JPH01301656A - Carbamate derivative of hydroxyproline - Google Patents

Abstract

NEW MATERIAL: A compound of formula I (wherein R₀ is H; and R₁ is a lower alkyl), a stereoisomer thereof and a salt thereof.

EXAMPLE: trans-1[D-(3-Acetylthio)2-methyl-1oxopropyl]-4-[[(methylamino) carboxyl]oxoy]L-proline.

USE: An intermediate for the synthesis of a carbamate derivative of metcaptoacylsubstituted hydroxyproline as an antihypertensive.

PREPARATION: A hydroxyproline of formula as a starting material is protected with an N-protective group, and then reacted with a duazoalkane to obtain an ester of formula III (wherein R¹ is a lower alkyl; and Cbz is a protective group). This ester is then reacted with an isocyanate, and the product is hydrolyzed with an alkali to obtain a compound of formula IV. This compound is reduced by a known process, and the protective group is removed from the product to obtain a compound of formula I.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to carbamate derivatives of hydroxyproline, and more particularly to novel intermediate compounds for use in the preparation of carbamate derivatives of hydroxyproline, and more particularly, novel mercaptoacyl-substituted carbamel derivatives of hydroxyproline useful as antihypertensive agents.

The intermediate compound according to the present invention is represented by the following formula [■],
It also includes stereoisomers thereof and their salts.

[In the formula, Ro is hydrogen and R is lower alkyl]

In addition, the target compound produced from the compound of the present invention [■] [wherein R is hydrogen, R2 is lower alkyl, R3 is hydrogen, Ro and R1 have the same meanings as above, R4 is hydrogen or R5C〇-
1R5 is lower alkyl, n is 1] and includes novel mercaptoacyl-substituted hydroxyproline carbamate derivatives and salts thereof.

The red stamp in the formula [T] represents the irregular center. Each asymmetric center forms a D-type and an L-type compound, which are responsible groups for their respective isomers in a conventional manner.

Throughout this specification, lower alkyl refers to straight chain or branched hydrocarbon groups not exceeding 7 carbon atoms (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t
-butyl, pentyl, impentyl, etc.).

Lower alkyl having not more than 4 carbon atoms (especially C0 and C2) is preferred.

Lower alkanoyl represented by R5-Co- is lower (C2
~C7) Includes acyl residues of fatty acids (eg acetyl, propionyl, butyryl, imbutyryl, etc.).

The lower alkanoyl has preferably no more than 4 carbon atoms (particularly acetyl).

Carbamate groups on the pyrrolidine ring include lower alkylcarbamoyl (tatoehamethylcarbamoyl, ethylcarbamoyl, furoylcarbamoyl, isoflovircarbamoyl, etc.).

The carbamate group is preferably present at the 3- or 4-position (particularly the 4-position) of the pyrrolidine ring.

Next, the intermediate compound of the present invention [■] and the target compound [■]
The synthesis method will be explained in detail.

The intermediate compound [■] of the present invention can be produced by the following method.

For example, the hydroxyproline starting material represented by
For example, carbobenzoxy, p-toluenesulfonyl,
Protected with acetyl etc., the formula [wherein, Cbz is a protecting group (
Preferably, the protected compound is carbobenzoxy).

This protected compound [III) is reacted with a diazoalkane such as diazomethane to give the formula: [wherein R' is lower alkyl (eg methyl or isobutyl, preferably methyl) and Cbz has the same meaning as above]. The ester shown is obtained.

The above ester [IV] and incyanate: Rnie NC
By reacting O in an inert organic solvent (such as benzene), the ester compound [wherein R' and Cbz have the same meanings as above] is obtained.

By allowing this reaction to proceed in the presence of a catalytic amount of a base (eg, pyridine or triethylamine), the cis isomer of the compound [■] can be obtained.

Compound [v] is obtained by reacting protected compound [IV] with phosgene to obtain a compound represented by the formula: [wherein R' and Cbz have the same meanings as above], and this compound (which is isolated and subjected to an isolation reaction). It can also be obtained by letting

By alkaline hydrolysis of these compounds [v] with a base (for example, sodium hydroxide, barium hydroxide, potassium hydroxide, etc.), the formula: [wherein RO, R1 and Cbz have the same meanings as above] An N-protected proline derivative represented by can be obtained.

This protected proline derivative [■] is then reduced in a conventional manner (e.g., hydrogenated in the presence of palladium/carbon) to remove the protecting group, giving the formula: [where Ro and R are as defined above] A carbamate derivative of hydroxyproline can be obtained.

The intermediate compound [■] of the present invention is a new compound, and the target compound [I] can be produced by using the compound [■] of the present invention as an intermediate. That is, this intermediate [■] and the acid represented by the formula: %formula% [:1 [wherein R2, R3, R5 and n have the same meanings as above] or its chemical equivalent (most preferably By reacting the acid chloride form thereof [in the formula, Ro
, R1, R2, R3, R5 and n have the same meanings as defined above.] A product (target compound in which R4 is R5-C〇-) can be obtained.

The proline derivative CXI is preferably purified and isolated. Purification is preferred, for example, by forming and crystallizing the corresponding salt (such as the dicyclohexylamine salt) and then converting the salt to the free acid form by treating the salt with an acid (eg, acidic potassium sulfate).

The compound [X] having an acyl group: R5C0- can be hydrolyzed with ammonia, sodium hydroxide, etc., if necessary, to obtain the target compound CI) in which R4 is hydrogen.

Other manufacturing methods for the starting material CII) and intermediate [■] are described in the following documents: U.S. Pat. No. 4,046,889, U.S. Pat. No. 4,105.
．． No. 776, Journal of the American Chemical Society (J-Chem, Soc,) Published in 1945, pp. 429-432, Journal of the American Chemical Society (J, Amer, Chem)
.

Soc, ) Vol. 79, pp. 185-192 (1957),
Volume 85, pp. 3863-3865 (1963). The methods described in the above-mentioned documents can be used for the general procedures for producing the compounds of the present invention and for converting them into stereoisomeric forms.

As mentioned above, the target compound C] has several asymmetric centers. Each of the target compounds IJ) exists as stereoisomers or racemic mixtures thereof. Various stereoisomers and mixtures thereof are all included within the scope of the target compound [■]. In the above synthetic method, starting materials (including intermediates)
The racemate or either type of enantiomer can be used as. When a mixture of stereoisomers is obtained as a product, it can be separated, if necessary, by conventional chromatography or fractional crystallization, or converted into a salt by treatment with an optically active base, followed by fractional crystallization. can be isolated as its individual stereoisomers by separation method or similar methods. Generally, the target compound [■] is preferably a compound in which the proline moiety is L-configuration, the carbamate group is cis-configuration, and the acyl side chain moiety is D-configuration.

The target compound CI) is treated with various inorganic or organic bases to form salts with the corresponding bases. Examples of salt-forming ions derived from such bases are as follows. Metal ions, such as aluminum ions, alkali metal ions (such as sodium or potassium), alkaline earth metal ions (such as calcium or magnesium) or ions of the many amine salts known for this purpose, such as aralkylamines (dibenzyl amines, N,N-dibenzylethylenediamine, etc.), lower alkyl amines (methylamine, triethylamine, t-butylamine, etc.), procaine, lower alkylpiperidines (N-ethylpiperidine, etc.), cycloalkylamines (cyclohexylamine, dicyclohexylamine, etc.) ), 1-adamantanamine, benzathine or amino acids (argin, lysine, etc.) and their derived salts. These or other salts need not be physiologically acceptable and may be used to isolate and purify products suitable for purposes such as those described below and to The salt is useful for isolating and purifying the intermediate as described.The salt is a base that provides the desired basic ion and the acid form of the desired compound] is added to the medium (the medium in which the salt is precipitated) or an aqueous solution. It can be obtained by reacting it in a medium and freeze-drying it.The free acid form of the compound can be obtained again by a conventional neutralization method (for example, by treating it with potassium hydrogen sulfate or hydrochloric acid). can.

The target compound [1] (including its stereoisomers and salts) inhibits the conversion of angiotensin I (decapeptide) to angiotensin It is useful in reducing or alleviating hypertension in dogs, mice, rats, etc.). Hypertension in mammals can be reduced or cured by administering an antihypertensive effective amount of a composition containing a mixture of one or more of the target compound [I) or its physiologically acceptable salts] .

Standard animal experiments [S, L, Engel
), Schaeffer = (T, R, 5chaeffer ),
Woff (M, H.

Waugh) and Rubin (B.) et al.: Proceedings of the Society for
Experimental Biology and Mesocine (Proc, Soc, Exp, Biol, M
ed, ) Vol. 143, p. 483 (see 1973)
As shown by (hereinafter, based on a dosage of about 0.1 to 100 μ/kQ/day, preferably about 1 to 50 μ/kQ/day of the target compound to lower blood pressure,
It is preferable to administer this once a day or in 2 to 4 divided doses. The active compound can be administered subcutaneously, although oral administration is preferred.
Administration may also be by parenteral methods such as intramuscular, intravenous or intraperitoneal administration.

The target compound [I] can also be formulated in combination with a diuretic for the treatment of hypertension.

Target compound per day for a mammal weighing 70 kq [
T] Total amount from about 30 to 600, preferably about 30 to 300
mQ and diuretic about 15~300■, preferably about 15~
A composition comprising the desired compound and a diuretic can be used by administering an effective amount of 200 μm to a mammal in need thereof. Diuretics that can be included include thiazide diuretics, such as chlorthiazide, hydrochlorothiazide, flumethiazide, hydroglumethiazide, pendroflumethiazide, methochlorthiazide, trichlormethiazide, polythiazide or benzthiazide, as well as ethacrylic acid, ticlinafene. ,
Examples include chlorthalidone, furosemide, bumetanide, triamterene, amiloride, and spironolactone or salts of these compounds.

Since the target compound [■] is used as an antihypertensive agent, it can be formulated into a composition such as a tablet, capsule, or elixir for oral administration, or a sterile solution or suspension for parenteral administration.

Target compound [■] and one or more physiologically acceptable salts thereof as a mixture of 10 to 500
It is preferable to mix (1) with a physiologically acceptable medium, carrier, excipient, binder, preservative, stabilizer, flavoring agent, etc. to formulate a pharmaceutically acceptable unit dosage form. The amounts contained in these compositions should be such that a suitable amount of active ingredient within the ranges described above is contained in a unit dosage form.

Examples of adjuvants that can be incorporated into tablets, capsules, etc. are as follows. Binders such as gum tragacanth, gum arabic, cornstarch, gelatin;
Excipients such as dicalcium phosphate, microcrystalline cellulose; disintegrants such as cornstarch, l-tetostarch, alginic acid, etc.; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, saccharin; Flavoring agents such as peppermint, wintergreen oil, and cherry.

When the dosage unit form is a capsule, it may contain, in addition to materials such as those enumerated above, a liquid carrier such as a fatty oil. Various materials can be used to coat or modify the external shape of the dosage unit form. For example, the tablets may be coated with shellac, sugar or a mixture of both. A syrup or elixir contains, in addition to the active compound, a sweetening agent, such as sucrose; and a preservative, such as methylparaben or propylparaben.

A coloring agent; a flavoring agent such as cherry flavor or orange flavor may be included.

Sterile injectable compositions include the active compound dissolved or suspended in a carrier such as sterile injectable water, a natural vegetable oil (such as sesame oil, coconut oil, peanut oil, cottonseed oil, etc.) or a synthetic oil (such as ethyl oleate). , can be formulated according to normal pharmaceutical practice.

Next, the present invention will be specifically explained with reference to Examples.

Example 1 trans-1-CD-(3-acetylthio)-2
-Methyl-1-oxopropyl)-4-[(methylamino)carbonyl]oxy]-L-proline production Ni a, N-carbobenzyloxy-trans -4-hydroxy-L-proline production Ni 200m+! and 100ml of acetone! In the presence of 20.9 p (0.20 mol) of potassium bicarbonate and 69.2 p (0.50 mol) of potassium carbonate, 26.5 p (0.20 mol) of trans-4-hydroxy-L-proline and chlorophyll were added. 32.8 mQ of benzyl acid (0.23 mol) was reacted, and the Canadian Journal of Biochemistry and Physiology (Can, J.
, Biochem, k Physiol, ) No. 37
The treatment with concentrated sulfuric acid 90 is completed according to the procedure described in Vol. 584 (1959). React the product with cyclohexylamine to obtain 69g of its cyclohexylamine salt.
get. Melting point: 193-195°C. 34.9 g of this salt was neutralized with N-hydrochloric acid to obtain 27 g of colorless glass-like free acid.

[α,] −−70° (in chloroform, concentration C = 1%)
.

b, Preparation of N-carbobenzyloxy-trans-4-hydroxy-L-proline methyl ester: - N-carbobenzyloxy-trans-4-hydroxy-L-proline 12.4. p (0,047 mol) in dioxane-ether, The Journal of the
American Chemical Nsaetei (J.

A, C, S,) Vol. 79, p. 191 (1957, 9), esterification is carried out with diazomethane. During this time, to avoid freezing of dioxane, the temperature is initially 10°C and finally 0 to 0.
Processing is carried out at 2°C. N-carbobenzyloxy-trans-4- is mostly produced as a colorless viscous oil.
Hydroxy-proline methyl ester product 14
．． 6. p(100%) was obtained. [α]--62° (in chloroform, concentration C - 1%).

c, trans -N-carbobenzyloxy-4-
Preparation of [[(methylamino)carbonyl]oxy)-L-proline methyl ester N-carbobenzyloxy-tranS-4-hydroxy-proline methyl ester (ml J.

A, C, S, see Volume 79) 6. O, F (o, 02
While stirring the solution of 120 m (1 mol) of benzene,
To this are added 6 mfl (0.10 mol) of methyl isocyanate and the mixture is kept at room temperature overnight. After further refluxing for 1 hour, the final 0.2 my
Remove the solvent under xHfil at 50°C. The viscous residue was dissolved in 150 mQ of ether and 50 mff1 of water.
After washing with water three times (50ml x 3) and drying with magnesium sulfate, the ether was evaporated and a syrupy
-N-carbobenzyloxy-4-4[(methylamine)carbonyl]oxy)-L-proline methyl ester product 6.5. p (90%) was obtained.

d, trans -N-carbobenzyloxy-4-
Production of [(methylamine)carbonyl]oxy-L-proline 7.6.9 (0,02
3 mol) in methanol 60 mff1, -1 to 4
14 mQ of 2N sodium hydroxide, (0028 mol) at °C
was fed and kept at 0°C for 1 hour and at room temperature overnight. After removing about half of the solvent on a rotary evaporator, the solution is diluted with 160 mQ of water, washed with ether, and the washing liquid is discarded. ), adjust the pH to 2 with 5.5-ml of hydrochloric acid (1:1) while cooling, and extract 4 times with 75ml of ethyl acetate. After washing with 50 ml of IJum and drying over magnesium sulfate, the solvent is evaporated to give 7.2 g of a very sticky syrupy substance. Add this to 3 ethanol
0 mQ, treated with a mixture of 2.3.7 cyclohexylamine and 5 ml of ethanol, and 600 m of ether.
Dilute with ff1. Seed and stir to form the crystalline cyclohexylamine salt. - After cooling overnight, 85 g of salt product are obtained. Melting point: 172-174°C. [α]ゎm−20° (in ethanol, concentration c=1%). Isoproper tool 25m1! trans -N-carbobenzyloxy-4-
C[(methylamine)carbonyl]oxy:1-L-florin cyclohexylamine salt 7.8y was obtained. Melting point: 174-176°C. [α]--18° (in ethanol,
Concentration c=1%].

This cyclohexylamine salt is suspended in ethyl acetate 60, stirred and treated with 40 mQ of N-hydrochloric acid.

When two clear layers are obtained, separate each layer and add 60ml of ethyl acetate to the aqueous layer! The organic layers were combined and dried over magnesium sulfate, and the solvent was evaporated to give a glass-like free acid product, 5.5.9 (81%).

e, production of trans -4-CC(methylamino)carbonyl]oxy]-L-proline: -pa/l/(
Parr) On the hydrogenation apparatus, trans -N-carbobenzyloxy)-4-4[(methylamine]carbonyl]oxy]-L-proline 2.7, p (0°00
A 100 mu solution of 84 mol) in methanol-water (2:1) is shaken for 6 hours with 1 g of 5% palladium-carbon and hydrogen 451b. The catalyst was filtered off under a nitrogen atmosphere, washed with methanol, the filtrate and the washing liquid were combined, and the final
Evaporation with mM Hp gives a residue 1.5.7 (96%). This stuff gradually crystallizes. trans -4-[[(methylamino)carbonyl] as a gray solid.
Oquin]-L-proline was obtained. When heated, it gradually turns dark in color and sinters and melts. Melting point 213-215℃ (decomposition)
. [α] row--12° (ethanol-methanol (1:
3) Medium, concentration c=0.25%).

f, trans-1-CD (3-acetylthio)-
2-Methyl-1-oxopropyl)-4-[(methylamine)carbonyl]oxy: Production of 1-L-proline゛-trans-4-CC(methylamine)carbonyl]
A solution of 2.9.7 (0,0154 mol) of oxy]-L-proline in 45 mff1 of water was cooled to 5° C. with stirring.
Solid carbonate) Add IJum little by little (total about 0.4g)
It takes. ), adjusted to pH 8.5. 25% (W
/V) D-3-acetylthio-2 was added dropwise to maintain the pH at 7.0 to 8.0, stirred, and cooled.
-Methylpropanoyl chloride 3.1g (0,Ol, 7
A solution of 4 mg of ether (mol) in ether is added dropwise in small portions. After about 10 minutes, the pH becomes stable at 8.1 to 83 (approximately 14% of sodium carbonate is added in advance to stabilize the pH).

). After stirring and cooling for a total of 125 hours, the solution was washed with 50 ml of ethyl acetate, 50 mcl of ethyl acetate was added to form an ethyl acetate layer, stirred, cooled, and diluted with hydrochloric acid (
After carefully adjusting the pH to 2.0 (1:1) and saturating with sodium chloride, the layers are separated. The aqueous layer is further extracted three times with 50 mQ of ethyl acetate, the organic layers are combined and dried over magnesium sulfate, and the solvent is finally evaporated under reduced pressure to 0.2ffffH7 to obtain 5.3 g of a glass-like residue. Dissolve this in 40 mQ of ethyl acetate, and add a 15-proof solution of 2.8 g of dicyclohexylamine in ethyl acetate.

Add seed crystals and stir to obtain crystalline trans-1-CD.
-(3-acetylthio)-2-methyl-1-oxopropyl)-4-[(methylamine)carbonyl]oxy)
-L-proline dicyclohexylamine salt precipitates. - After cooling overnight, 5.8 g of colorless product were obtained. Melting point 1
87-189°C (sintering point 183°C. [α:]--64
° (in methanol, concentration c=1%). Methanol 15m
Recrystallization from 100 mQ of Q-ether gave 4.5 g of a colorless solid product. Melting point: 190-192°C. [α] -
−67° (in methanol, concentration c=1%).

Co(71)dicyclohexylamine salt was converted into acetic acid-[-f-
10% potassium hydrogen sulfate 50mQ
and stir until a clear liquid with two layers is obtained.

The dicyclohexylamine salt is converted to its free acid by separating each layer, extracting the aqueous layer three times with 50 mQ of ethyl acetate, and combining the organic layers and drying over magnesium sulfate. Evaporate the solvent and leave as a hygroscopic foamy residue.
ns -1-CD -(3-acetylthio)-2-methyl-1-oxopropyl]-4-[(methylamine)carbonyl]oxy]-L-proline 2.8.7 (55%
) was obtained.

Example 2 trans-1-(D-3-mercapto-2-methyl-
Preparation of (1-oxopropyl)-4-[(methylamino)carbonyl]oxy]-L-proline: 6 mQ of concentrated ammonium hydroxide and 4 mQm of water were heated and argon was passed for 10 minutes. Add this to the product of Example 1 while cooling under an argon atmosphere and stir on a water bath until the mixture becomes a pale yellow solution (approximately 3 minutes). After continued stirring at room temperature under an argon atmosphere for 2 hours, the solution was diluted with ethyl acetate.
Extract at 0 mA (this operation and subsequent operations should be performed under an argon atmosphere as much as possible). The aqueous layer was cooled, stirred, extracted with 20 mQ of ethyl acetate, and diluted with hydrochloric acid (1:1) for approx.
Add 3mQ little by little to make acidic. The layers were separated, the aqueous layer was further extracted three times with 20 m ethyl acetate (!), the ethyl acetate layers were combined and dried over magnesium sulfate, and the solvent was evaporated to leave a sticky foamy residue. -3-
Mercapto-2-methyl-1-oxopropyl)-4-
[[(Methylamino]carbonyl]oxy]-L-proline is obtained. This is stirred with ether and finally 0
．． Evaporation under reduced pressure to 1-0.2 mffH7 yielded 2.2 p (9
0%) was obtained. Melting point: 54-57℃ (sintering point: 45℃)
α), -53° (in ethanol, concentration c=1%).

In place of the L-type amino acids in Examples 1 and 2 above, L-type amino acids were used and the same operations were carried out to obtain racemic products of the respective examples.

Similarly, D-type amino acids were used in place of L-type amino acids in Examples 1 and 2 to obtain D-type products.

Example 3 Production of cis-1-[D-(3-acetylthio)-2-methyl-1-oxopropyl]-4-[[(methylamine)carbonyl]oxy]-L-proline Preparation of benzyloxy-cis-4-hydroxy-proline methyl ester N-carbobenzyloxy-cis-4-hydroxy-L-
Proline [J, A, C, S, Vol. 79, p. 189 (195
7th grade) Reference) 6.5. P (0,024 mol) was dissolved in methanol 65 mff1, stirred, and concentrated sulfuric acid 0°65 md
! Add. After stirring this for 30 minutes at room temperature, the solution is left overnight. Most of the solvent was evaporated on a rotary evaporator and 13.7 ml of the oily residue was dissolved in 70 mQ of ether and 35 ml of 10% sodium bicarbonate! Wash with Washing liquid with 35ml of ether! Reverse extract with . The organic layers were combined and dried over magnesium sulfate and the ether was evaporated to give the product asy (96%) as a thick pale yellow oil. [α]0--24° (in chloroform, concentration c=1
%).

b, Production of cis-N-carbobenzyloxy-4-[[(methylamine)carbonyl]oxy]-L-proline methyl ester N-carbobenzyloxy-cis-4-hydro+'/
-L-j Lorin Methyl Ester 5.4. @(0゜01
9 mol) of acetonitrile 120ml! While stirring the solution, 5.4 m(!) of triethylamine are added, followed by 5.4 mQ of methyl isocyanate. After standing overnight at room temperature and refluxing for 2 hours, the reaction mixture is treated as in Example 1c. 5.6 g (86%) of a viscous pale yellow oil.
) was obtained.

c, cis -N-carbobenzyloxy-4-[[
Production of (methylamine)carbonyl]oxy]-L-proline 5.6 g (0,017
mol) and methanol 45m+! in the same manner as in Example 1d. During,
Saponification with 11 mQ (0,022 mol) of 2N sodium hydroxide gives 51 g of a foamy residue. Add this to ethanol 25
+r+L! : 400ml of 114'l of ether and 1.7y of cyclohexylamine were treated to obtain 4.8g of colorless cyclohexylamine salt. Melting point: 171-173°C. [α]
−16° (in ethanol, concentration c=L%). Recrystallization from ethanol-ether gives a salt having the same melting point and specific rotation as above. From this cyclohexylamine salt the desired free acid 3.5. p
(65%).

d, Preparation of cis -4-C[(methylamine)carbonyl]oxy]-L-proline in 130 mM of methanol-water (2:1).
-carbobenzyloxy-4-[(methylamine)carbonyl]oxy]-L-proline 3.5.9 (0,01
1 mol) was added to 5% palladium-carbon 1 as in Example 1e.
．． Hydrogenated with 3.9 to give product 1.9,9 as a gray solid
(95%). When heated, it gradually becomes dark and sintered. Melting point: 232-234°C (during decomposition, concentration c = 0.5%)
.

e, cis-1-CD-(3-acetylthio)-2-methyl-1-oxopropyl)-4-[(methylamine)
Preparation of cis-4[:[(methylamino)carbonyl]oxy)-L-proline 1.85.7 (0,0098 mol) and D-3-acetylthio-2-methyl Propanoyl chloride 2, O,p (0,011 mol) is reacted in 30 mR of water in the presence of sodium carbonate as in Example 1f to give 335 g of a gummy product.

Add this to 35ml of ethyl acetate! Inside, dicyclohexylamine 1.8! Treatment with y gives its synchhexylamine salt 4.0,9. Melting point: 177-179°C.

[α] 25--54° (in methanol, concentration c = 1%)
. Treat with 20 mQ acetonitrile and cool to form a colorless solid 3.6. Get @. Melting point: 179-181°C.

[α] 25--54° (in methanol, concentration c = 1%)
. This salt was treated with 10% potassium hydrogen sulfate and extracted with ethyl acetate to give the desired free acid as a colorless foamy residue.
17 (76%) was obtained.

Patent Applicant: E.R. Squibb & Sons, Inc.

Claims (1)

[Claims] 1. A compound represented by the following formula, ▲Mathical formula, chemical formula, table, etc.▼ [In the formula, R_0 is hydrogen and R_1 is lower alkyl] or a stereoisomer thereof, or a salt thereof.