CA2015098A1 - Preparative process for 3-amino-2-thioxo-oxazolidin-4-ones - Google Patents

Abstract

TITLE
PREPARATIVE PROCESS FOR

ABSTRACT OF THE DISCLOSURE
A new process for the preparation of 3-amino-2-thioxo-oxazolidin-4-ones comprising sequential reaction, in an organic medium, of a 2-hydroxy-carboxylic acid ester with a base, with carbon disulfide, with an acylating agent, and with a substituted hydrazine. The products are useful as antifungal agents. An exemplary compound prepared by the process is 5-methyl-5-phenyl-3-phenylamino-2-thioxo-oxazolidin-4-one.

Description

5PREPARATIvE PROCESS FOR

BACKGROUND OF THE INVENTION
3-Amino-2-thioxo-oxazolidin-4-ones are reported in Z. Naturforsch., ~: Anorg. Chem., Org. Chem.
101983, 38B(8) 1008 (Detlef Geffken), without suggestion of utility. The method given there for their preparation is exemplified below for compound ~-~ ~

Ph ~<OH (~ Ph ~ PhNHNH2 Ph ~
20 ~ c- NOH o Et o : ~
11 111 ' `

Preparation of compound i requires use of an expensive N-substituted hydroxylamine. Preparation of the intermediate ii requires use of the expensive reagent l,l'-thiocarbonyldiimidazole.
Copending application (Du Pont Case No. BA-8790 describes the antifungal utility of compounds , , ~:

~t '` , ' : :; . ' ' .. ~' ' '' ' " ''" ' :, ' .. ' ' r à ~
.
- 201~098 ^~ prepared by the method of the present invention, of which structure iii represents one such compound.

2-Hydroxycarbo~ylic acids can be purchased from commercial sources, or generally prepared from ketones or aldehydes by formation of cyanohydrins, .. .
, then hydrolysis, as is known in the art. For e~ample, Org. Syn. Coll. Vol. IV, S8 (1968) teaches the preparation of atrolactic acid from , acetophenone. Esters can be prepared from the ~, 2-hydro~ycarbo~ylic acids by methods known in the 3 art. The "Dictionary of Organic Compounds~, Vol. 3, 4th ed. (1965), page 1791 (O~ford Univ. Press) lists atrolactic acid and esters.
' DESCRIPTIO~ OF THE PROCESS
The process comprises four sequential reactions:
~, (1) reaction of a 2 hydroxycarbo~ylic acid ~, 20 ester with a base;
(2) reaction of the product of reaction (1) ~- with carbon disulfide;
(3) reaction of the product of reaction (2) with an acylating agent; and 2S (9) reaction of the product of reaction (3) with a substituted hydrazine.
, This sequence of reactions can be conveniently con-, ducted in a single reaction vessel without isolation of chemical intermediates.
The process is represented in Scheme 1 for the specific case of preparation of compound iii, and in Scheme 2 for the general case:

.' --` 2015098 R~ tlon 9t-p~

Ph OH 1. e- 8uOK Ph ~

¦1 10 9ch~ X 3 EtOCOCl Ml~>~ ~NHPh ~ ~

4. PhNMNH~ ~ :
111 ~ ~;
~
:

~:

9che~e 2: X 2 C9 R1 O ~

.~a CO2Z 4. H2NNR3R~ R ~ N~ R

i II (I) wherein:
Z is alkyl (Cl-cl2); alkenyl (C3-C4);
. cycloalkyl (C3-cl2); cycloalkylalkyl `~ 30 (C6-c7); alko~yalkyl (C2-C4); benzyl;
l is H; alkyl (Cl-C6); haloalkyl (Cl-c6~
cycloalkyl (C3-c6); alkenyl (C2-C6); alkynyl (C2-c6); alko~yalkyl (C2-C6); alkyl (Cl-c3) , substituted with cycloalkyl (C3-c6); phenyl . 35 or benzyl substituted on the ring with R6;
O

~01~98 '~
R2 is phenyl substituted with R5 and R6;
naphthyl substituted with 1-2 groups 7 5 selected from R6; thienyl substituted with .
~ R5 and R6; furyl substituted with R6;
pyridyl substituted with R6, phenoxy or phenylthio; alkyl (Cl-C6); alkyl (Cl-C2) substituted with R6-substituted phenoxy or 1 10 with R6-substituted phenylthio;
! Rl and R2 can be taken together, along with the carbon atom to which they are attached, to form a carbocyclic or heterocyclic ring (containing O, N-R7, or S) of 5-7 ring 7 15 atoms. The heterocylic ring can be fused 7 with an R5-substituted benzene ring or an R6-substituted thiophene ring, the heteroatom not being attached to the spiro center; the carbocyclic ring can be fused with 1-2 R5-substituted benzene rings or with an R6-substituted thiophene ring.
~ R3 is phenyl substituted with R5 and R6; benzyl :~ substituted on the benzylic carbon with R7 :~
] and or the phenyl ring with R6; naphthyl .l 25 substituted with R6; thienyl substituted with R6; furyl substituted with R6; pyridyl substituted with R6; pyrazyl substituted , with R6; pyridazyl substituted with R6;
pyrimidyl substituted with R6; alkyl (C2-C10); cycloalkyl (C5-C7);
~ R4 is ~; formyl; alkylcarbonyl (C2-C4);
, haloalkylcarbonyl (C2-C4); alkoxyalkyl-' carbonyl (C2-C4); alkoxycarbonyl (C2-C4);
`~ alkylaminocarbonyl (C2-C5); alkylsulfonyl 7 35 (Cl-C4); alkyl (Cl-C6); alkenyl (C3-C4);
. ~.,::
.. .
.; :
.~
- .
`: ::

r ~ : 7~

-" 201~098 `
: 5 : ~ .

alkynyl (C3-C4); cycloalkyl (C4-C6); benzyl 3 substituted or phenyl with R6 or on the benzylic carbon with R7; phenylaminocarbonyl ~:
wherein the phenyl is substituted with R6; ~ :
R3 and R4 can be taken together, along with the --~ nitrogen atom to which they are attached, to ~-i form a pyrrolidino, piperidino or hexamethyleneimino ring, which rings can be fused to an R6-substituted benzene ring;
R5 is H; halogen; alkyl (Cl-C6); haloalkyl ' (Cl-C4); alkoxy (Cl-C6); alkenyloxy (C3-C4);
alkylthio (Cl-C5); haloalkylthio (Cl-C4);
haloalkoxy (C1-C4); alkylsulfonyl (Cl-C4);
haloalkylsulfonyl (Cl-C4); nitro; phenyl ' substituted with R6; pheno~y substituted with R6; phenylthio substituted with R6;
~:` cyano; alkynyloxy (C3-C4); alkoxyalkyl (C2-C6); alkoxyalkyloxy (C2-C6);
I phenoxymethyl with phenyl substituted by R6;
:~, benzyloxy with phenyl substituted by R6;
.~ phenethyloxy with phenyl substituted by R6;
; benzyl with phenyl substituted by R6;
' 25 phenethyl with phenyl substituted by R6;
;' carboalkoxy (C2-C6); cycloalkyl (C5-C6);
.. i R6 is H; halogen (1-2); methyl; trifluoro-methyl; alko~y (Cl-C4); methylthio; nitro;
R7 is H; or alkyl (Cl-C4).
Preferred for reasons of ease of synthesis, lower e~pense or greater utility are compounds of structure (I), wherein: :~
Z is Cl-C4 alkyl;
Rl is methyl;
; 35 R2 is phenyl substituted with R5 and R6;
. R3 is phenyl substituted with R6; and R4 is hydrogen.
, ~
.:

201~098 In each of the reaction steps of Scheme 2 it will be understood by those skilled in the art that the optimum combination of reaction time, reaction temperature, stoichiometry, solvent(s), and the like will depend on the exact product being prepared, as well as on the relative importance of these factors and the results to the individual operator. For example:
The reaction time should be sufficient to effect the desired reaction; the reaction temperature should be sufficient to effect the desired reaction in the desired time without undue decomposition or side reactions; the stoichiometry of reactants should generally be the theoretical values, in the interest of economy, with variations as needed to compensate for evaporative or other losses; and solvent(s) can be selected, e.g., so that reaction ingredients have a substantial solubility, in the interest of obtaining relatively fast reaction rates.
In Reaction Step 1 - Usable bases are those capable of deprotonation of the hydroxy group without unacceptable side reactions. Included are the alkali metal tertiary alkoxides, hydrides, and hydroxides.
Preferred among these in the interest of higher solubility, reactivity, ease or safety of use, higher yields, or economy are the potassium tertiary alkoxides such as potassium tert.-butoxide and potassium tert.-amylate. Especially preferred is potassium tert.-butoxide.

.. . .

:
, . . .

~.. , ,- . ' :

Usable solvents are the 2-hydroxycarbo~ylic acid ester itself and generally the non-hydroxylic solvents, including ethers (e.g. diethyl ether, tetrahydrofuran, dio~ane, 1,2-dimetho~yethane), esters (e.g. methyl and ethyl acetate), amides (e.g.
N N-dimethylformamide, N,N-dimethylacetamide, l-methyl-2-pyrrolidone), nitriles (e.g.
acetonitrile), and the like, and mi~tures containing one or more of these solvents. Preferred among these solvents are those in which the reactants have substantial solubility.
The temperature can vary from about -80C to about ~100C, with about -20C to +80C preferred, and with about -5C to +50C more preferred. Ambient temperature is a convenient temperature at which to conduct the reaction.
The needed reaction time is short with soluble reactants. No more than a few minutes are required i at ice to ambient temperatures, e.g. 0.5 to 15 minutes.
Preferred groups Z are Cl-C4 alkyl.
In Reaction Step 2, carbon disulfide (CS2) is , 25 contacted with the product of Step 1 at about -20C
to l100C, preferably -10C to ~50C, for about 5 seconds to about 24 hrs., preferably for about 5 to ` 30 min. The reaction is rapid for soluble reactants. Ambient temperature is a convenient temperature at which to conduct the reaction.
In Reaction Step 3 an acylating agent capable of forming a mixed-anhydride with the product of Reaction Step 2 is contacted with the product of Reaction Step 2. Such acylating agents include chloroformates, e.g. methyl chloroformate, ethyl chloroformate, propyl chloroformate, butyl i~

,..... : . ~ . :

.,,~.. . .

^`` 2015098 chloroformate, and benzyl chloroformate, and other acylating agents. Preferred acylating agents are methyl and ethyl chloroformate. The reaction is rapid, and is complete in about 5 seconds to an hour with soluble reactants. Most reactions are complete in about 1 to 30 minutes. The temperature can range from about -20C to +50C. The preferred range is from about -10C to +25C. Ice to ambient temperatures is a convenient temperature range for conducting this reaction.
In Reaction Step 4 the substituted hydrazine reactant is contacted with the product of Reaction Step 3. The substituted hydrazine can be used as the free base or as a mixture of its acid salt with a free-basing agent such as a tertiary amine base ~e.g.
triethylamine, N,N-diisopropyl-N-ethylamine). The reaction is rapid, re~uiring no more than a few minutes for completion with soluble reactants.
Reaction times may be 10 seconds to about 1 day, preferably about 1 minute to 8 hrs. Reaction temperatures can range from about -20C to ~100C.
Ice to ambient temperatures is a convenient range at which to conduct the reaction.
The product of Step 4 can be isolated by evaporation of the reaction solvent, and it can be purified if desired by washing in a water-immiscible solvent (e.g. carbon tetrachloride, butyl chloride, ether) with water, mineral acid, and base, followed ~ by drying and evaporation of solvent, in turn `` follcwed by crystallization or chromatography as desired.
. :

:

,.~

-" 201~098 The compounds that can be made by the process of this invention are described in the E~amples and Tables which follow, and are intended to be only exemplary.

Preparation of S-Methyl-5-phenyl-3-(phenylamino)-2-thio~o-oxazolidin-4-one [Compound iii]
A solution of methyl atrolactate (7.64 g, 0.0424 mole) in tetrahydrofuran (80 ml) was stirred and cooled in an ice bath, and potassium tert.-buto~ide (4.76 9, 0.0424 mole) was added. The ice bath was removed, and the mixture was stirred for 10 minutes. This procedure provided a clear, yellow solution at 21C.
Carbon disulfide (2.8 ml, 0.046 mole) was added, and caused the formation of an orange color and a temperature rise to 32C. The solution was cooled in an ice bath for 10 minutes, causing the temperature to fall to 4C.
I Ethyl chloroformate (4.1 ml, 0.043 mole) was ¦ 25 added to the ice-cooled solution, inducing the formation of a turbid yellow mi~ture and a temperature rise to 12C. The mi~ture was stirred with ice-bath cooling for 5 minutes as the temperature fell to 5C.
Phenylhydrazine (97%, 4.5 ml, 0.044 mole) was added. The temperature rose to 24C while the ~i cooling bath was applied. ~fter the temperature fell ~ to 20C, the mi~ture was stirred for 10 minutes, then i evaporated under reduced pressure to an oil.
, 35 ., '' ~

~ ~s ~

--` 2015098 The oil was mixed with l-chlorobutane and water, and the layers were separated. The organic layer was washed with lN HCl, water, and saturated aq. sodium bicarbonate solution. The organic ' solution was dried (magnesium sulfate), filtered, and ' evaporated under reduced pressure to an oil. The oil t was crystallized from carbon tetrachloride/hexane (~40 ml/20 ml), providing the product (7.40 g, 58.5%
of theory) as a light-yellow solid, m.p. 104-105C.
The product was further purified by recrystallization ! from carbon tetrachloride/hexane with 93% recovery.
In another preparation of the same product, , 15 carbon tetrachloride was used instead of ; l-chlorobutane during the workup. Crystallization from the carbon tetrachloride solution by dilution ; with hexane p~ovided the product in 54% yield.
Recrystallization from isopropanol/water provided the product as a white solid, m.p. 108-109C, with 92%
recovery.

, Preparation of -; 25 3'-(Phenylamino)-2'-thioxo-spiro(9H-~ fluorene-9,5'-oxazolidin)-4'-one .~
;, :

` 30 ;~N--NHPh `'; ~''' ~

~ ' '~ :

201~098 A solution of 9-hydroxy-9-fluorenecarboxylic acid, methyl ester (8.91 g, 0.0371 mole) in tetrahydrofuran (89 ml~ was treated with potassium tert.-buto~ide (4.16 9, 0.0371 mole). After 6 minutes the solution was cooled in an ice bath and carbon disulfide (2.3 ml, 0.038 mole) was added.
After 7 minutes ethyl chloroformate (3.6 ml, 0.038 mole) was added to the cold solution. After 7 minutes 97% phenylhydrazine (3.9 ml, 0.038 mole) was added. After 3 minutes, the mixture was evaporated under reduced pressure to a yellow syrup. The syrup was treated with l-chlorobutane and water, and the organic layer was washed with saturated sodium bicarbonate solution, water, lN HCl, and water. The dried (magnesium sulfate) solution was filtered and evaporated under reduced pressure to an oil. The oil was crystallized from carbon tetrachloride/hexane, and the solid product further purified by boiling with isopropanol (without dissolution of all solid), cooling, and filtering. The product was obtained as 3.56 9 (27% of theoretical) of analytically-pure white solid, m.p. 187-189C.
Anal. Calcd. for C21H14N2O2S: C, 70.3 ;
3.99; N, 7.82%. Anal. Found: C, 70.28; H, 4.19; N, 7.68%. The infrared spectrum (Nujol*mull) showed absorption at 3275 cm~l (N-H) and 1770 cm~l (imide 0 C,O).
' E~AMPLE 3 Preparation of 5-Phenyl-3-(phenylamino)-2-thioxo-o~azolidin-4-one ~.

* trade mark ~ ~
:.
.~, ~.

~,z-.. , . ~

,~. , . - . .: - -201~098 .

s ,,, 1 0 ~N~NHPh A stirred solution of potassium tert.-butoxide (11.22 9, 0.1 mole) in tetrahydrofuran (100 ml), held at 0C to -5C, was treated portionwise with a solution of methyl mandelate (16.62 9, 0.1 mole) in tetrahydrofuran (70 ml~, providing an orange-red solution. After ~ minutes carbon disulfide (6.04 ml, -~ -0.1 mole) was added. After 5 minutes at 0C to -5C, the orange solution was cooled to -30C and treated with ethyl chloroformate ~9.S ml, 0.1 mole). After 2 minutes the solution was warmed to -10C. After 5 minutes at -10C, the solution was cooled to -30C
and treated with 97% phenylhydrazine (10.1 ml, 0.1 mole). The yellow solution was warmed to 25C, and after 10 minutes the mixture was evaporated under reduced pressure to a turbid oil. The oil was mixed with water and l-chlorobutane, the layers were separated, and the organic solution was washed with lN HCl, water (twice), and saturated sodium bicarbonate solution. The dried (magnesium sulfate) solution was evaporated under reduced pressure to a yellow-orange oil, and the oil was dissolved in -chloroform. A silica-gel filtration of the - ,~
:

chloroform solution followed by evaporation of the filtrate under reduced pressure provided a green oil which began to solidify. Further purification was accomplished by crystalliæation from l-chlorobutane.
This procedure provided the product as 9.9 g (35% of theoretical) of a white solid, m.p. 140-141C. The infrared spectrum (Nujol mull) showed the characteristic absorption at 3295 cm~l (N-H) and 1760 cm~l (imide C~O).
Other compounds that can be prepared according to the present invention, from the appropriate 2-hydroxycarboxylic acid ester, base, carbon disulfide, acylating agent, and substituted hydrazine are illustrated in the Tables which follow. The Tables are not intended to be all-inclusive.

.
:~0 ,.

j ~ ~.

201~98 , R~ o J~
>~ N ( I ) \R4 Rl ~ ~

Ethyl Phenyl ~ Phenyl H
¦ 20 ~-He~yl Phenyl Phenyl H
¦ Cyclopropyl Phenyl Phenyl H
, Cyclohe~yl Phenyl Phenyl H
¦ Vinyl Phenyl Phenyl H
i Allyl Phenyl Phenyl H
25 Propargyl Phenyl Phenyl H
Methoxymethyl Phenyl Phenyl H
I Ethosyethyl Phenyl Phenyl H
! Cyclopropylmethyl Phenyl Phenyl H
Cyclohexylmethyl Phenyl Phenyl H
. 30 ~enzyl Phenyl Phenyl H
j Methyl 4-Fluorophenyl Phenyl H
Methyl 2,4-Difluorophenyl Phenyl H
Methyl 4-Metho~yphenyl Phenyl H
Methyl 4-(Trifluoromethyl)phenyl Phenyl H
Methyl 4-(n-Buto~y)phenyl Phenyl H

.
;`
:~

.

Rl ~ ~ R4 5 Methyl 4-Methylthiophenyl Phenyl H
Methyl 4-Nitrophenyl Phenyl H
Methyl 2-Methylphenyl Phenyl H
Methyl 3-Methylphenyl Phenyl H
Methyl 4-Methylphenyl Phenyl H
10 Methyl 4-Pentyloxyphenyl Phenyl H
jMethyl 4-Hexyloxyphenyl Phenyl H
Methyl 4-Allyloxyphenyl Phenyl H
'Methyl 4-Butylthiophenyl Phenyl H
Methyl 4-(Trifluoromethylthio)phenyl Phenyl H
'.15 Methyl 9-(Difluoromethoxy)phenyl Phenyl H
Methyl 4-(Trifluoromethoxy)phenyl Phenyl H
~,Methyl 4-Methylsulfonylphenyl Phenyl H
`, Methyl 4-(Trifluoromethylsulfonyl)phenyl Pheny~ H
! Methyl 4-Phenylphenyl Phenyl H
20 Methyl 4-(4-Chlorophenyl)phenyl Phenyl H
Methyl 4-(4-Methoxyphenyl)phenyl Phenyl H
~Methyl 3-(4-Chlorophenoxy)phenyl Phenyl H
~Methyl 4-(4-Phenylthio)phenyl Phenyl H
'Methyl 4-(4-Chlorophenylthio)phenyl Phenyl H
25 Methyl 4-Cyanophenyl Phenyl H
Methyl 4-Propargyloxyphenyl Phenyl H
Methyl 4-(Methoxymethyl)phenyl Phenyl H
Methyl 4-(2-Methoxyethyl)phenyl Phenyl H
Methyl 4-(2-Ethoxyethyl)phenyl Phenyl H
30 Methyl 4-(Methoxymetho~y)phenyl Phenyl H
Methyl 4-(2-Methoxyethoxy)phenyl Phenyl H
Methyl 4-(Pheno~ymethyl)phenyl Phenyl H
Methyl 4-(Benzyloxy)phenyl Phenyl H
Methyl 3-Pheno~yphenyl Phenyl H
~'35 Methyl 2-Pheno~yphenyl Phenyl H
Methyl 4-(2-Phenethyloxy)phenyl Phenyl H

.~

,,I,j~,'. ~ ,, . : ' ' ' 5~

2~15098 Bl Bl/B~ B~ ~3 5 Methyl 4-Benzylphenyl Phenyl H
Methyl 4-(2-Phenylethyl)phenyl Phenyl H
Methyl 4-Carbometho~yphenyl Phenyl H
Methyl 2-Naphthyl Phenyl H
Methyl 2-Thienyl Phenyl H
10 Methyl 3-Thienyl Phenyl H
Methyl 2-Furyl Phenyl H
Methyl 3-Furyl Phenyl H
Methyl 2-Pyridyl Phenyl H
Methyl 3-Pyridyl Phenyl H
lS Methyl 4-Pyridyl Phenyl H
Methyl 3-Methyl-2-thienyl Phenyl H
Methyl 5-Methyl-2-furyl Phenyl H
Pentamethylene Phenyl H
Tetramethylene Phenyl H
CH2CH2N(CH3)cH2cH2 Phenyl H
CH2CHzOCH2CH2 Phenyl H
CH2CH2ScH2cH2 Phenyl H

~ H2CH2CH2 Phenyl H

~H2CH2CH2cH2 Phenyl H

~ .
S CH2CH2CH2cH2 Phenyl H

35 4-Fluorophenyl 4-Fluorophenyl Phenyl H

pl ~ ~ R3~4 Methyl Phenyl 4-Fluorophenyl H
Methyl Phenyl 2-Fluorophenyl H
Methyl Phenyl 3-Fluorophenyl H
Methyl Phenyl 4-Pentyloxy H
Methyl Phenyl 2,6-Dimethylphenyl H
Methyl Phenyl Phenyl Methyl Methyl Phenyl Phenyl Formyl Methyl Phenyl Phenyl Acetyl Methyl Phenyl Phenyl Allyl Methyl Phenyl Phenyl Methoxyacetyl Methyl Phenyl (CH2)5 Methyl 4-Chlorophenyl Phenyl H
Methyl Phenyl 3-Chlorophenyl H
H Cyclohexyl Phenyl H
Methyl 4-Cyclohexylphenyl Phenyl H
Methyl Pheno~ymethyl Phenyl H
Methyl Phenylthiomethyl Phenyl H

~` 201~098 X I I
C02Z :' Bl ~ z Phenyl Methyl Ethyl 20 Phenyl Methyl Propyl : :
Phenyl Methyl Butyl Phenyl Methyl Pentyl Phenyl Methyl Dodecyl Phenyl Methyl Allyl 25 Phenyl Methyl 2-Methyl-2-propen-1-yl Phenyl Methyl Cyclopropyl Phenyl Methyl Cyclohexyl Phenyl Methyl Cyclododecyl Phenyl Methyl Cyclopentylmethyl 30 Phenyl Methyl Cyclohe~ylmethyl Phenyl Methyl Metho~ymethyl ~ Phenyl Methyl Etho~yethyl il Phenyl Methyl ~enzyl '~ Methyl 9-Phenoxyphenyl Methyl ~,35 Methyl 3-Fluorophenyl Methyl Methyl 3-Thienyl Methyl ~, :

Claims (12)

1. A process for the preparation of substituted 3-amino-2-thioxo-oxazolidin-4-ones of Formula I, comprising conducting the following reactions in an organic solvent: (1) reacting a

2-hydroxycarboxylic acid ester of Formula II with a base, (2) reacting the reaction product of (1) with carbon disulfide, (3) reacting the reaction product of (2) with an acylating agent, and (4) reacting the reaction product of (3) with a substituted hydrazine, followed by recovery of the product from the reaction mixture wherein:

Formula II is , Formula(I)is .

Z is alkyl (C1-C12); alkenyl (C3-C4);
cycloalkyl (C3-C12): cycloalkylalkyl (C6-C7); alkoxyalkyl (C2-C4); benzyl;

R1 is H; alkyl (C1-C6); haloalkyl (1-C6);
cycloalkyl (C3-C6); alkenyl (C2-C6); alkynyl (C2-C6); alkoxyalkyl (C2-C6); alkyl (C1-C3) substituted with cycloalkyl (C3-C6); phenyl or benzyl substituted on the ring with R6;
R2 is phenyl substituted with R5 and R6;
naphthyl substituted with 1-2 groups selected from R6; thienyl substituted with R5 and R6; furyl substituted with R6;
pyridyl substituted with R6, phenoxy or phenylthio; alkyl (C1-C6); alkyl (C1-C2) substituted with R6-substituted phenoxy or with R6-substituted phenylthio;
R1 and R2 can be taken together, along with the carbon atom to which they are attached, to form a carbocyclic or heterocyclic ring (containing O, N-R7, or S) of 5-7 ring atoms. The heterocylic ring can be fused with an R5-substituted benzene ring or an R6-substituted thiophene ring, the heteroatom not being attached to the spiro center; the carbocyclic ring can be fused with 1-2 R5-substituted benzene rings or with an R6-substituted thiophene ring;
R3 is phenyl substituted with R5 and R6; benzyl substituted on the benzylic carbon with R7 and or the phenyl ring with R6; naphthyl substituted with R6; thienyl substituted with R6; furyl substituted with R6; pyridyl substituted with R6; pyrazyl substituted with R6; pyridazyl substituted with R6;
pyrimidyl substituted with R6; alkyl (C2-C10); cycloalkyl (C5-C7);

R4 is H; formyl; alkylcarbonyl (C2-C4);
haloalkylcarbonyl (C2 C4); alkoxyalkyl-carbonyl (C2-C4); alkoxycarbonyl (C2-C4);
alkylaminocarbonyl (C2-C5); alkylsulfonyl (C1-C4); alkyl (C1-C6); alkenyl (C3-C4);
alkynyl (C3-C4); cycloalkyl (C4-C6); benzyl substituted or phenyl with R6 or on the benzylic carbon with R7; phenylaminocarbonyl wherein the phenyl is substituted with R6;
R3 and R4 can be taken together, along with the nitrogen atom to which they are attached, to form a pyrrolidino, piperidino or hexamethyleneimino ring, which rings can be fused to an R6-substituted benzene ring;
R5 is H; halogen; alkyl (C1-C6); haloalkyl (C1-C4); alkoxy (C1-C6); alkenyloxy (C3-C4);
alkylthio (C1-C5); haloalkylthio (C1-C4);
haloalkoxy (C1-C4); alkylsulfonyl (C1-C4);
haloalkylsulfonyl (C1-C4); nitro; phenyl substituted with R6; phenoxy substituted with R6; phenylthio substituted with R6;
cyano; alkynyloxy (C3-C4); alkoxyalkyl (C2-C6); alkoxyalkyloxy (C2-C6);
phenoxymethyl with phenyl substituted by R6;
benzyloxy with phenyl substituted by R6;
phenethyloxy with phenyl substituted by R6;
benzyl with phenyl substituted by R6;
phenethyl with phenyl substituted by R6;
carboalkoxy (C2-C6); cycloalkyl (C5-C6);
R6 is H; halogen (1-2); methyl; trifluoro-methyl; alkoxy (C1-C4); methylthio; nitro;
R7 is H; or alkyl (C1-C4).

2. A process of Claim 1 wherein the base is an alkali-metal alkoxide, hydroxide, or hydride.

3. A process of Claim 1 wherein the organic solvent is an ether, ester, amide, nitrile or a 2-hydroxycarboxylic acid ester of Formula II.

4. A process of Claim 3 wherein the organic solvent is the 2-hydroxycarboxylic acid ester of Formula II, tetrahydrofuran, N,N-dimethyl-formamide, N,N-dimethylacetamide, or 1-methyl-2-pyrrolidone.

5. A process of Claim 1 wherein the acylating agent is a chloroformate.

6. A process of Claim 5 wherein the acylating agent is ethyl chloroformate or methyl chloroformate.

7. A process of Claim 1 wherein the substituted hydrazine is of the formula H2NNR3R4 where R3 is phenyl substituted with R5 and R6; benzyl substituted on the benzylic carbon with R7 and or the phenyl ring with R6; naphthyl substituted with R6; thienyl substituted with R6; furyl substituted with R6; pyridyl substituted with R6; pyrazyl substituted with R6; pyridyl substituted with R6;
pyrimidyl substituted with R6; alkyl (C2-C10); cycloalkyl (C5-C7); and R4 is H; formyl; alkylcarbonyl (C2-C4);
haloalkylcarbonyl (C2-C4); alkoxyalkyl-carbonyl (C2-C4); alkoxycarbonyl (C2-C4);
alkylaminocarbonyl (C2-C5); alkylsulfonyl (C1-C4); alkyl (C1-C4); alkenyl (C3-C4);
alkynyl (C3-C4); cycloalkyl (C4-C6); benzyl substituted or phenyl with R6 or on the benzylic carbon with R7; phenylaminocarbonyl wherein the phenyl is substituted with R6;
and R3 and R4 can be taken together, along with the nitrogen atom to which they are attached, to form a pyrrolidino, piperidino or hexamethyleneimino ring, which rings can be fused to an R6-substituted benzene ring.

8. A process of Claim 7 wherein the substituted hydrazine is phenylhydrazine or 4-fluorophenylhydrazine.

9. A process of Claim 1 wherein:
Z is C1-C4 alkyl;
R1 is methyl;
R2 is phenyl substituted with R5 and R6;
R3 is phenyl substituted with R6; and R4 is hydrogen.

10. A process of Claim 9 wherein Z is methyl or ethyl, R1 is methyl, and R2 is phenyl, 4-fluorophenyl, or 4-phenoxyphenyl.

11. A process of Claim 1 wherein the base is potassium t-butoxide, the solvent is tetrahydrofuran, the acylating agent is ethyl chloroformate, the substituted hydrazine is phenylhydrazine, Z is methyl, R1 is methyl, R2 is phenyl, R3 is phenyl and R4 is hydrogen.

12. A process of Claim 1 wherein:
Reaction 1 is conducted at -80°C to 100°C;
Reaction 2 is conducted at -20°C to 100°C;
Reaction 3 is conducted at -20°C to 50°C; and Reaction 4 is conducted at -20°C to 100°C.