CA1058198A - Carbonic acid esters, and the preparation thereof and their use - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A process and novel carbonic acid ester for the protect-ion of amino and ?mino groups in amino and imino group - containing compounds is provided; the process comprises reacting an amino or imino group - containing compound with a crabonic acid ester of the formula:

wherein R1 is a lower alkyl which may have one or more substituents selected from the group of halogen, lower alkoxy and aryloxy, or ar(lower)-alkyl which may be unsubstituted or substituted with a substituant selected from the group of lower alkoxy ha??gen, nitro and cyano, and R2 is a group represented by the formula:

Description

1058~98 The present invention relates to new carbonic acid ester which is useful as an agent for introducing esterified carboxy-type protective group(s) on amlno and/or imino group(s) in amino and/or imino group(s)-containing compounds and to processes for the preparation thereof.
Further, the present invention relates to a process for the temporary protection of amino and/or imino group(s) in amino and/or imino group(s)-containing compounds with esterified carboxy-type protective group(s), As is known, such a temporary protection of amino and/or imino group(s) is of great importance in the ~ield o~
preparative chemistry as well as of degradation reactions, for example, in peptide-chemistry, penicillin-chemistry, cephalo-sporin-chemistry, alkaloid-chemistry, determination of the constitution o~ unknown compounds such as natural products, and the like.
The present invention i9 based on the observation that a carbonic acid ester of the formula (I) as shown below is a much more favourable agent for the temporary protection of amino and,/or imino group(s) in the compound in comparison with the agents which have been conventionally employed in the arts in the following regards.
That i9 to sly:
(1) that said carbonic acid ester is present in stable oil or crystals and is free from explosiveness, corrosiveness or irritativeness which are oft~n caused by the conventional agents so that it is much more favourable and safe for handling in experimentally as well as industrially practical use,

(2) that said carbonic acid ester can be easily prepared, and r n

(3) that said caxbonic acid ester reacts rather rapidly with amino and/or imino group(s)-containing organic compounds under milder reaction conditions to give protected amino and/or imino group(s)-containing compound so that undesired troublesome side reactions and production of by-products, which often occur unfavourably in case of using the conventional agents, can be minimized or in some case substantially avoided.
And, in such a reaction of said carbonic acid ester with the amino and/or imino group(s)-containing co~pound, there may be produced a compound of the formula:

wherein R2 is as defined below, as a substantially sole by-product which can be so easily recovered in practical purity from the reaction mixture by a conventional manner such a~
extraction and may be used repeatedly without any further purification, as a starting material, for the preparation of 0 the compound (I) of the present invention, Accordingly, the present invention provides a process for the protection of amino and/or imino group(s) in an amino and/or imino group(s)-containing compound, which co~prises reacting an amino and/or imino group(s)-containing compound with a carbonic acid ester of the formula:
RlOCOOR2 (I) wherein Rl is lower alkyl which may have substituent(s) selected from the group of halogen, lower alkoxy and aryloxy, or ar(lower)alkyl which may have substituent(s) selected from the group of lower alkoxy, halogen, nitro and cyano, and R2 is a group represented by the formula:

Q 2 _ . ~

.

- 105~198 -N=C ~
~z wherein ~ and Z are each aryl which may have substituent(~) selected from the group of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl, or an electron withdrawing group.
According to said reaction, the esterified carboxy group (RlOCO-) in the carbonic acid ester (I) can be intro-duced on the amino and/or imino group(s) in the amino and/or imino group(s)-containing compound for the protection to pro-vide the protected amino and/or imino group(s)-containing compound, For this purpoce, there may be used as starting material any desired amino and/or imino group(s)-containing compounds, especially an organic compound including all of an aliphatic, an aromatic or a heterocyclic compound, etc., each of which contains at least one amino or imino group in the molecule.
In this specification and claims, the term "lower" is intended to mean a group having 1 to 6 carbon atom(s) unless otherwise indicated.
A suitable example of lower alkyl for Rl may include one, which may be branched or cyclic and, having 1 to 6 carbon atom(s) such as methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, 1-cyclopropylethyl, cyclopropyl, cyclopentyl, cyclohexyl or the like, and preferably one having 2 to 5 carbon atoms, and these lower alkyl groups may have optionally at least one substituent selected from the group of halogen (e.g., chlorine, bromine, fluorine or iodine), lower alkoxy having 1 to 6 carbon atom(s) (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-b~to~y, pentyloxy, hexyloxy, etc.) and aryloxy having 6 to 10 carbon lQ5~3~98 atoms (e.g., phenoxy, tolyloxy, xylyloxy, naphthyloxy, etc.).
A suitable example of ar(lower)alkyl for Rl may include one having 7 to 10 carbon atoms such as benzyl, phenethyl, tolylmethyl, xylylmethyl, mesitylmethyl or the like, and pre-ferably one having 7 to 8 carbon atoms, and these ar(lower)alkyl groups may have optionally at least one substituent selected from the group of the aforementioned lower alkoxy, halogen, nitro and cyano.
A suitable example of aryl for Y and Z may include one having 6 to 10 carbon atoms such as phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl or the like, and these aryl groups may have optionally at least one substituent selected from the group of the aforementioned halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl (e.g., trichloromethyl, trifluoromethyl, etc.).
A suitable electron withdrawing group for Y and Z may include cyano; nitro; an acyl such as lower alkanoyl having 1 to 6 carbon atom(s) (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, etc.), aroyl having 7 to 11 carbon atoms (e.g., benzoyl, toluoyl, xyloyl, naphthoyl, etc.), e~terified carboxy, for example, lower alkoxycarbonyl having 2 to 7 carbon atoms (e.g., methoxycarbonyl, ethoxy-carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, l-cyclopropylethoxy-carbonyl, cyclohexyloxycarbonyl, etc,), ar(lower)alkoxy-carbonyl having 8 to 9 carbon atoms (e.g., benzyloxycarbonyl, p~enethyloxycarbonyl, etc.) or aryloxycarbonyl having 7 to 8 carbon atoms (e.g., phenoxycarbonyl tolyloxycarbonyl, etc.), carbamoyl, disubstituted carbamoyl, for example di(lower)alkyl-carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, methyl-ethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl, dibutyl-carbamoyl, etc.), lower alkylarylcarbamoyl (e.g., methylphenyl-1~ 3 - 4 -1058~98 carbamoyl, ethylphenylcarbamoyl, etc.) or diarylcarbamoyl (e.g., diphenylcarbamoyl, ditolylcarbamoyl, etc.) or the like: or the like.
The present reaction may be conducted in a conventional manner, i.e. under conditions which have been used in the known reaction for the protection of amino and/or imino group(s) in the compound with an esterified carboxy group. More particularly, the reaction may be conducted in a conventional solvent such as water, an alcohol (e.g., methanol, ethanol, propyl alcohol, butyl alcohol, tert-butyl alcohol, etc.), ethyl acetate, chloroform, dimethylformamide, methylene chloride, tetrahydrofuran, acetone or the like, or a mixture thereof, or other solvents which do not adversely affect the present reaction. The reaction may be optionally carried out in the presence of a base such as an inorganic base, for example, an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkaline earth metal hydroxide (e.g., calcium hydroxide, ma~nesium hydroxide, etc.), an alkali metal carbonate (e.g., sodium carbonate,-potassium carbonate, etc.), an alkaline earth metal carbonate (e.g., calcium carbonate, magnesium carbonate, etc.); an alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), or the like; an organic base, for example, an alkali metal acetate (e.g., sodium acetate, potassium acetate, etc.), tri-alkylamine ~e.g., trimethylamine, triethylamine, etc.), tri-ethanolamine, ~,N-dimethylaniline, N,N-dimethylbenzylamine, N,N'-; dimethylpiperazine, N-methylmorpholine, pyridine, quinoline, or the like; or a basic ion-exchange resin, or a mixture thereof.
The reaction temperature is not particularly limited, but the reaction is preferably carried out around room temperature.
The product having the protected amino and/or imino group(s) thus prepared can be isolated by a conventional method.

Thu~ prepared the protected amino and/or imino group(s)-containing compound can be used for further synthesis of known or new compounds, in which it is inevitable to protect amino and/or imino group(s) in the compound in order to avoid any side-reaction, production of by-product and the like, And, the protected amino and/or imino group(s)-containing product thus synthesized may be subsequently ~ubjected to scission of the said protective group, i,e., e~terified carboxy group, to regenerate the free amino and/or imino group(s)-containing product, Such subsequent scission of the esterified carboxy type protective ~roup(s) can be carried out by a conventional method, The representative examples of the present carbonic acid ester (I) may be illustrated as follows:
2-Lower alkoxycarbonyloxyimino-2-cyanoacetamide (e.g., 2-ethoxy-carbonyloxyimino-2-cyanoacetamide~ 2-i~obutoxycarbonyloxyimino-2-cyanoacetamide or 2-methoxycarbonyloxyimino-2-cyanoacetamide), di(lower)alkyl 2-lower alkoxycarbonyloxyiminomalonate (e.g., diethyl 2-ethoxycarbonyloxyiminomalonate or diethyl 2-tert-butoxycarbonyloxyiminomalonate),lower alkyl 2-lower alkoxycarbonyloxyimino-2-cyanoacetate (e.g., ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate, ethyl~2-i~obutoxycarbonyloxyimino-2-cyanoacetate, ethyl 2-methoxycarbonyl-oxyimino-2-cyanoacetate or ethyl 2-tert-pentyloxycarbonyloxy-imino-2-cyanoacetate), lower alkyl 2-halo(lower)alkoxycarbonyloxyimino-2-cyanoacetate [e.g., ethyl 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyâno-acetate], - lower alkyl 2-ar(lower)alkoxycarbonyloxyimino-2-cyanoacetate (e.g., ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate), ~ - 6 -.~ ~

~058~98 lower alkyl 2-lower alkoxycarbonyloxyiminoacetoactetate (e,g., ethyl 2-tert-butoxycarbonyloxyimlnoacetonacetate), di(lower)alkyl 2-lower alkoxysubstituted ar(lower)alkoxycarbonyl-oxyiminomalonate ~e,g,, diethyl 2-(4-methoxybenzyloxycarbonyl-oxyimino)malonate], 2-lower alkoxycarbonyloxyimino-1-aryl(lower)alkane-1,3-dione (e,g,, 2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione), l-lower alkoxycarbonyloxy-6-halobenzotriazole (e,g,, l-tert-butoxycarbonyloxy-6-chloro-lH-benzotriazole or l-ethoxycarbony~-loxy-6-chloro-lH-benzotriazole), , 1-artlower)alkoxycarbonyloxybenzotriazole (e,g., 1-benz~loxy-carbonyloxy-IH-benzotriazole), 2-lowex alkoxycarbonyloxyimino-2-arylacetonitrile [e,g,, 2-tert-butoxycarbonyloxyimino-2-phenyl-acetonitrile, 2-tert-butoxycarbonyloxyimino-2-(l-naphthyl)acetonitrile or 2-(1-cyclopropylethoxycarbonyloxy-imino)-2-phenylacetonitrile~, benzophenone 0-lower alkoxycarbonyl-oxime (e,g,, benzophenone 0-tert-butoxycarbonyloxime), 2-halo(lower)alkoxycarbonyloxyimino-2-arylacetonitrile [e,g,, 2-(2,2,2~trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile], 2-lower alkoxy substituted or unsubstituted ar(lower)alkoxy-carbonyloxyimino-2-arylacetonitrile [e,g,, 2-(4-methoxybenzyl-oxycarbonyloxyimino)-2-phenylacetonitrile or 2-benzyloxy-carbonyloxyimino-2-phenylacetonitrile), 2-lower alkoxycarbonyloxyimino-2-halogen substituted aryl-acetonitrile [e,g., 2-tert-butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile] or the like.
The carbonic acid ester o~ the ~ormula (I) to be used for the said protection includes,new and known compounds, and the present invention also provides new carbonic acid esters and processes for the preparation thereof, ni L ~ ~ - 7 -~058~98 The new carbonic acid ester is represented by the following formula:

R'lOCOOR 2 (I') wherein R'l i9 lower alkyl which may have substituent(s) selected from the group of halogen, lcwer alkoxy and aryloxy, or ar(lower)alkyl which may have substituent(s) selected from the group of lower alkoxy, halogen, nitro and cyano, and R'2 is a group represented by the formula:

~ Z ' wherein Y' and Z' are each aryl which may have substituent(s) selected from the group of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl, cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl, aroyl or disubstituted carbamoyl;
provided that when R'2 is a group represented by the formula:

~Y "
-N=C~

wherein Y' and Z' are each cyano, nitro, carbamoyl or esterified carboxy, R'l is ar(lower)alkyl having substituent(s) selected from the group of lower alkoxy, halogen, nitro and cyano, and further provided that when R'l is lower alkyl and R'2 is a group represented by the formula:

~ l z wherein Y' is cyano and Z' is aryl,;the number of carbon atoms of lower alkyl for R'l is 4 or 5~
Suitable examples of lower alkyl and ar(lower)alkyl for R'l and the substituents thereof may be the same ones as illustrated as the examples of the definitions for Rl, respectively.

~ , - 8 -Suitable examples or aryl, the substitutents thereof,, esterified carboxy, lower alkanoyl, aroyl and disubstituted carbamoyl for Y' and z' may be the same ones as illustrated as the examples of the definitions for Y and z.
The new carbonic acid ester o~ the formula (Il) can be prepared by reacting a haloformic acid ester of'the formula:
X-COOR12 (II) wherein X is halogen and R'2 is as defined above, with a hydroxy-compound of the formula:
R'l - OH (III) wherein Rll is as defined above.
A suitable example of halogen for X can be also referred to the ones exemplified as the substitutent'of lower alkyl for Rl.
~ he reaction of the compound (II) with the compound (III) is usually carried out in a conventional solvent such as chloroform, tetrahydrofuran, ether, acetonitrile, ethyl acetate, acetone, benzene, n-hexane, petroleum ether, dioxane or any other organic solvent which does not adversely affect the reaction.
These solvents may also be used in a mixture thereof. The re-action is preferably carried out in the presence of a base suchas inorganic base, for example, alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc~), alkaline earth metal hydroxide (e.g., calcium hydroxide, magnesium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., calcium carbonate, magnesium carbonate, etc.), alkali metal bicarbonate , (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or the like, or organic base (e.g., trimethylamine, triethylamine, tri-ethanolamine, dimethylaniline, pyridine, qùinoline, etc.). These bases may be used alone or in combination. The reaction tempera-ture is not limitative, and the reaction is preferably carried out around room temperature or comparatively lower temperature.

;1~ 9 Alternatively, the new carbonic acid ester (I') can be prepared by reacting a formic acid ester of the formula:
R'l - OCOX' (IV) wherein R~ as defined above and x' is halogen, with a compound of the formula:
R 2 OH (V) ~herein R'2 is as defined above or a salt thereof.
The suitable halogen for X,' is also referred to the ones exemplified as the substituent of lower alkyl for Rl, The suitable salt of the compound (V) is also referred to the ones exemplified below for the compound (VI).
In the present reaction, there can be employed almost the same solvent, base and reaction temperature as those employed in the reaction of the compound (II) with the compound (III) as mentioned above, and in addition, water or its mixture with the solvents mentioned above may also be used optionally according to the property of the compound (IV).
The compound (I') can be also prepared by reacting a mixture of the compounds (V) or a salt thereof, (III) and (VII) or a reactive equivalent thereof, in which the reaction may proceed via the same mechanism of reacting the compound (II) with the compound (III) and/or reacting the compound (IV) with the compound (V).
The starting compound (II) to be used in the above process include partially new compounds, which are represented by the following formula:
X - COOR"2 (II'~
wherein X is as defined abo~e and R"2 is a group represented by the formu-la:

~Y
-N=C
~Z"

~ ..

1058~8 wherein Y" is aryl which may have substituent(s) selected from the group of halogen, lower alkoxy, nitro, cyano and halo(lower)-alkyl, cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl, aroyl or disubstituted carbamoyl and Z" is naphthyl, aryl having substituent(s) selected from the group of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl, lower alkanoyl, aroyl or disubstituted carbamoyl.
The said new starting compounds (II') can be prepared by reacting a compound of the formula:
R"2 ~ OH (VI) wherein R"2 is as defined above, or a salt thereof with a carbonyl halide of the formula:

COX2 (VII) wherein X is as defined above, or a reactive equivalent thereof.
A ~uitable salt of the compound (VI) may include alkali metal salt (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.) or the like.
A suitable reactive equivalent of the compound (VII) may include polymer of the compound (VII), for example, the dimer (trichloromethyl chloroformate) or trimer [di(trichloro-methyl)carbonate] of the compound (VII), in which the suitable halogen for X is chlorine.
The reaction of the compound (VI) with the compound (VII) is usually carried out in a conventional solvent such as benzene, toluene, tetrahydrofuran, dioxane or any other organic solvent which does not adversely affect the reaction.
The solvent may be used alone or`in combination. The reaction is preferably carried out in the presence of a base such as inorganic base for example, alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaline earth , -- 11 --~ .

105~98 metal hydroxide (e.g., calcium hydroxide, magnesium hydroxide, etc.), alkali metal carbonate (e.g., sodîum carbonate, potassium carbonate, etc.), alkaline earth metal carbonate (e.g., calcium carbonate, magnesium carbonate, etc.), alkali metal bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.) or the like, or organic base (e.g., triethylamine, pyridine, dimethyl-aniline, etc.).
The reaction temperature is not limitative, and the reaction is preferably carried out under cooling or around room temperature.
In this process, the compound (II'), may be isolated from the reaction mixture, and also the reaction mixture per se can be preferably employed for the successive reaction with the compound (III) without isolating the compound (II').
Among the carbonic acid ester of the formula (I) and the haloformic acid ester of the formula (II), known compound also can be prepared according to substantially the same method as mentioned in the explanation of the processes for preparing the new carbonic acid ester (I'),and the new haloformic acid ester of the formula (II'), respectively.
The following examples are given for the purpose of illustrating the present invention:
Example 1 [Process for the protection of amino and/or imino group(s)]
(A) Triethylamine (0.42 ml.) was added to a suspension of D-2-(3-mesylaminophenyl)glycine (488 mg.) and diethyl 2-tert-butoxycarbonyloxyiminomalonate (770 mg.) in a mixture of tert-butyl alcohol (10 ml.) and water (10 ml.), and the mixture was stirred for 1.5 hours at room temperature. To the reaction mixture were added water and a sodium bicarbonate aqueous solu-tion, and then ethyl acetate, after which the mixture was adjusted to pH 7 with a citric acid aqueous solution. The , ~ - 12 -1058~98 aqueous layer was separated, washed with e~hyl acetate, adjusted to pH 3.5 with a citric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to give ~-tert-butoxycarbonyl-D-2-(3-mesylaminophenyl)glycine (634 mg.).
[~]D= -96~ (methanol, C=l) Nuclear Magnetic Resonance Spectrum ~(CD3)2SO, ~]
ppm 7.00 - 7,60 (5H, m) 5.11 (lH, d, J=8Hz) 3.00 (3H, s) ~ 0 (9H, s) (B) D-2-(3-Mesylaminophenyl)glycine (2.44 g.) was suspended a mixture of methanol:water (1:1) (volume ratio) (25 ml.) and dissolved by adding triethylamine (2.1 ml.). To the solution was dropwise added a solution of diethyl 2-tert-butoxycarbonyloxyiminomalonate (3~47 g.) in methanol (15 ml.) over 10 minutes at 10 to 15C, and the mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure to about 1/3 of the whole volume from the reaction mixture and to the residue were added water (30 ml.) and a saturated sodium bicarbonate aqueous solution (10 ml.).
Ethyl acetate (40 ml.) and 0.5N hydrochloric acid (26 ml.) were added to the mixture and then the mixture was shaken. The aqueous layer was separated and ethyl acetate (100 ml.) was added thereto, after which the mixture was adjusted to pH 7.20 with 0.5~ hydrochloric acid (12 ml.). The aqueous layer was again separated, adjusted to pH 2.6 with 0.5~ hydrochloric acid (27 ml.), followed by addition of-`a saturated sodium chloride aqueous solution, and extracted twice with ethyl acetate (150 ml.). The extract was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate D; 13 .. ,.., ~ ~

and treated with activated charcoal, and the solvent was distilled off under reduced pressure to give ~-tert-butoxycar-bonyl-D-2-(3-mesylaminophenyl)glycine (3.50 g.).
(C) A solution of diethyl 2-tert-butoxycarbonyloxyimino-malonate (700 mg.) in acetone (5 ml.) was dropwise added to a solution of D-2-(3-mesylaminophenyl)glycine (488 mg.) and triethylamine (0.42 ml) in a mixture of acetone (5 ml.) and water (5 ml.) over 5 minutes at room temperature, and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was concentrated under reduced pressure and to the residue were added a sodium bicarbonate aqueous solution and water, which brought pH of the solution to 9 to 10. The solution was adjusted to pH 7 with a 0.5M citric acid aqueous solution and washed with ethyl acetate. This aqueous solution was adjusted to pH 3.5 with a 0.5M citric acid aqueous solution and extracted twice with ethyl acetate (30 ml.). ~he extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give ~-tert-butoxycarbonyl-D-2-(3-mesyl-aminophenyl)glycine (672 mg.) gummy.
(D) A solution of diethyl 2-tert-butoxycarbonyloxy-iminomalonate (1.9 g.) in tert-butyl alcohol (5 ml.) was added to a solutlon of L-isoleucine (656 mg.) in a lN sodium hydroxide aqueous solution (5.0 ml.), and the mixture was stirred for 3 hours at room temperature. tert-Butyl alcohol was removed from the reaction mixture under reduced pressure and water was added to the residue. The mixture was washed with ether, adjusted to pH 3 with a 5% citric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give N-tert-butoxycarbonyl-L-isoleucine (1.2 g.) oil.

~ - 14 -(E) Diethyl 2-tert-butoxycarbonyloxyiminomalonate (1.93 g.) was added to a solution of ~G-nitro-L-arginine (1.1 g.) and sodium bicarbonate (0.63 g.) in a mixture of water (50 ml.) and tert-butyl alcohol (20 ml.), and the mixture was stirred for 3 hours at room temperature. The reac~ion mixture was adjusted to pH 7.0 with a citric acid aqueous solution, washed with ethyl acetate, ad]usted to pH 3 with a citric acid aqueous solution and extracted with ethyl acetate (100 ml.). The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized with a mixture 'of ethyl acetate and petroleum ether and the precipitates were collected by filtration to give ~ -tert-butoxycarbonyl-~G-nitro-L-arginine (1.1 g.), mp 114 to 116~C (dec.).
(F) L-Phenylalanine (330 mg.) and sodium bicarbonate (202 mg.) were dissolved in water (10 ml.) with heating and allowed to stand. To the solution was added a solution of diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (1.0 g.) in tert-butyl alcohol (10 ml.) with stirring at room temperature and water (10 ml.) was added thereto, after which the mixture was stirred for 2 hours at room temperature. The reaction mixture was brought to pH 9 by adding water (20 ml.) and a saturated sodium bicarbonate aqueous solution (10 ml.), and water (10 ml.) was added thereto, after which the mixture was washed twice with ethyl acetate (20 ml.). The aqueous layer was adjusted to pH 7 with a 10% citric acid aqueous solution, washed twice with ethyl acetate (30 ml.), adjusted to pH 3.5 with a l~/o citric acid aqueous solution and extracted three times with ethyl acetate (30 ml.). The extract was washed with a sodium chloride aqueous solution and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give ~-~4-methoxybenzyl-oxycarbonyl)-L-phenylalanine (410 mg.), oil.

~, - 15 -~, ...i .~ .

~058198 (G) A solution of ethyl 2-tert-butoxycarbonyloxyiminoaceto-acetate (646 mg.) in a mixture o~ tert-butyl alcohol ~5 ml . ) and water (5 ml.) was added at once to a solution of L-phenylalanine (330 mg,) and triethylamine (0.28 ml.) in a mixture of tert-butyl alcohol (8 ml.) and water (8 ml.) at room temperature, and the mixture was stirred for 2 hours at room temperature.
Water (100 ml.) was added to the reaction mixture and the mixture was adjusted to pH 7 with a 0.5M citric acid aqueous solution and washed twice with ethyl acetate (40 ml.) The aqueous layer was adjusted to pH 3 with a 0. SM citric acid aqueous solution, followed by addition of a sodium chloride aqueous solution, and extracted twice with ethyl acetate (40 ml.).
The extract was washed with water and dried, and the solvent was distilled off under reduced pressure to give N-tert-butoxy-carbonyl-L-phenylalanine (286 mg.).
(H) Triethylamine (1.68 ml.) was added to a suspen.sion of L-alanine (0.89 g.) in a mixture of water (5 ml.) and tert-butyl alcohol (5 ml.) to give homogeneous solution. To the solution was added diethyl 2-tert-butoxycarbonyloxyiminomalonate (4.0 g.) and the mixture was stirred for 1 hour at room tempera-ture. tert-Butyl alcohol was distilled bff from the reaction mixture under reduced pressure and to the residue were added ether and a 5% sodium bicarbonate aqueous solution, after which the mixture was adjusted to pH 7 with a citric acid aqueous solution. The aqueous layer was separated and ethyl acetate was added thereto, and the mixture was adjusted to pH 3 with a citric acid aqueous solution. The mixture was shaken enough and the ethyl acetate layer was separated, washed with water and dried.
The solution was concentrated under reduced pressure and the residue was recrystallized from a mixture of ether and petroleum ether to give N-tert-butoxycarbonyl-L-alanine (1.59 g.), - 16 ~
L~, 1~)5~3i98 mp 82 to 84~C.
(I) A suspension of l-tert-butoxycarbonyloxy-6-chloro-lH-benzotriazole (2.7 g.), L-isoleucine (1.3 g) and triethylamine (3.5 ml.) in a mixture of water (8 ml.) and tert-butyl alcohol (12 ml.) was stirred for 2 hours at 60 to 62UC. tert-Butyl alcohol was distilled off from the reaction mixture under reduced pressure and water (15 ml.) was added to the residue.
The mixture was adjusted to pH 3 with a citric acid aqueous solution under ice-cooling and extracted with ethyl acetate.
The extract was in turn washed with water and a saturated Qodium chloride aqueous solution, and then precipitates were filtered off, after which the filtrate was dried over magnesium sulfate. The solution was concentrated and to the residue was added a mixture of ether and petroleum ether (1 1). An insoluble material was filtered off and the filtrate wa~ concentrated under reduced pressure to give N-tert-butoxycarbonyl-L-isoleucine (2.4 g.), oil.
Infrared Absorpotion Spectrum (Film) 2980, 1725 (~houlder), 1710, 1165 cm 1 (J) A solution of diethyl 2-tert-butoxycarbonyloxyimino-malonate (4.5 g.) in tert-butyl alcohol (40 ml.) was added at once to a solution of D-2-(3-dime~ylaminophenyl)glycine (3.22 g.
and sodium bicarbonate (1.26 g.) in a mixture of tert-butyl alcohol (80 ml.) and water (120 ml.) under ice-cooling and stirring. After stirring for 1.5 hours at room temperature, an insoluble ~aterial was filtered off. The filtrate was adjusted to pH 7.5 with a 0.2M citric acid aqueous solution and tert-butyl alcohol was distilled off under reduced pressure.
The residue was washed with ether and adjusted to pH 3 with a 0.2M citric acid aqueous sol~tion. The aqueous solution was ~ 17 -;~
~, .. ...

lOS8~98 saturated with sodium chloride and extracted with ethyl acetate.
The extract was washed with a saturated sodium chloride aqueous solution and dried, and the solvent was distilled off under reduced pressure to give N-tert-butoxycarbonyl-D-2(3-dimesyl-aminophenyl)glycine (2.1 g.), foamy solid.
Nuclear Magnetic Resonance Spectrum ~(CD3)2SO, ~]
ppm 7.50 (4H, m) 5.20 (lH, d) 3.33 (6H, s) 1.40 (9H, s) (K) N-tert-Butoxycarbonyl-L-phenylalanine was obtained according to a similar manner to that of Example 1 (G) by using L-phenyIalanine and 2-tert-butoxycarbonyloxyimino-1-phenylbutane-1,3-dione.
(L) N-Benzyloxycarbonyl-L-phenylalanine was obtained according to a similar manner to that of Example 1 (G) by using L-phenylalanine and ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate.
(M) 6-Benzyloxycarbonylaminopenicillanic acid was obtained according to a similar manner to that of Example 1 (G) by using 6-aminopenicillanic acid and ethyl 2-benzyloxycarbonyloxyimino-2-cyanoacetate.
(N) 2-(4-Methoxybenzyl)oxycarbonyloxyimino-2-phenylaceto-nitrile (1.55 g.) was added to a solution of L-phenylalanine (826 mg.) and triethylamine (0~75 ml.) in a mixture of methanol (10 ml.), dioxane (1.5 ml.) and water (7.5 ml.) at room tempera-ture, and the mixture was stirred for 2 hours at room temperature.
The reaction mixture was concentrated, and to the residue were added benzene and a sodium bicarbonate aqueous solution. After shaking the resultant mixture, the aqueous layer was separated 1058~98 from the mixture, washed with ether, acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated. To the residue was added n-hexane, and the precipitated crystals were collected by filtration and dried to give N-(4-methoxybenzyl)oxycarbonyl-L-phenylalanine (1.064 g.), mp 87 to 88C.
(o) 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile (1.25 g.) was added to a solution of L-proline (575 mg.) and triethylamine (0.7 mI.) in a mixt;ure of methanol (7.5 ml.), dioxane (2.5 ml.) and water (5.0 ml.) at room temperature, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and to the residue were added benzene and water. After shaking the resultant mixture, the aqueous layer was separated from the mixture, washed with benzene, acidified with hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated. To the residue was added a mixture of ether and n-hexane and the precipitated crystals were collected by filtration and dried to give N-tert-butoxycarbonyl-L-proline (845 mg.), mp 133 to 134~C.
(P) According to a similar manner to that of Example 1 (0), N-tert-butoxycarbonyl-L-leucine hemihydrate (899 mg.), mp 78 to 84~C, was obtained by using L-leucine (656 mg.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.35 g.) as starting materials.
(Q) According to a similar manner to that of Example I (O), - ~-tert-butoxycarbonyl-L-methionine dicyclohexylamine salt (1.768 . . .
g.), mp 137 to 139C, was obtained by using L-methionine (746 mg.) and 2-tert-butoxycarbonyloxyimino-2~phenylacetonitrile (1.35 g.) as starting materials.

105819~3 .

(R) According to a similar manner to that of Example 1 (0), ~-tert~butoxycarbonyl-L-phenylalanine dicyclohexylamine salt (1.463 g.), mp 222 to 223~C ~dec.), was obtained by using L-phenylalanine (826 mg.) and 2-tert-butoxycarbonyloxyimino-2-~henylacetonitrile (1.25 g.) as starting materials.
(S) According to a similar manner to that of Example 1 (O), ~-tert-butoxycarbonyl-L-asparagine (918 mg.), mp 166 to 167~C
(dec.), was obtained by using L-asparagine hydrate (0.75 g.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1.85 g.) as starting materials. ~~
(T) According to a similar manner to that of Example 1 (0), N -tert-butoxycarbonyl-~G-nitro-L-arginine (2.56 g.), mp 123 to 125~C, was obtained by using NG-nitro-L-arginine (2.20 g.) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (2.71 g.) as starting materials.
(U) According to a similar manner to that of Example 1 (0), N-tert-butoxycarbonyl-L-threonine dicyclohexylamine salt (5.50 g.), mp 152 to 153UC, was obtained by using L-threonine (2.4 g,) and 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (5.4 g.) as starting materials.
(V) According to a similar manner to that of Example l(O), ~-tert-butoxycarbonylglycine (1.523 g.), mp 86.5 to 87.5~C, was obtained by using glycine (0.75 g.) and 2-tert-butoxycarbonyloxy-imino-2-phenylacetonitrile (2.71 g.) as starting materials.
(W) In the similar manner as described in the foregoing Examples 1 (A) to 1 (V), the process for the protection of amino and/or imino group(s) is carried out by using the following various carbonic acid esters, which give the similar results.
(1) 2-Ethoxycarbonyloxyimino-2-cyanoacetamide, mp 194 to 196~C.
(2) Diethyl 2-ethoxycarbonyloxyiminomalonate, oil.

.~ .1 ~,j_,.1 ~, . . .

(3) Ethyl 2-ethoxycarbonyloxyimino-2-cyanoacetate, oil.

(4) 2-Isobutoxycarbonyloxyimino-2-cyanoacetamide~ mp 156 to 158UC.

(5) Ethyl 2-isobutoxycarbonyloxyimino-2-cyanoacetate, mp 60 to 62~C.
t6) 2-Methoxycarbonyloxyimi-no-2-cyanoacetamide, mp 174 to 175C
(dec.).
(7) Ethyl 2-methoxycarbonyloxyimino-2-cyanoacetate, mp 69 to 71C.
(8) Ethyl 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-cyano-acetate, mp 51 to 53~C.
(9) Ethyl 2-tert-pentyloxycarbonyloxyimino-2-cyanoacetate, oil.
Infrared Absorption Spectrum 1810, 1740 cm L
~10) 1-Ethoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 160 to 162~C.
(11) l-Benzyloxycarbonyloxy-lH-benzotriazole, mp 130 to l31~C.
(12) Benzophenone 0-tert-butoxycarbonyloxime, mp 131 to 133~C.
(13) 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile, mp 91 to 92C.
(14) 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile, mp 73 to (15) 2-tert-Butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile, mp 90 to 92~C.
(16) 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile, mp 65 to 67UC.
(17) 2-(2,2,2-Trichloroethoxycarbonyloxyimino')-2-phenylaceto-nitrile, mp 82 to 84UC.
Example 2 [Preparation of carbonic acid esters]
(A) Benzene (20 ml.) was added to a solution of phosgene r ~ 21 -~' 105~98 (2.5 g.) in benzene (11.4 ml.). To the solution was dropwise added a solution of diethyl 2-hydroxyiminomalonate (4.73 g.) and N,N-dimethylaniline (3.03 g,.) in benzene (30 ml.) over 40 minutes at 5~C in nitrogen stream. The mixture was stirred for 1 hour at the same temperature and overnight at room temperature.
To the resultant mixture containing diethyl 2-chlorocarbonyloxy-iminomalonate was dropwise added a solution of 4-methoxybenzyl alcohol (3.11 g.) and pyridine (4.04 ml.) in benzene (30 ml.) over 40 minutes at 5VC. The mixture was stirred for 2 hours at the same temperature, for 3 hours at room temperature and allowed to stand overnight. Cold water (100 ml.) was added to the reaction mixture to dissolve an insoluble material and cooled lN-hydrochloric acid (20 ml.) was added thereto, after which the mixture was shaken. The organic layer was in turn washed 3 times with lN hydrochioric acid (20 ml.), 3 times with a 5% sodium carbonate aqueous solution (20 ml.) and a sodium chloride aqueous solution, and then dried over magnesium sulfate. After drying the solvent was distilled off to give di-ethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (6.89 g.), pale brown oil, which was solidified on standing at ambient temperature.
Nuclear Magnetic Resonance Spectrum (CCe4, ~) ppm 6.88 7.38 (4H, ABq, J=9.0 Hz) 5,23 (2H, s) 4.39 (4H, q, J=7.1 Hz) 3.80 (3H, s) 1.37 (3H, t, J=7.1 Hz) 1.33 (3H, t, J=7.1 Hz) (B) A solution of ethyl 2-hydroxyiminoacetoacetate (3.98 g.) and pyridine (1.98 g.) in benzene (25 ml.) was dropwise added to a solution of phosgene (2.48 g.) in benzene (30 ml.) over 30 . ~ , ~ , .

11)58~98 minutes at 4 to 5UC. After stirring for 1 hour at the same temperature, the mixture was stirred for 1 hour at room tempera-ture and allowed to stand overnight. To the resultant solution containing ethyl 2-chlorocarbonyloxyiminoacetoacetate was drop-wise added, over 30 minutes at 5 to 7~C, a solution of tert-butyl alcohol (3.7 g.) and pyridine (3.96 g.) in benzene (25 ml.).
After stirring for 1 hour at the same temperature, the reaction temperature was slowly elevated to room temperature, after which the mixture was stirred for 6 hours at the same temperature and allowed to stand overnight. A precipitate was dissolved by adding about same volume of water to that of the organic layer to the reaction mixture, after which the aqueous layer was separated. The organic layer was in turn washed with a 0.5M
citric acid aqueous ~olution, a 5% sodium carbonate aqueous solution and a sodium chloride aqueous solution, and dried over magnesium sulfate. After drying the solvent was distilled off to give ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate (3.7 g.), oil.
Infrared Absorption Spectrum (Film) 1780, 1730, 1690 cm~
~uclear Magnetic Resonance Spectrum (CCe4, 6 ppm 4.34 (3H, q) 2.48 (3H, s) 1.57 (9H, s) 1.37 (3H, t) (C) A solution of 2-hydroxyimino-1-phenylbutane-1,3-dione ; - (3.82 g.) and pyridine (1.62 ml.) in benzene (30 ml.) was drop-wise added to a solution of phosgene (1.98 g.) in benzene (25 mL) over 40 minutes at 5 to 9~C. After stirring for 1 hour at the same temperature, the mixture was allowed to stand overnight.

~,`
. . .

lOS8198 To the resultant solution containing 2-chlorocarbonyloxyimino-1-phenylbutane-1,3-dione was dropwise added, over 30 minutes at 5UC, a solution of tert-butyl alcohol (2.96 g.) and pyridine (3.16 g.) in benzene (30 ml.). After stirring for 1 hour at the same temperature, the mixture was stirred for 6 hours at room temperature, after which the mixture was allowed to stand over-night. Cooled water (100 ml.) was added to the reaction mixture, and the organic layer was in turn washed with water, a 0.5M
citric acid aqueous solution (20 ml.) (4 times) and a 5% sodium carbonate aqueous solution (20 ml.) (4 times) until the aqueous layer became almost colorless, and further washed with a sodium chloride aqueous solution and then dried over magnesium sulfate.
After drying, the solution was treated with activated charcoal and the solvent was distilled off to give oil (3.48 g.). The oil was partly crystallized by allowing to ctand and to the mixture was added ether to precipitate crystals. The precipitates were collected by filtration and recrystallized from a mixed solvent of carbon tetrachloride and petroleum ether to give 2-tert-butoxycarbonyloxyimino-l-phenylbutane-1,3-dione (350 mg.), mp 90 to 103~C (dec.~.
Infrared Absorption Spectrum (Nujol) 1785, 1700, 1680 cm~
Analysis : C15H17~ 5 Calcd. : C 61.85, H 5.88, N 4.81 Found : C 62.00, H 5.92, N 4.98 (D) A solution o~ phosgene (5 g.) in benzene (23.5 ml.) was dropwise added under ice-cooling to a suspension of l-hydroxy-

6-chloro-lH-benzotriazole (8.5 g.) and pyridine (3.9 g.) in benzene (50 ml.), and the mixture was stirred for 30 minutes at the same temperature and allowed to stand overnight. To the ~1 ....,i lOS8198 resultant solution containing l-chlorocarbonyloxy-6-chloro-lH-benzotriazole was dropwise added, over 20 minutes under ice-cooling, a solution of tert-butyl alcohol (3.7 g.) and pyridine (4.0 g.) in benzene (-50 ml.). The resultant mixture was stirred for 2 hours at the same temperature and allowed to stand over-night.
The reaction mixture was filtered, and the filtrate was concentrated. Ether and petroleum ether were added to the residue to pulverize the residue and obtained crystals were collected by filtration to give 1-tert-butoxycarbonyloxy-6-chloro-lH-benzotriazole (5.3 g.). The mother liquor was concentrated to give the same object compound (0.6 g.). Both crystals were put together and dissolved in benzene, after which the solution was washed with a sodium bicarbonate aqueous solution and water and then dried. The solvent was removed by distillation to give the object compound (3.2 g.), powder, mp 98 to lOO~C (dec.).
Analygi8 : CllH12N303C~
Calcd. : C 48.98, H 4.48, ~ 15.58, C~ 13.14 Found : C 49.25, H 4.32, N 15.88, C~ 13.36 (E) A solution of 2~hydroxyimino-2-phenylacetonitrile (7.3 g.) and dimethylaniline (6.0 g.) in a mixture of benzene (50 ml) and dioxane (5 ml.) was dropwise added to a solution of phosgene (5.5 g.) in benzene (50 ml.) over 1 hour at 3 to 5~C, and the mixture was stirred for 3.5 hours at the same temperature and allowed to stand overnight. To the resultantsolution containing 2-chlorocarbonyloxyimino-2-phenylacetonitrile was dropwise added, over 1 hour un~der ice-cooling, a solution of tert-butyl alcohol (7.4 g.) and pyridine (5.0 ml.) in benzene (20 ml.). The resultant mixture was stirred for 4 hours at .~.

the same temperature, and pyridine (3.0 ml.) was dropwise added thereto, after which the mixture was stirred for 1 hour at room temperature and allowed to stand overnight. Water was added thereto and the organic layer was separated. The organic layer was in turn washed with lN hydrochloric acid (3 tlmes), a sodium chloride aqueous solution, a sodium bicarbonate aqueous solution (twice) and a sodium chloride aqueous solution (twice) and concentrated. The residue was allowed to stand to give crystals. The crystals were triturated in aqueous methanol, collected by filtration, washed with n-hexane and dried to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (7.0 g.), mp 84 to 86UC.
Infrared Absorption Spectrum (Nujol) 1785 cm 1 Nuclear Magnetic Resonance Spectrum (CDCe3, ~) ppm 7.3 - 8.1 (5H, m) 1.60 (9H, s) Analysis : C13H143~2 Calcd. : C 63.40, H 5.73, N 11.38 Found : C 63.69, H 5.71, N 11.20 (F) A solution of 2-hydroxyimino-2-phenylacetonitrile (7.3 g), dimethylaniline (6.0 g.) and tert-butyl alcohol (3.7 g.) in benzene (50 ml.) was dropwise added to a solution of phosgene (5.0 g.) in benzene (50 ml.~ over 30 minutes under ice-cooling.
To the mixture was dropwise added a solution of pyridine (4.0 ml.) in benzene (20 ml.) and the mixture was stirred for 1 hour at - the same temperature and allowed to stand overnight. Water and benzene were added to the reaction mixture and an insoluble material was filtered off. The organic layer was in turn washed with lN hydrochloric acid, water, a sodium bicarbonate aqueous ,~, lOS8198 solution and water, and dried over magnesium sulfate. The solvent was distilled of~ and to the residue were added n-hexane and a small amount of methanol. An insoluble material was filtered off and the filtrate was concentrated. Methanol was added to the residue and the mixture was allowed to stand. The precipitates were collected by filtration to give 2-tert-butoxy-carbonyloxyimino-2-phenylacetonitrile (3.5 g.). Mp 83 to 85UC.
Water was added to the mother liquor and the mixture was allowed to stand. The precipitates were collected by filtration to give the object compound (1.5 g.). Total yield (5.0 g.).
(G) A solution of 2-hydroxyimino-2-phenylacetonitrile (14.6 g.) and dimethylaniline (13.2 g.) in a mixture of acetone (5 ml.) and benzene (80 ml.) was dropwise added to a solution of trichloromethyl chloroformate (phosgene dimer) (6.7 ml.) in benzene (30 ml.) under ice-cooling. The mixture was stirred for 6 hours at the same temperature and allowed to stand over-night. To the resultant mixture containing 2-chlorocarbonyloxy-imino-2-phenylacetonitrile was dropwise added a mixture of tert-butyl alcohol ~;11.1 g.), pyridine (16.0 ml.) and benzene (20 ml.) under ice-cooling, and the mixture was stirred for 7 hours at room temperature and allowed to stand overnight. The reaction mixture was treated as described in the above Examples 2(A) to 2(F) to give 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (17.0 g.), mp 84 to 86~C.
(H) A solution of dimethyIaniline (6.0 ml.) in benzene (15nml.) was dropwise added to a suspension of 2-hydroxyimino-2-phenylacetonitrile (7.3 g.) and phosgene (5.0 g.) in benzene (50 ml.) over 40 minutes under ice-cooling. The mixture was stirred for 2 hours at the same temperature and allowed to stand overnight. To the mixture containing 2-chlorocarbonyloxyimino--2-phenylacetonitrile was dropwise added a solution of 4-methoxy-benzyl alcohol (6.9 g.) and pyridine (4.0 ml,) in benzene (20 ml.) over 30 minutes under ice-cooling, and the mixture was stirred for 7 hours at room temperature. The reaction mixture was in turn washed with water, lN hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated, and the residual crystals were triturated in n-hexane and collected by filtration.
The crystals were recrystallized from a mixture of ethyl acetate and n-hexane to give 2-(4-methoxybenzyl)oxycarbonyloxyimino-2-phenylacetonitrile (3.1 g.). Mp 112 to 113C. The mother liquor was concentrated to give the object compound (2.4 g,), Total Yield (5.5 g.), Infrared Absorption Spectrum (Nujol) 1785 cm 1 Nuclear Magnetic Resonance Spectrum (CDCe3, ~) . ., ppm 6.8 - 8.0 (9H, m) 5.30 (2H,-s) 3,80 (3H, s) Analysis : C17H~4O4N2 Calcd. : C 65.79, H 4~54, N 9.03 Found : C 65.99, H 4.38, N 9.03 (I) A solution of 2-hydroxyimino-2-phenylacetonitrile (14.6 g.) and dimethylaniline (13.2 g.) in a mixture of benzene (80 ml.) and dioxane (8 ml.) was dropwise added to a solution of trichloromethyl chloroformate (phosgene dimer) (11 g.) in benzene (50 ml,~ under ice-cooling, and the mixture was stirred for 3 hours at the same temperature and allowed to stand over-night. To the mixture containing 2-chlorocarbonyloxyimino-2-phenylacetonitrile was dropwise added a solution of tert-'~
.. ~

~058~98 butyl alcohol (14.8 g.) and pyridine (16.0 ml.) in benzene (20 ml.) under ice-cooling. The reaction mixture was stirred for 6 hours together with gradual elevation of the reaction temperature to room temperature and allowed to stand overnight.
Water was added to the reaction mixture, and the organic layer was separated. The organic layer was in turn washed with lN
hydrochloric acid, a sodium chloride aqueous solution, a sodium bicarbonate a~ueous solution and water and then dried. The solvent was distilled off,-and methanol was added to the residue.
The mixture was cooled by ice-w,ater, and the precipitates were collected by filtration and washed with a small amount of cooled methanol to give 2-tert-butoxycarbonyloxyimino-2-phenylaceto-nitrile (9.5 g.). From the mother liquor the object compound (9.4 g.) was further obtained. ~oth of the object compounds obtained above were combined and recrystallized from methanol to give the pure compound (14.6 g.), mp 84 to 86UC.
(J) A solution of benzophenone oxime (9.85 g.) and dimethyl-aniline (6.6 g.) in a mixture of benzene (50 ml.) and dioxane (10 ml.) was dropwise added to a solution of trichloromethyl chloroformate (phosgene dimer) (5.5 g.) in benzene (15 ml.) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature, for 2 hours at room temperature and allowed to stand overnight. To the resultant mixture containing benzophenone 0-chlorocarbonyloximine was dropwise added a solution tert-butyl alcohol (5.6 g.) and pyridine (6.0 ml.) in benzene (20 ml.) under ice-cooling, and the mixture was stirred for 6 hours at the same te~perature and allowed to stand overnight. The reaction mixture was in turn washed with water, lN hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solvent was distilled off and to the resulting crystals was added petroleum ether. The crystals ~ .
~, .

1(~58198 were collected by filtration and dried to give benzophenone 0-tert-butoxycarbonyloxime ~10.5 g.), mp 126 to 133UC. A small amount of the crystals was recrystallized from a mixture of toluene and petroleum ether to give pure compound, mp 131 to 133~C.
Infrared Absorption Spectrum (Nujol) 1770 cm 1 Nuclear Magnetic Resonance Spectrum (CDC~3, ~) ppm 7.17 - 7.65 (lOH, m) 1.48 (9H, s) (K) A suspension of 2-hydroxyimino-2-(4-chlorophenyl)aceto-nitrile (6.75 g.) and dimethylaniline (4.5 g.) in a mixture of dichloromethane (70 ml.), dioxane (10 ml.) and tetrahydrofuran (10 ml,) wa~ dropwise added to a solution of trichloromethyl chloroformate (phosgenedimer) (16 g.) in benzene(`22 ml.) under ice-cooling, and the mixture was stirred for S hours at the same temperature and allowed to stand overnight. To the resultant mixture containing 2-chlorocarbonyloxyimino-2-(4-chlorophenyl)-acetonitrile was dropwise added a solution of tert-butyl alcohol (8.9 g.) and pyridine (9.6 ml.) in dichloromethane (20 ml.) under ice-cooling, and the mixture was stirred for 5 hours at the same temperature and allowed to stand for 48 hours. The reaction mixture was in turn washed with water, lN hydrochloric acid, water, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solvent was distilled off and n-hexane was added to the residue. An insoluble material was filtered off and the filtrate was concentrated. To the residue was added petroleum ether and the mixture was allowed to stand to precipitate crystals. The crystals were dissolved in hot petroleum ether and the solution was filtered. The filtrate ~ ~ - 30 ---was cooled to precipitate crystals and the crystals were collected by filtration to give 2-tert-butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile (1.6 g.). These crystals were recrystallized from methanol to give the pure compound (0~7 g.), mp 91 to 92UC.
Infrared Absorption Spectrum (Nujol) 1790 cm~l ~uclear Magnetic Resonance Spectrum (CDC~3, ~) ppm 7.90 (2H, ABq, J=4.5Hz)

7.50 (2H, ABq, J=4.5Hz) 1.63 (9H, s) (L) (1~ Preparation of the starting compound:
2-(1-naphthyl)acetonitrile (16.7 g.) was added to a solution of sodium hydroxide (4.2 g.) in methanol (80 ml.), To the mixture was introduced under ice-cooling gaseous methyl nitrite which was prepared by adding a solution of conc sulfuric acid t5 ml.) in water (10 ml.) to a solution of sodium nitrite (8 J 3 g.) in a mixture of methanol (5,5 ml,) and water (5 ml.).
The mixture was stirred for 4 hours at the same temperature and the reaction mixture was treated by conventional method to give 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.1 g.), oil.
Infrared Absorption Spectrum (Film) ~
1700 cm~l (2) Preparation of the object compound:
A solution of 2-hydroxyimino-2-(1-naphthyl)acetonitrile (7.0 g.) and dimethylaniline (12.0 g,) in toluene ~100 ml.) was dropwise added under ice-cooling to a solution of trichloromethyl chloroformate (phosgene dimer) (3.56 g.~ in benzene (30 ml.).

The mixture was stirred for 3 hours at the same temperature and ~ l - 31 -lOSt~198 allowed to stand overnight. To the resultant mixture containing 2-chlorocarbonyloxyimino-2-(1-naphthyl)acetonitrile was dropwise added a solution of tert-butyl alcohol (11.1 g.) and pyridine ~12 ml.) in toluene (20 ml.) under ice-cooling, and the mixture ~as stirred for 6 hou~s at the same temperature and allowed to stand overnight. The reaction mixture was in turn washed with water, lN hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solution was concentrated under reduced pressure and to the residue were added n-hexane and methanol. The mixture was allowed to stand in a refrigerator, and the precipitated crystals were collected by filtration and recrystallized twice from methanol to give 2-tert-butoxycarbonyloxyimino-2-(1-naphthyl)-acetonitrile (3.3 g.), mp 90 to 92UC.
Analy9is : C17H163N2' Calcd. : C 68.90, H 5.44, N 9.46 Found : C 68.85, H 5.38, N 9.40 Infrared Absorption Spectrum (Nujol) 1790 cm 1 (M) A solution of 2-hydroxyimino-2-phenylacetonitrile (2.2 g.) and dimethylaniline (1.80 g.) in a mixture of benzene (25 ml.) and dioxane (3 ml.) was dropwise added to a solution of trichloromethyl chloroformate (phosgene dimer) (1.5 g.) in ben-zene (20 ml.) under ice-cooling. The mixture was stirred for 3 hours at the same temperature and allowed to stand overnight.
To the resultant mixture containing 2-chlorocarbonyloxyimino-2-phenylacetonitrile was dropwise add~d a solution of l-cyclo-propylethanol (1.4 g.) and pyridine (1.2 ml.) in benzene (lO ml.) under ice-cooling. The mixture was stirred for 2 hours at the same temperature, for 4 hours at room temperature and allowed r~
- 32 _ .... . . .

lV58~98 to stand overnight. The reaction mixture was in turn washed ~
with lN hydrochloric acid, water, a sodium bicarbonate aqueous solution and water, and dried over magnesium sulfate. The solvent was distilled off and to the oily residue was added a small amount of methanol. The mixture was allowed to stand in a refrigerator, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 2-(l-cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile (0.7 g;), mp 65 to 67~C.
Infrared Absorption Spectrum (Nujol) 1785 cm 1 Analysis : C14H143N2 Calcd. : C 65.ilO, H 5.46, N 10.85 Found : C 65.07, H 5.15, N 10.84 (N) The following compounds were obtained according to a similar manner to those of Examples 2(A) to 2(M).
(1) 1-Ethoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 160 to 162C.
(2) l-Benzyloxycarbonyloxy-lH-benzotriazole, mp 130 to 131C.
(3) 2-Benzyloxycarbonyloxyimino-2-phenylacetonitrile~ mp 73 to 75~CL
(4) 2-(2,2,2-Trichloroethoxycarbonyloxyimino)-2-phenylaceto-nitrile, mp 82 to 84UC.
Example 3 ~Preparation of carbonic acid esters]
(A) Ether (10 ml.) was added to a solution of phosgene (2 g.) in benzene (12.4 ml.). To the solution was dropwise added a solution of 4-methoxybenzyl alcohol (2.76 g.) in ether (10 ml.~ over 25 minutes at -10UC with stirring and paying attention to exotherm. The mixture was stirred for 20 minutes at -10 to -7C and phosgene was removed by introducing nitrogen ~ - 33 -~, ',ib, 1058~98 stream for 15 minutes at the same temperature. To the resultant solution containing 4-methoxybenzyl chloroformate was added a solution of diethyl 2-hydroxyiminomalonate (3.78 g.) in benzene (20 ml.) over 10 minutes and then was added a solution of triethylamine (5.6 ml.) in benzene (20 ml.) over 30 minutes at -7 to -2C. Benzene (20 ml.) was added thereto and the mixture was stirred for 30 minutes at 5UC, for 1 hour at room temperature and allowed to stand for 64 hours. Water was added to the reaction mixture to dissolve an insoluble material and the organic layer was in turn washed with water, 3 times with a 0.5M citric acid aqueous solution (20 ml.), 3 times with a 5%
sodium carbonate aqueous solution (20 ml.) and a sodium chloride aqueous solution, and then dried over magnesium sulfate. After drying the solvent was distilled off to give diethyl 2-(4-methoxybenzyloxycarbonyloxyimino)malonate (5.62 g.), oil.
(B) A solution of ethyl chloroformate (2.17 g.) in benzene (10 ml.) was dropwise added to a solution of 1-hydroxy-6-chloro-lH-benzotriazole (3.38 g.) and triethylamine (2.80 ml.) in benzene (30 ml.) under ice-cooling and stirring. Benzene (30 ml.) was further added to the mixture and the reaction temperature was slowly elevated to room temperature, and the mixture was allowed to stand overnight. Precipitated crystals were filtered off and the filtrate was concentrated. Benzene was added to the residue and an insoluble material was filtered off, after which the filtrate was concentrated to give l-ethoxycarbonyloxy-6-chloro-lH-benzotriazole (2.2 g.), crystal. These crystals, the precipitated crystals filtered off and the insoluble material in ~enzene were put together, in turn washed with water, a sodium bicarbonate aqueous solution, 1~ hydrochloric acid and water, and recrystallized from methanol (75 ml.) to give the object compound r~

1058~98 (3.5 g.), white needles, mp 160 to I62C.
Analysis : CgH8N303C~
Calcd. : C 44.73, H 3.36, N 17.39, C~ 14.67 Found : C 44.71, H 3.25, ~ 17.34, C~ 14.72 (C) Benzyl chloroformate (8.5 g.) was dropwise added under ice-cooling to a solution of l-hydroxy-lH-benzotriazole (6.8 g.
and triethylamine (7.0 ml.) in a mixture of benzene (100 ml.) and water (50 ml.), and the mixture was stirred far 3 hours at the same temperature. The reaction mixture was filtered and the precipitated crystals were washed with water and dried. The benzene iayer was washed with water, dried and concentrated.
The residue and the crystals above obtained were put together and recrystallized from a mixed solvent of benzene and petroleum ether to give l-benzyloxycarbonyloxy-lH-benzotriazole (12.1 g.), mp 130 to 131~C.
Analysis : C14HllN303 Calcd. : C 62.44, H 4.12, ~ 15.61 Found : C 62.62, H 4.16, N 15.49 (D) A solution of benzyl chlbroformate (5.1 g.) in ether (40 ml.) was added to a solution of 2-hydroxyimino-2-phenylaceto-nitrile (4.4 g.) in a mixture of a lN potassium hydroxide aqueous ~olution (30 ml.) and dioxane (10 ml.) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature and for 4 hours at room temperature. The ether layer was separated from the reaction mixture and the aqueous layer was further extracted with ether. Both ether layers were combined, washed with water and dried over magnesium sulfate. The solvent was distilled off and to the residue was added n-hexane. The precipitated crystals were collected by filtration to give 2-benzyloxycarbonyloxylmino-2-phenylacetonitrile (5.2 g.), mp 73 to 75~C.

~' 1058~98 Infrared Absorption Spectrum (Nujol) 1795 cm 1 . . .
(E) A solution of 2,2,2~trichloroethyl chloroformate (2.2 g.) in benzene (10 ml.) was dropwise added to a solution of 2-hydroxyimino-2-phenylacetonitrile (l.S g.) and triethyl-amine (1.40 ml.) in benzene (20 ml.) at room temperature, and the mixture was stirred for 3 hours at the same temperature.
To the reaction mixture were added benzene and water, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was crystallized by adding a small amount of ether and n-hexane.
The crystals were collected by filtration and recrystallized from methanol to give 2-(2,2,2-trichloroethoxycarbonyloxyimino)-2-phenylacetonitrile (2.7 g.), mp 82 to 84~C.
Infrared Absorption Spectrum (Nujol) ! 1800, 1790 cm~
Analysis CllH73N2C~3 Calcd. : C 41.08, H 2.19, ~ 8.71, C~ 33.08 Found : C 41.29, H 2.05, N 8.81j C~ 32.31 (F) The following compounds were obtained according to a similar manner to those of Examples 3(A) to 3(E).
(1) Ethyl 2-tert-butoxycarbonyloxyiminoacetoacetate, oil.
~nfrared Absorption Spectrum (Film) 1780, 1730, 1690 cm 1 (2) 2-tert-Butoxycarbonyloxyimino-l-phenylbutane-1,3-dione, mp 90 to 103C (dec.).
(3) 1-tert-Butoxycarbonyloxy-6-chloro-lH-benzotriazole, mp 98 to lOOaC (dec.).
(4) 2-tert-Butoxycarbonyloxyimino-2-phenylacetonitrile, mp 84 to 86~C~
(5) 2-(4-Methoxybenzyloxycarbonyloxyimino)-2-phenylacetonitrile, mp 112 to 113~C.

~J~

-~058198 (6) Benzophenone O-tert-butoxycarbonyloxime, mp 131 to 133~C.
(7) 2-tert-Butoxycarbonyloxyimino-2-(4-chlorophenyl)acetonitrile, mp 91 to 92~C.

(8) 2-tert-Butoxycarbonyloxyimino-2-(1-naphthyl)acetonitrile, mp 90 to 92~C.

(9) 2-(1-Cyclopropylethoxycarbonyloxyimino)-2-phenylacetonitrile, mp 65 to 67~C.

. . .

Claims (80)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:-

1. In the protection of an amino and/or imino group in an amino and/or imino group-containing compound by reacting said compound with an agent for introducing a protective group on an amino and/or imino group, a process wherein the agent for introducing the protective group on the amino and/or imino group is a carbonic acid ester of the formula:

wherein R1 is lower alkyl that is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, lower alkoxy and aryloxy, or aryl(lower)alkyl that is unsubstituted or substituted with at least one substituent selected from the group consisting of lower alkoxy, halogen, nitro and cyano, and R2 is a group represented by the formula:

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wherein Y is aryl that is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl, or is an electron withdrawing group and Z is aryl which is unsub-stituted or substituted with at least one substituent selected from the group consisting of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl.

2. A process according to claim 1, for protecting at least one amino group in an amino group-containing compound comprising reacting said amino group-containing compound with said agent.

3. A process according to claim 1, for protecting at least one imino group in an imino group-containing compound comprising reacting said imino group-containing compound with said agent.

4. A process according to claim 1, wherein R1 is lower alkyl that is unsubstituted or substituted with halogen, or aryl(lower)alkyl group, said aryl(lower)alkyl group being un-substituted or substituted with lower alkoxy, Y is aryl or an electron withdrawing group and Z is aryl that is unsub-stituted or substituted with halogen.

5. A process according to claim 4, wherein Y is aryl or cyano.

6. A process according to claim 5, wherein R1 is 1-cyclopropylethyl, 2,2,2-trichloroethyl, tert-butyl, benzyl or 4-methoxybenzyl, Y is phenyl or cyano and Z is phenyl, 1-naphthyl or 4-chlorophenyl.

7. A process according to claim 6, wherein R1 is tert-butyl, Y is cyano and Z is phenyl.

8. A carbonic acid ester of the formula:

R'1OCOOR'2 wherein R'1 is lower alkyl that is unsubstituted or substituted with at least one substituent selected from the group consist-ing of halogen, lower alkoxy and aryloxy, or aryl(lower)alkyl that is unsubstituted or substituted with at least one sub-stituent selected from the group consisting of lower alkoxy, halogen, nitro and cyano, and R'2 is a group represented by the formula:

wherein Y' is aryl that is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl or is an electron with drawing group selected from cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl and aroyl, and Z' is aryl that is unsubstituted or substituted with at least one substituent selected from the group consisting of halogen, lower alkoxy, nitro, cyano and halo(lower)alkyl; provided that when R'1 is lower alkyl, Y' is aryl or cyano and Z' is aryl, Y' has 4 or 5 carbon atoms.

9. An ester according to claim 8, wherein Y' is aryl that is unsubstituted or substituted with at least one sub-stituent selected from the group consisting of lower alkoxy, nitro, cyano and halo(lower)alkyl or is cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl or aroyl, and Z' is aryl that is unsubstituted or substituted with at least one sub-stituent selected from the group consisting of lower alkoxy, nitro, cyano and halo(lower)alkyl.

10. An ester according to claim 9, wherein R'1 is lower alkyl that is unsubstituted or substituted with halogen, or aryl(lower)alkyl that is unsubstituted or substituted with lower alkoxy, Y' is aryl or cyano and Z' is aryl, provided that when R'1 is lower alkyl, the number of carbon atoms of lower alkyl for R'1 is 4 or 5.

11. An ester according to claim 10, wherein R'1 is lower alkyl that is unsubstituted or substituted by halogen.

12. An ester according to claim 11, wherein R'1 is lower alkyl having 4 or 5 carbon atoms.

13. An ester according to claim 12, wherein Y' is cyano and Z' is aryl.

14. An ester according to claim 13, wherein R'1 is tert-butyl or 1-cyclopropylethyl and Z' is phenyl or naphthyl.

15. An ester according to claim 14, wherein R'1 is tert-butyl.

16. An ester according to claim 15, wherein Z' is phenyl.

17. An ester according to claim 15, wherein Z' is naphthyl.

18. An ester according to claim 14, wherein R'1 is 1-cyclopropylethyl and Z' is phenyl.

19. An ester according to claim 12, wherein Y' is aryl and Z' is aryl.

20. An ester according to claim 19, wherein R'1 is tert-butyl, Y' is phenyl and Z' is phenyl.

21. An ester according to claim 11, wherein R'1 is lower alkyl substituted by halogen, Y' is cyano and Z' is aryl.

22. An ester according to claim 21, wherein R'1 is ethyl substituted by chlorine and Z' is phenyl.

23. An ester according to claim 22, wherein R'1 is 2,2,2-trichloroethyl.

24. An ester according to claim 10, wherein R'1 is aryl(lower)alkyl that is unsubstituted or substituted with lower alkoxy, Y' is cyano and Z' is aryl.

25. An ester according to claim 24, wherein R'1 is benzyl that is unsubstituted or substituted by methoxy and Z' is phenyl.

26. An ester according to claim 25, wherein R'1 is benzyl or 4-methoxybenzyl.

27. An ester according to claim 26, wherein R'1 is benzyl.

28. An ester according to claim 26, wherein R'1 is 4-methoxybenzyl.

29. An ester according to claim 8, wherein R'1 is lower alkyl, Y' is cyano and Z' is aryl substituted by halogen.

30. An ester according to claim 29, wherein R'1 is tert-butyl and Z' is phenyl substituted by chlorine.

31. An ester according to claim 30, wherein Z' is 4-chlorophenyl.

32. A process for preparing a carbonic acid ester of the formula:
R'1OCOOR'2 wherein R'1 and R'2 are as defined in claim 8, which comprises a) reacting a haloformic acid ester of the formula:
X - COOR'2 wherein X is halogen and R'2 is as defined above, with a hydroxy-compound of the formula:
R'1 - OH
wherein R'1 is as defined above, or b) reacting a formic acid ester of the formula:
R'1 - OCOX' wherein R'1 is as defined above and X' is halogen, with a compound of the formula:
R'2 - OH
wherein R'2 is as defined above or a salt thereof.

33. A process according to claim 32(a), which comprises reacting said haloformic acid ester with said hydroxy-compound.

34. A process according to claim 33, wherein Y' is aryl that is unsubstituted or substituted with a substituent selected from the group consisting of lower alkoxy, nitro, cyano and halo(lower)alkyl or is cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl or aroyl and Z' is aryl that is unsubstituted or substituted with a substituent selected from the group consisting of lower alkoxy, nitro, cyano and halo-(lower)alkyl.

35. A process according to claim 34, wherein R'1 is lower alkyl that is unsubstituted or substituted with halogen or an aryl(lower)alkyl group that is unsubstituted or sub-stituted by lower alkoxy, Y' is aryl or cyano and Z' is aryl, provided that when R'1 is lower alkyl, the number of carbon atoms of lower alkyl for R'1 is 4 or 5.

36. A process according to claim 35, wherein R'1 is lower alkyl that is unsubstituted or substituted with halogen.

37. A process according to claim 36, wherein R'1 is lower alkyl having 4 or 5 carbon atoms.

38. A process according to claim 37, wherein Y' is cyano and Z' is aryl.

39. A process according to claim 38, wherein R'1 is tert-butyl or l-cyclopropylethyl and Z' is phenyl or naphthyl.

40. A process according to claim 39, wherein R'1 is tert-butyl.

41. A process according to claim 40, wherein Z' is phenyl and X is chlorine.

42. A process according to claim 40, wherein Z' is naphthyl and X is chlorine.

43. A process according to claim 39, wherein R'1 is 1-cyclopropylethyl and Z' is phenyl and X is chlorine.

44. A process according to claim 37, wherein Y' is aryl and Z' is aryl.

45. A process according to claim 44, wherein R'1 is tert-butyl, Y' is phenyl and Z' is phenyl and X is chlorine.

46. A process according to claim 36, wherein R'1 is lower alkyl substituted with halogen, Y' is cyano and Z' is aryl.

47. A process according to claim 46, wherein R'1 is ethyl substituted with chlorine and Z' is phenyl.

48. A process according to claim 47, wherein R'1 is 2,2,2-trichloroethyl.

49. A process according to claim 35, wherein R'1 is aryl(lower)alkyl that is unsubstituted or substituted with lower alkoxy, Y' is cyano and Z' is aryl.

50. A process according to claim 49, wherein R'1 is benzyl that is unsubstituted or substituted with methoxy and Z' is phenyl.

51. A process according to claim 50, wherein R'1 is benzyl or 4-methoxybenzyl.

52. A process according to claim 51, wherein R'1 is benzyl.

53. A process according to claim 51, wherein R'1 is 4-methoxybenzyl and X is chlorine.

54. A process according to claim 33, wherein R'1 is lower alkyl, Y' is cyano and Z' is aryl substituted by halogen.

55. A process according to claim 54, wherein R'1 is tert-butyl and Z' is phenyl substituted by chlorine.

56. A process according to claim 55, wherein Z' is 4-chlorophenyl and X is chlorine.

57. A process according to claim 32(b), which comprises reacting said formic acid ester with said compound of the formula:
R'2 - OH.

58. A process according to claim 57, wherein Y' is aryl that is unsubstituted or substituted by at least one sub-stituent selected from the group consisting of lower alkoxy, nitro, cyano and halo(lower)alkyl, or is cyano, nitro, carbamoyl, esterified carboxy, lower alkanoyl or aroyl, and Z' is aryl that is unsubstituted or substituted by at least one substituent selected from the group consisting of lower alkoxy, nitro, cyano and halo(lower)alkyl.

59. A process according to claim 58, wherein R'1 is lower alkyl that is unsubstituted or substituted by halogen or aryl(lower)alkyl that is unsubstituted or substituted by lower alkoxy, Y' is aryl or cyano and Z' is aryl provided that when R'1 is lower alkyl, the number of carbon atoms of lower alkyl for R'1 is 4 or 5.

60. A process according to claim 59, wherein R'2 is lower alkyl that is unsubstituted or substituted by halogen.

61. A process according to claim 60, wherein R'1 is lower alkyl having 4 or 5 carbon atoms.

62. A process according to claim 61, wherein Y' is cyano and Z' is aryl.

63. A process according to claim 62, wherein R'1 is tert-butyl or 1-cyclopropylethyl and Z' is phenyl or naphthyl.

64. A process according to claim 63, wherein R'1 is tert-butyl.

65. A process according to claim 64, wherein Z' is phenyl.

66. A process according to claim 64, wherein Z' is naphthyl.

67. A process according to claim 63, wherein R'1 is 1-cyclopropylethyl and Z' is phenyl.

68. A process according to claim 61, wherein Y' is aryl and Z' is aryl.

69. A process according to claim 68, wherein R'1 is tert-butyl, Y' is phenyl and Z' is phenyl.

70. A process according to claim 60, wherein R'1 is lower alkyl substituted with halogen, Y' is cyano and Z' is aryl.

71. A process according to claim 70, wherein R'1 is ethyl substituted with chlorine and Z' is phenyl.

72. A process according to claim 71, wherein R'1 is 2,2,2-trichloroethyl and X' is chlorine.

73. A process according to claim 59, wherein R'1 is aryl(lower)alkyl that is unsubstituted or substituted with lower alkoxy, Y' is cyano and Z' is aryl.

74. A process according to claim 73, wherein R'1 is benzyl that is unsubstituted or substituted with methoxy and Z' is phenyl.

75. A process according to claim 74, wherein R'1 is benzyl or 4-methoxybenzyl.

76. A process according to claim 75, wherein R'1 is benzyl and X' is chlorine.

77. A process according to claim 75, wherein R'1 is 4-methoxybenzyl.

78. A process according to claim 57, wherein R'1 is lower alkyl, Y' is cyano and Z' is aryl substituted by halogen.

79. A process according to claim 78, wherein R'1 is tert-butyl and Z' is phenyl substituted by chlorine.

80. A process according to claim 79, wherein Z' is 4-chlorophenyl.