3 (R) -Amino-2,3-dihydro-1,5-benzothiazepin-4-one (1.0 g), ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate A mixture of acetic acid (6.0 g), acetic acid (0.37 g), molecular sieves 3A (3.0 g) and ethanol (25 ml) was stirred at room temperature for 20 min. A solution of sodium cyanoborohydride (0.66 g) in ethanol (20 ml) is added dropwise over 5 h to the stirred mixture. After the reaction mixture is concentrated under reduced pressure, the residue is diluted with a mixture of ethyl acetate (80 ml) and water (100 ml). After the insoluble matter is removed by filtration, the ethyl acetate layer is washed successively with dilute hydrochloric acid, water and sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) amino-2,3-dihydro- 1,5- (5H) -benzothiazepin-4-one (1.1 g) as a colorless oil.

IR δ neat cm-1: 3230 (NH); 1730, 1700, 1680 (C = O) max NMR (CDCl 3) δ: 7.3 (5H), 7.0. . . 7.7 (4H), 5.1 (2H), 3.9. . .4.3 (5H), 2.4 .. .3.7 (7H), 1.0 ... 1.8 (16H)

Mass spectrum (m / e): 553 (M +) Use Example 28 3 (R) -Amino-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one (2.7 g) and ethyl 6-ol A mixture of (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyloxyhexanoate (5.4 g) is heated at 100-130 ° C for 3 h. After cooling, the mixture is dissolved in ethyl acetate (200 ml) and the solution is washed with water, dried anhydrous magnesium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane: ethyl acetate * 2: 1) to give 3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) amino-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one (2.9 g) as a colorless oil.

Use Example 29 3 (R) - (5- (1-Benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) amino-2,3-dihydro-1,5 (5H) -benzothiazepin-4-one (1.0 g), a mixture of tert-butyl chloroacetate (0.27 g), potassium iodide (0.3 g), potassium carbonate (0.24 g) and N, N-dimethylformamide is stirred for 15 h at room temperature. The mixture is poured into water (50 ml) and extracted with ethyl acetate (40 ml). The extract is washed successively with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is purified by silica gel chromatography (hexane: ethyl acetate = 2.1) to give first tert-butyl-81 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (R) -ethoxycarbonylpentyl) amino- 4-Oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate (0.45 g) as a colorless oil. The second fraction gives tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonylpentyl) amino-4-oxo-2,3,4,5-tetrahydro 1,5-Benzothiazepine-5-acetate (0.42 g) as a colorless oil.

Use Example 30 5.2 g of tert-butyl-3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1 (S) -ethoxycarbonyl-lipentyl) amino-4-oxo-2 are dissolved in 10 ml of acetic acid. , 3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 10 ml of 30% hydrobromic acetic acid are added to the solution. After allowing the solution to stand at room temperature for 1.5 h, 200 ml of ethyl ether are added to the mixture, and the resulting mixture is left to stand. The supernatant is removed by decantation and the precipitate is dissolved in 90 ml of 1N aqueous sodium hydroxide solution. After allowing the mixture to stand at room temperature for 1.5 h, the mixture is neutralized with 10 ml of acetic acid and purified by MCI gel column chromatography (aqueous methanol = 1: 1). The eluate is concentrated under reduced pressure to a volume of about 10 ml and the precipitated crystals are collected by filtration and dried to give 2.1 g of 3 (R) - (1 (S) -carboxy-5- (4-piperidyl) pentyl) -amino-4- oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid as a colorless crystalline powder, melting at a temperature higher than 270 ° C (decomposition) (C? () D ”130 ° ( water)

Elemental analysis, C 22 H 31 N 3 O 5 S Calculated: C, 58.78; H, 6.95; N, 9.35 Found: C, 58.59; H, 6.99; N, 9.37 IR KBr cm-1: 1670 (amide), 1635, 1610 (carboxylate) max 58 81 089 Application example 31

S- (o-nitrophenyl) -L-cysteine (0.5 g) is dissolved in a mixture of ethanol (40 ml) and water (30 ml) with heating. After cooling to room temperature, ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate (2.3 g) is added to the solution. A solution of sodium cyanoborohydride (0.38 g) in ethanol (50 ml) is added dropwise over 2 h and the reaction mixture is allowed to stand overnight. The reaction mixture is concentrated under reduced pressure, and ethyl acetate (100 ml) and 1% aqueous phosphoric acid solution (50 ml) are added to the residue, followed by extraction. The ethyl acetate layer is washed with 1% aqueous phosphoric acid (50 ml) and water (50 ml), to which is added hexane (100 ml) and saturated sodium hydrogencarbonate solution (50 ml), followed by vigorous stirring. The precipitated yellow oil is separated, weakly acidified with 10% hydrochloric acid and extracted with ethyl acetate (200 ml). The extract is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether is added to the residue to give 2 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) amino-3- (o-nitrophenyl) thiopropionic acid as a yellow powder.

Elemental analysis, C30H39N3O3S · I / 2H2O Calculated: C, 59.00; H, 6.60; N, 6.88 Found: C, 59.06; H, 6.58; N, 7.33 NMR spectrum δ (DMSO-d 6): 7.3 ... 7.6, 7.4, 7.65 ... 7.8, 8.1 ... 8.3 (9H, fenyyliprotoni); 5.1 (2H, methylene proton of the benzyl group) Use Example 32

To a mixture of acetic acid (4 ml) and water (2 ml) is dissolved 2 (r) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) amino-3- (o-nitrophenyl) thiopropionic acid (0.3 g) and zinc powder (0.3 g) is added to the solution. The reaction mixture is stirred at room temperature for 1 h, diluted with water (50 ml) and extracted with ethyl acetate (200 ml). The ethyl

II

59 81 089 The layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Ethyl ether (30 ml) and 5N hydrochloric acid-ethyl acetate solution (0.5 ml) are added to the residue. The precipitated colorless powder was collected by filtration to give 3- (o-aminophenyl) thio-2 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) aminopropionic acid dihydrochloride (0.3 g). .

NMR Spectrum & (DMSO-d 6): 6.8-7.6, 7.4 (9H, phenyl proton); 5.1 (2H, methylene of the benzyl group methylene propron) Elemental analysis, C 30 H 41 N 3 O 6 S · 2HCl • 1 / 2H 2 O Calculated: C, 55.12; H, 6.78; N, 6.43 Found: C, 54.82; H, 6.84; N, 6.68 Use Example 33 3- (o-Aminophenyl) -thio-2 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) is dissolved in N, N-dimethylformamide (5 ml). ) aminopropionic acid dihydrochloride (0.16 g) and diethyl phosphorocyanidate (0.3 ml) is added dropwise to the solution. Triethylamine (0.2 ml) is added to the mixture, and the reaction mixture is stirred under ice-cooling for 1 h. The reaction mixture is diluted with water (100 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography (hexane: acetone = 2: 1) to give 3 (R) - (5- (1-benzyloxycarbonyl-4-piperidyl) -1-ethoxycarbonylpentyl) -amino-2,3-dihydro-1,5 (5H ) -benzothiazepin-4-one as a colorless oil.

IR neat cm-1: 3230, 1730, 1700, 1680 \> max

Claims (5)

6o 81089 A compound of the formula R 6 - A - E-COOR 3 wherein R 3 is hydrogen, C 1-4 alkyl R 6 is 1-benzyloxycarbonyl-4-piperidyl, A is C 2-6 alkylene and E is} C = O or CH- Wa, wherein Wa is halogen or a group represented by the formula RaSO 2 -O-, wherein Ra is C 1-4 alkyl, trifluoromethyl, phenyl or p-tolyl, or a pharmaceutically acceptable salt thereof. Compound according to Claim 1, characterized in that A is tetramethylene. Compound according to Claim 1, characterized in that R a is C 1-4 alkyl. Compound according to Claim 1, characterized in that it is ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-methanesulfonyloxyhexanoate, or ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2- chlorohexanoate, or ethyl 6- (1-benzyloxycarbonyl-4-piperidyl) -2-oxohexanoate. A process for preparing a compound of the formula r 6 -A-e-COOR 3 (L) wherein R 3 is hydrogen or C 1-4 alkyl; R® is 1-benzyloxycarbonyl-4-piperidyl; A is C 2-6 alkylene and E is ^ C = O or CH-Wa, where Wa is halogen or a group represented by the formula li 6i 81089 RaSO 2 -O-, wherein Ra is lower alkyl, trifluoromethyl, phenyl or p-tolyl , or a salt thereof, characterized in that a) a compound of formula R 6 -A-COOR 3 'wherein R 6 and A are as defined above and R 3' is C 1-4 alkyl, and a compound of formula COOR 3 '' COOR 3 '' wherein r 3, is C 1-4 alkyl is reacted in the presence of a base followed by heating and if desired b) a compound of formula (L) wherein E is> 00 is subjected to a reduction reaction followed by a halogenation or sulphonylation reaction , and if desired c) a compound of formula (L) wherein R 3 is C 1-4 alkyl is hydrolysed to give a compound of formula (L) wherein R 3 is hydrogen, and if desired d) the compound of formula (L) thus obtained is converted to its as a pharmaceutically acceptable salt. (62 81 089