The present invention relates to a process for making key intermediates to therapeutically active heterocyclic compounds.

This invention provides a process for preparing key intermediates useful for the preparation of heterocyclic compounds. Such compounds include, but are not limited to azacyclic and azabicyclic compounds which are useful as stimulants of the cognitive function of the forebrain and hippocampus of mammals and especially in the treatment of Alzheimer's disease.

The process of this invention is particularly useful for preparing intermediates which are useful for making compounds of formula I' . The formula I' compounds exhibit muscarinic cholinergic agonist activity. Such

compounds have the following structure:

wherein

is oxygen or sulphur;

R is hydrogen, amino, halogen, NHR ⁶ , NR ⁶ R ⁷ , R ⁴ , -OR ⁴ , -SR ⁴ , -SOR ⁴ , -SO ₂ R ⁴ , C ₃ _ιo*-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , -Z-C ₃ _ιo-cycloalkyl and -Z-C ₄ - ₁₂ -(cycloalkylalkyl) wherein R ⁴ is Cι_i ₅ -alkyl, C ₂ -i ₅ *-alkenyl, C2-i5*-alkynyl, each of which is optionally substituted with one or more halogen(s), -CF ₃ , -CN, Y, phenyl or phenoxy wherein phenyl or phenoxy is optionally substituted with halogen, -CN, Cι_ ₄ -alkyl, Cι_ ₄ -alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ or -CSNH ₂ ; or R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with halogen, -CN, Cι_ ₄ -alkyl, Cχ_ ₄ - alkoxy, -OCF ₃ , -CF ₃ , -CONH ₂ or -CSNH ₂ ; or

R is -OR ⁵ Y, -SR ⁵ Y, OR ⁵ -Z-Y, -SR ⁵ ZY, -0-R ⁵ -Z-R ⁴ or -S-R ⁵ -Z-R ⁴ wherein Z is oxygen or sulphur, R ⁵ is Cι_i ₅ -alkyl, C2-15- alkenyl, C2-i5-alkynyl, and Y is a 5 or 6 membered heterocyclic group; and

G is selected from one of the following azacyclic or azabicyclic ring systems:

het-1 het-2 bet-3 het-4

het-5 het-6 het-7

or G can optionally be substituted C ₃ -C ₈ cycloalkyl or optionally substituted Cι__-alkyl wherein the substitution is -NR ⁶ R ⁷ ''

R ⁶ and R ⁷ independently are hydrogen, Ci-β-alkyl; or R ⁶ and

R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R ¹ and R ² independently are hydrogen, Cι- ₁₅ -alkyl, C2-5- alkenyl, C2-5*-alkynyl, Cι_ιo~alkoxy, Cι_5-alkyl substituted with -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2, carboxy, or phenyl;

R ³ is hydrogen, Cι_ ₅ -alkyl, C ₂ - ₅ *-alkenyl or _ ₂ - ₅ -alkynyl; n is 0, 1 or 2; m is 0, 1 or 2; p is 0, 1 or 2; q is 1 or 2; r is 0, 1 or 2; is a single or double bond. The present invention provides a process for making key intermediates which are useful for making heterocyclic compounds. Further, the processes claimed

herein provides a method for inverting the stereochemistry at the carbon bearing the hydroxyl group in the G substituent described supra . Such inverted stereochemistry can be important for the commercial development of pharmaceutically active compounds.

A process for preparing a compound of formula I

wherein

R ^R is hydrogen, R ⁴ , C ₃ -ιo*-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , R -Z-C ₃ __o-cycloalkyl and R ⁴ -Z-C ₄ _i ₂ - (cycloalkylalkyl) ;

R ⁴ is selected from the group consisting of Cι_i ₅ -alkyl, ^c 2-15-alkenyl, and C2-l5*-alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), -CF ₃ , Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, Cι- ₄ -alkyl, Cι_ ₄ ~alkoxy, and -CF ₃ ; or R ^R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, Cι_ ₄ -alkyl, Cι_4-alkoxy, and -CF ₃ ; or

R ^R is R ⁴ -OR ⁵ Y, R -SR ⁵ Y, R -OR ⁵ -Z-Y, R -SR ⁵ ZY, R -0-R ⁵ -Z-R ⁴ or R ⁴ -S-R ⁵ -Z-; Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of Cι_i5-alkyl, C2-i5-alkenyl, and C2-i5*-alkynyl;

Y is a 5 or 6 membered heterocyclic group; and R ⁶ , and R ⁷ independently are hydrogen, Cι-6-alkyl, or R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R ¹ and R ² independently are hydrogen, Cι_i5-alkyl, C2-5- alkenyl, C2-5-alkynyl, Cι_ιo-alkoxy, Ci-5-alkyl substituted with -OH, -COR ⁶ ', CH2-OH, halogen, -NH2, carboxy, or phenyl;

R ⁶ ' is hydrogen or C1-C3 alkyl; comprising contacting a compound of the formula II

HAL is selected from the group consisting of Cl, Br, F, and I; with an aqueous alkaline metal hydroxide. Another process of this invention is a process for preparing a compound of formula I

wherein

R ^R is hydrogen, R ⁴ , C ₃ _ιo*-cycloalkyl, C ₄ - ₁₂ - (cycloalkylalkyl) , R ⁴ -Z-C ₃ _ιo*-cycloalkyl and R ⁴ -Z-C ₄ _i ₂ - (cycloalkylalkyl) ;

R ⁴ is selected from the group consisting of Cι-15-alkyl, C2-15-alkenyl, and C2-i5-alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), -CF ₃ , Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, Cι- ₄ -alkyl, Cι- ₄ -alkoxy, and -CF ₃ ; or R ^R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more selected from the group consisting of halogen, Cι_ ₄ -alkyl, _ι_ ₄ -alkoxy, and -CF ₃ ; or R ^R is R ⁴ -OR ⁵ Y, R ⁴ -SR ⁵ Y, R ⁴ -OR ⁵ -Z-Y, R ⁴ -SR ⁵ ZY, R ⁴ -0-R ⁵ -Z-R ⁴ or R -S-R ⁵ -Z-; Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-i5-alkenyl, and C2-i5*-alkynyl; Y is a 5 or 6 membered heterocyclic group; and

R ⁶ , and R ⁷ independently are hydrogen, Cι_ ₆ -alkyl, or R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring; R ¹ and R ² independently are hydrogen, Ci-is-alkyl, C2-5- alkenyl, C2-5*-alkynyl, Cι- ₁₀ -alkoxy, Ci-5-alkyl substituted with -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH2, carboxy, or phenyl;

R ⁶ ' is hydrogen or C1 _. -C ₃ alkyl; comprising contacting a compound of the formula II

I

HAL is selected from the group consisting of Cl, Br, F, I, and S0 ₂ R ⁴ ';

R ⁴ ' is C ₁ -C ₃ alkyl or phenyl; with an aqueous alkaline metal hydroxide.

Detailed Description of the Invention

It is to be understood that the invention extends to each of the stereoisomeric forms of the compounds of the present invention as well as the pure diastereomeric, pure enatiomeric, and racemic forms of the compounds of this invention.

As used herein the term "treating" includes prophylaxis of a physical and/or mental condition or amelioration or elimination of the developed physical and/or mental condition once it has been established or alleviation of the characteristic symptoms of such condition.

As used herein with reference to the G substituent, the - (CH ₂ ) _r -*W-thiadiazole moiety can be attached at any carbon atom of the azacyclic or azabicyclic ring. Further, R ¹ and R ² of the G substituent may be present at any position, including the point of attachment of the - (CH ₂ ) _r ^-w *"thiadiazole moiety.

As used herein with reference to the G substituent, the phrase "R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring" means that R ⁶ and R ⁷ are each independently hydrogen, C ₁ -C ₆ alkyl wherein the R ⁶ and R ⁷ groups may optionally join to form a

4- to 6-member ring including the nitrogen. For example, optionally joined groups include, but are not limited to:

As used herein the phrase "interacting with a muscarinic cholinergic receptor" shall include compounds which block muscarinic cholinergic receptors or modulate such receptors. The phrase shall include the effect observed when compounds act as agonists, partial agonists and/or antagonists at a muscarinic cholinergic receptor. As used herein, the term "alkoxide metal" means a metal suitable for alkoxide formation. Such alkoxide metals include, but are not limited to, Li ⁺ , K ⁺ , Na ⁺ , Cs ⁺ , and Ca ⁺⁺ . Especially preferred alkoxide metals include Li+, K ⁺ , and Na ⁺ . As used herein the term "alkaline metal hydroxide" shall include, but are not limited to Li ⁺ , K ⁺ , Na ⁺ , Cs ⁺ , and Ca ⁺⁺ . Preferred alkoxide metal include Li ⁺ , K ⁺ , and Na ⁺

As used herein, the term "halogen" or the term "HAL" means Cl, Br, F, and I. Especially preferred halogens include Cl, Br, and I.

As used herein the term "aprotic solvent" shall have the art recognized meaning. The term shall most preferably refer to DMSO and DMF. The aprotic solvent DMSO is especially preferred. The aprotic solvent may be used with water for the processes of this invention.

The terms "Cι-C _n - alkyl" wherein n'can be from 2 through 15, as used herein, represent a branched or linear alkyl group having from one to the specified number of carbon atoms. Typical Ci-C _δ alkyl groups include, but are not limited to, methyl, ethyl, Ω-propyl, iso-propyl, butyl, iso- butyl, sec-butyl, tert-butyl, pentyl, hexyl and the like.

The terms "C ₂ -C _n * alkenyl" wherein n' can be from 3 through 10, as used herein, represents an olefinically unsaturated branched or linear group having from 2 to the

specified number of carbon atoms and at least one double bond. Examples of such groups include, but are not limited to, 1-propenyl, 2-propenyl (-CH ₂ -CH=CH ₂ ) , 1,3-butadienyl, (-CH=CHCH=CH ₂ ) , 1-butenyl (-CH=CHCH ₂ CH ₃ ) , hexenyl, pentenyl, and the like.

The term "C2-C ₅ alkynyl" refers to an unsaturated branched or linear group having from 2 to 5 carbon atoms and at least one triple bond. Examples of such groups include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 1-pentynyl, and the like.

The terms "halogen (C±-Cζ )alkyl" and "halogen{C2*- CQ )alkenyl" refer to alkyl or alkenyl substituents having one or more independently selected halogen atoms attached at one or more available carbon atoms. These terms include, but are not limited to, chloromethyl, 1-bromoethyl, 2-bromoethyl, 1,1, 1-trifluoroethyl, 1,1,2-trifluoroethyl, 1,2,2- trifluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, trifluoroethylenyl, 3-bromopropyl, 3-bromo-l-propenyl, 2- bromopropyl, 2-bromo-l-propenyl, 3-chlorobutyl, 3-chloro-2- butenyl, 2,3-dichlorobutyl, 1-chloroethylenyl, 2- chloroethylenyl, 5-fluoro-3-pentenyl, 3-chloro-2-bromo-5- hexenyl, 3-chloro-2-bromobutyl, trichloromethyl, 1,1- dichloroethyl, 1,2-dichloroethyl, 2,2-dichloroethyl, 1,4- dichlorobutyl, 3-bromopentyl, 1,3-dichlorobutyl, 1,1- dichloropropyl, and the like.

The term "C ₂ -C ₁₀ alkanoyl" represents a group of the formula C(O) (C1-C ₉ ) alkyl. Typical C2-C ₁₀ alkanoyl groups include acetyl, propanoyl, butanoyl, and the like.

The term " (Ci-Cβ alkyl) amino" refers to a monoalkylamino group. Examples of such groups are methylamino, ethylamino, iso-propylamino, _ι-propylamino, (n- propyl)amino, (iso-propyl)amino, __-propylamino, t-butylamino, and the like.

The term "C ₃ -C _n cycloalkyl" wherein n=4-8, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term "substituted(C5-C _n > ) cycloalkyl" refers to a cycloalkyl group as described supra wherein the cycloalkyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, Cχ-C ₆ alkyl, NO ₂ , halogen, halogen(Ci-Cδ)alkyl, halogen(C ₂ - Cβ )alkenyl, C ₂ -C6 alkenyl, CO2R ²⁰ , (C1-C6 alkyl) amino, -SR ²⁰ , and OR ²⁰ ; wherein R ²⁰ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-i5-alkenyl, C2-i5~alkynyl.

The term "C ₃ -C8 cycloalkyl- (C1-C3)alkyl" represents an alkyl group substituted at a terminal carbon with a C ₃ -C ₈ cycloalkyl group. Typical cycloalkylalkyl groups include cyclohexylethyl, cyclohexylmethyl, 3-cyclopentylpropyl, and the like.

The term "C ₅ -C ₈ cycloalkenyl" represents an olefinically unsaturated ring having five to eight carbon atoms. Such groups include, but are not limited to, cyclohexyl-1,3-dienyl, cyclohexenyl, cyclopentenyl, cycloheptenyl, cyclooctenyl, cyclohexyl-1, 4-dienyl, cycloheptyl-1, -dienyl, cyclooctyl-1,3, 5-trienyl and the like.

The term "substituted (C5-C ₈ ) cycloalkenyl" refers to a cycloalkenyl group as described supra , wherein the cycloalkenyl group may be substituted with from one to four substituents independently selected from the group consisting of hydrogen, Cχ-C ₆ alkyl, NO ₂ , halogen, halogen(Ci-Cβ)alkyl, halogen(C ₂ -C ₆ )alkenyl, C ₂ -C ₆ alkenyl, COR ²⁰ , C ₂ -C ₁₀ alkanoyl, C7-C ₁₆ arylalkyl, CO ₂ R ²⁰ , (Cι-_ ₆ alkyl) amino, -SR ²⁰ , and -OR ²⁰ ; wherein R ²⁰ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-15-alkenyl, and C2-i5-alkynyl. The term "C ₅ -C ₈ cycloalkenyl- (C ₁ -C ₃ )alkyl" represents a C ₁ -C ₃ alkyl group substituted at a terminal carbon with a C ₅ -- ₈ cycloalkenyl group.

As used herein, the phrase "5 or 6 membered heterocyclic group" means a group containing from one to four N, 0 or S atom(s) or a combination thereof, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with Ci-g-alkyl, -CF3, phenyl, benzyl or

thienyl, or a carbon atom in the heterocyclic group together with an oxygen atom form a carbonyl group, or which heterocyclic group is optionally fused with a phenyl group. The phrase "5 or 6 membered heterocyclic group" includes, but is not limited to, 5-membered heterocycles having one hetero atom (e.g. thiophenes, pyrroles, furans); 5-membered heterocycles having two heteroatoms in 1,2 or 1,3 positions (e.g. oxazoles, pyrazoles, imidazoles, thiazoles, purines) ; 5-membered heterocycles having three heteroatoms (e.g. triazoles, thiadiazoles) ; 5-membered heterocycles having 3-heteroatoms; 6-membered heterocycles with one heteroatom (e.g. pyridine, quinoline, isoquinoline, phenanthrine, 5, 6-cycloheptenopyridine) ; 6- membered heterocycles with two heteroatoms (e.g. pyridazines, cinnolines, phthalazines, pyrazines, pyrimidines, quinazolines) ; 6-membered heterocycles with three heteroatoms (e.g. 1,3,5-triazine) ; and 6-member heterocycles with four heteroatoms. Particularly preferred are thiophenes, pyridines, and furans. As used herein the term "carboxy" refers to a substituent having the common meaning understood by the skilled artisan, wherein the point of attachment may be through the carbon or oxygen atom of the group.

As used herein the term "aryl" means an organic radical derived from an aromatic hydrocarbon by the removal of one atom; e.g., phenyl or naphthyl. Most preferably, aryl refers to C _δ -Cio aryl, wherein the aryl ring system, including any alkyl substitutions, comprises from 6 to 10 carbon atoms; e.g., phenyl, 3,3-dimethylphenyl, naphthyl, and the like. The aryl radical may be substituted by one or two Cι-_ ₆ straight or branched alkyl. The term "aryl(C ₁ -C ₃ )alkyl" refers to any aryl group which is attached to the parent moiety via the alkyl group.

Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or

similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977) which are known to the skilled artisan. The compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.

The starting materials for the illustrated processes are commercially available or may be prepared using methods known to the skilled artisan.

The process of this invention, illustrated by Scheme VII, is the synthesis of 3-hydroxy-4-alkylthio-l,2,5- thiadiazoles by treating 3-halo-4-alkylthio-l,2,5- thiadiazoles with aqueous alkaline metal hydroxides in the presence or absence of a dipolar aprotic solvent. In this scheme, R and Hal have the meanings defined supra , and M is an alkali metal. W is S or O.

Scheme VII

wherein

R ^R is hydrogen, R ⁴ , C ₃ _ιo-cycloalkyl, C ₄ _i ₂ ~

(cycloalkylalkyl) , R -Z-C3_ιo-cycloalkyl and R ⁴ -Z-C ₄ -i ₂ ~

(cycloalkylalkyl) ;

R ⁴ is selected from the group consisting of Cι_i ₅ -alkyl, _2-i5-alkenyl, and C2-i5-alkynyl, each of which is optionally substituted with one or more independently selected from the group consisting of halogen(s), -CF ₃ , Y, phenyl and phenoxy; wherein phenyl or phenoxy is optionally substituted with one or more selected from the group consisting of halogen, Cι- ₄ -alkyl, Cι- ₄ -alkoxy, and -CF ₃ ; or R ^R is phenyl or benzyloxycarbonyl, each of which is optionally substituted with one or more selected from the

group consisting of halogen, Cι_ ₄ -alkyl, C _ ₄ -alkoxy, and -CF ₃ ; or

R ^R is R ⁴ -OR ⁵ Y, R -SR ⁵ Y, R -OR ⁵ -Z-Y, R ⁴ -SR ⁵ ZY, R -0-R ⁵ -Z-R ⁴ or R ⁴ -S-R ⁵ -Z-; Z is oxygen or sulphur;

R ⁵ is selected from the group consisting of Cι- ₁₅ -alkyl, C2-15-alkenyl, and C2-i5*-alkynyl;

Y is a 5 or 6 membered heterocyclic group; and R ⁶ , and R ⁷ independently are hydrogen, Cι- ₆ -alkyl, or R ⁶ and R ⁷ together with the nitrogen atom optionally form a 4- to 6-member ring;

R ¹ and R ² independently are hydrogen, Cι_i ₅ -alkyl, C2-5- alkenyl, C2-5-alkynyl, Cι_ιo-alkoxy, Cι_5-alkyl substituted with -OH, -COR ⁶ ', CH ₂ -OH, halogen, -NH ₂ , carboxy, or phenyl;

R ⁶ ' is hydrogen or C ₁ -C ₃ alkyl;

Hal is selected from the group consisting of Br, Cl, F, I, and if W is 0 then Hal may be SO ₂ R ⁴ ' wherein R ⁴ ' is C ₁ -C ₃ alkyl or phenyl.

The compounds prepared using the process of this invention can be used for making pharmaceutically active compounds as illustrated by the following Schemes I, II, and III.

As used in Scheme I, R, h ⁺ , and G are as defined supra . As used in Scheme I, the term "Hal" refers to Cl, Br, and R ⁹ S0 ₂ - Preferred oxidizing agents for the process of Scheme I include oxone and sodium periodate. Oxone is an especially preferred oxidizing agent for the process of Scheme I. Compounds of Formula 3, as illustrated in Scheme I wherein the OR group is replaced by an R ⁴ group, can be prepared using methods well known in the art. See for example, U.S. Patent Number 5,043,345.

Further, compounds of Formula I may be prepared using the process illustrated in the following Scheme II

Scheme II

As used in Scheme II, Q may be N, O or S; R ²⁴ is selected from the group consisting of hydrogen, R ⁴ , R ⁵ , R ⁶ , and R ^7; R ²⁵ is selected from the group consisting of SOR ⁴ and SO ₂ R ⁴ ; all other meanings are as defined supra .

Additional compounds of Formula I may be prepared using the process illustrated by Scheme III.

Scheme m

amine

reduction

As used in Scheme III, Hal, , r, and G are as defined supra . As used in Scheme III, R ²² and R ²³ are independently selected from the group consisting of hydrogen, R ⁶ and R ⁷ .

The concentration of the reactants is not critical. The art worker can alter the concentration of the

reactants to achieve the desired rate of reaction and product yield.

The length of time for carrying out the processes described are not critical. As is always the case in chemistry, the rate of the reaction depends on a variety of factors, such as the temperature and the exact compound which is to be prepared. The course of the reaction may be followed using methods such as thin layer chromatography (TLC) , high performance liquid chromatography (HPLC) , gas chromatography (GO and nuclear magnetic resonance spectroscopy (NMR) to detect the degree of completion of the reaction. The operator may obtain maximum yields using the process by extending the reaction time. Alternatively, the operator may wish to obtain maximum throughput by cutting off the reaction at the point at which it reaches an economical degree of completion.

When the product of a step in the following process is an oil, it may be isolated by standard methods. Such methods include distillation, flash chromatography, HPLC and the like.

The intermediates and processes of the present invention are useful for preparing compounds having beneficial muscarinic receptor activity.

The following examples are provided for illustrative purposes only, and are not intended to limit the scope of the claimed invention in any way.

Preparation 1

3-Chloro-4- (1-butylthio)-1,2,5-thiadiazole

Cyanogen (36 g, 0.69 mol) was bubbled into ether (250 mL) maintained at -10°C. To the solution was added dropwise diethylamine (3 mL) followed by dropwise addition of 1-butylthiol (47 mL, 0.64 mol) at such a rate that the temperature did not exceed -5°C. The reaction was maintained below 0°C for 5 h then stirred at ambient overnight. Ether was distilled from the reaction until the

- 17 - pot temperature reached 50°C. The reaction was cooled to ambient and then added dropwise to a solution of sulfur monochloride (55 mL, 0.688 mol) in DMF (50 mL) that was cooled to 5°C. Cooling was removed and reaction was stirred overnight. The reaction was cooled in an ice-water bath and excess sulfur monochloride destroyed by careful addition of H2O while maintaining the temperature below 40°C. The liquid was decanted from the semi-solid sulfur precipitant and the sulfur residue triturated with hexane. The aqueous fraction was extracted with hexane (3 X) and the combined extracts and triturants were washed with H ₂ O, aqueous NaHCθ ₃ , brine, dried, and the solvent evaporated. The residue was distilled at 2 mm Hg to give a yellow liquid (24.6 g) , b.p. 105-110°C. (Compound 1).

Preparation 2 3-Chloro-4-ethoxy-l.2.5-thiadiazole

A solution of ethanol (60 mL, 1.02 mol) and triethylamine (1.5 mL) was cooled to -8 °C and cyanogen (59 g, 1.13 mol) was slowly bubbled through the solution while maintaining the temperature below 2 °C. The reaction was then added dropwise to a solution of DMF (275 mL) and sulfur monochloride (225 mL, 2.81 mol) that was cooled to 5 °C while maintaining the temperature of the DMF solution below 10 °C. Cooling was removed and the reaction was stirred over night. The reaction was cooled in an ice- water bath and the excess sulfur monochloride destroyed by dropwise addition of H ₂ O such that the temperature did not exceed 30 °C. Additional H ₂ O (400 mL) was added and the reaction internally steam distilled until the distillate was almost homogeneous. The distillate was extracted with hexane (3 X) and the combined extracts washed with H20, aqueous NaHCθ ₃ , brine, dried, and the solvent carefully evaporated. The liquid residue was distilled at 21 mm Hg to give a clear liquid (154.3 g) , b.p. 88-93 °C. (Compound 93)

Example 1

3-Butylthio-4-hvdroxy-l.2,5-thiadiazole

A solution of Compound 1 (20.9 g) , DMSO (20 mL) and 2N NaOH (205 mL) was headed to reflux overnight. The solution was cooled to 15 °C and concentrated HCl was added until the pH was 1. The solid was collected, washed with water, and dried to give a solid (17.68 g) . Recrystallization from heptane gave white crystals, m.p. 72-72.5 °C (Compound 300).

Example 2

3-Ethoxy-4-hvdroxy-l.2,5-thiadiazole

A mixture of Compound 93 (8.2 g), 2 N NaOH (100 mL) , and DMSO (10 mL) was heated to reflux over night. The reaction was cooled and extracted with ether. The aqueous fraction was acidified with cone. HCl and cooled 30 min in ice-water. The solid was collected from the resulting mixture by filtration and washed with a small amount of cold water to give white crystals (4.4 g) . Recrystallization from heptane gave white flakes, m.p. 104.5-105.5 °C. (Compound 303).

Example 3 3-Propylthio-4-hvdroxy-l,2,5-thiadiazole

A mixture of 3-chloro-4-propylthio-l,2,5- thiadiazole (10 g) , 2 N NaOH (100 mL) , and DMSO (10 mL) was heated to reflux for 24 h. The solution was cooled and extracted with ether. The aqueous fraction was acidified with cone. HCl and cooled in ice-water for 3 h. The resulting solid was collected, washed with a small amount of cold water to give a white solid (8.15 g) .

Recrystallization from heptane gave white crystals, m.p. 84-85 °C. (Compound 304).