FI62533C - EXTERNAL FRAMEWORK FOR ALLERGIC REACTION FOR 2-PHENYL-5- (5-1H-TETRAZOLYL) PYRIMIDIN-4- (3H) -ONDERIVAT - Google Patents

Description

Ι ..- ^ TJI rftl NOTICE .ΛΓ77 jSTa LBJ (11) UTLÄGGNINGSSKRIFT PZ ο ο ό 38s8> CL- Patent granted 10 Cl 1933 "45) Pr tent rr.ci.Iciit i C 07 D 403/04 (51) Kv .ik? /int.ci.3 // e 07 D 239/36, 257/04 ENGLISH — Fl N LAN D (21) 7701 * 27 (22) Hakwnliptlvf - AmBknlnpdig 09.02.77 (Fl) (23) Alkupthrl— GIW | Hrad «c 09-02.77 (41) Tullut JulklMktl -« Mt off «ntH | lU.08.77 r * tuutl- And rukitt« rlhallitud / 4

Patent- och ragiftaratyrelsan 7 Aiw6kan utta | d och utUkriftmi publkurad (32) (33) (31) Pyydetty «Tuoikuu» —fegird priority 13-02-76

08.12.76 USA (US) 657787, 7W85I

(71) Bristol-Myers Company, 31 + 5 Park Avenue, New York, New York 10022, USA (72) Peter Frederick Juby, Jameeville, New York, Richard Anthony Partyka, Liverpool, New York, USA (7I +) Oy Kolster Ah (5I +) Method for the preparation of 2-phenyl-5- (5-1H-tetrazolyl) -pyrimidin-1 * - (3H) -one derivatives which inhibit allergic reactions - For the preparation of allergic reactions for allergic reactions 2- Phenyl-5- (5H-1H-tetrazolyl) -pyrimidin-1 - (3H) -derivatives

The invention relates to a process for the preparation of 2-phenyl-5- (5-1H-tetrazolyl) pyrimidin-4- (3H) -one derivatives of the formula I which inhibit allergic reactions and their pharmaceutically acceptable salts,

0 N-N

2 (I>

VAX

wherein R 1 is hydrogen, C 1 -C 6 alkoxy, cyclo- (lower) alkyl- ** -V 2 (lower) alkoxy or (lower) alkenyloxy and R is hydrogen, 262533 C 1 -C 6 alkoxy, nitro, amino or di (lower) alkylamino, JL o

Various drugs have been used to treat allergic reactions, such as asthma and allergic rhinitis, which are thought to be mainly due to the antigen-antibody reaction. , epinephrine and atropine. However, these substances have undesirable side effects, e.g., a heart-stimulating and indigestion-inducing effect.

Recently, J.S.G., Cox et al., Avd. in Drug Res., 5, 115-196 (1970), has provided physicians with an agent which, when administered to asthma patients prior to inhalation of certain antigens, prevents the release of neurotransmitters, e.g., histamine and SRS-A (slow-acting anaphylaxis agent), which are believed to be the cause of the asthma reaction. However, while disodium cromoglycate allows the treatment of asthma without cardiovascular side effects and is thus a substantial advance, it has the significant disadvantage of not being absorbed through the gastrointestinal tract and must be administered by inhalation, The 2-phenyl-5- (5-1H) -trim Structurally related, previously known compounds of -4 (3H) -one derivatives are disclosed in the following references.

1. S. Ruhemann, Ber: 30, 30, 821 (1897): preparation of an unsubstituted acid and ester of formula r & r *, wherein R is hydrogen or ethyl.

2. Mitter et al., J. Chem. Soc., 123, 2179 (1923) and Quart. J. Indian Chem. Soc ,, 2, 61 (1925): p-methylphenyl- and p-methoxyphenyl-substituted esters and acids of formula 3 (L η Π ~ L 7.

O

C09R

x wherein R is hydrogen or ethyl, and X is methyl or methoxy.

3. Shen et al., U.S. Patent Nos. 3,660,403 and 3,745,161: compounds of the general formula

R_ Ar _ | ___ COX

Cl -J y where R — can be e.g. substituted phenyl, Y may be hydrogen, and X is one of several different substituents such as hydroxy, alkoxy or N-heterocycle. The patented compounds are said to have anti-inflammatory, antipyretic and analgesic effects, no mention of use as antiallergic agents.

4. U.S. Patent No. 3,883,653 discloses antiallergic compounds of the formula

X

H0oC-N

Xk (CHO) -Ar 2 m where m is an integer 0 or 1, and Ar is pyridyl, thienyl, furyl, phenyl or hydroxy, methyl, methoxy, nitro, chloro, fluoro, 3,4- dimethoxy-, 3,4,5-trimethoxy- or alkanoylamino-substituted phenyl.

5. U.S. Patent 3,448,107 discloses lipid level regulators of formula 4 2 f Ο Π. 7. 7.

. J -J · J

Ö- “''" "T J 'A N — N <# ^

X

12 wherein X and X may be various substituents such as hydroxy, phenyl, p-chlorophenyl, p-methylphenyl and p-aminophenyl, and n may be 0-4. The patent does not disclose compounds of the formula above wherein n is 0 and the pyrimidinyl ring system has a hydroxybust substituent at the 4-position and a phenyl substituent substituted at the 2-position.

The compounds of the present invention and pharmaceutical compositions containing them are of particular value in the prophylactic treatment of allergic asthma when administered orally.

1 2

The substituents R and R may be the same or different, but it is within the scope of this invention, when R and R are the same, only those compounds in which R and R are both C 1 -C 6 alkoxy groups. The above substituents may be further defined as follows: (a) (lower) alkyl groups may be straight or branched chain saturated hydrocarbon groups having 1 to 10 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl or n-Decyl. Preferred substituents are C 1 -C 4 alkyl groups containing 1 to 6 carbon atoms.

(b) (lower) alkenyl may be a straight or branched chain unsaturated aliphatic hydrocarbon group having one double bond and containing from 2 to 10 carbon atoms, e.g. vinyl, allyl, isopropenyl, 2- or 3-methallyl, or 3-butenyl. Preferred groups are C2-C6 alkenyl groups.

(c) (lower) alkoxy comprises C 1 -C 4 alkoxy groups having an alkyl moiety as defined in (a) above. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, n-bentyloxy, isopentyloxy, n-hexyloxy, etc.

5 O 2 (d) (lower) alkenyloxy groups are groups whose alkynyl moiety is as defined in (b) above, e.g. vinyloxy, allyloxy or isopropenyloxy. The most preferred group is allyloxy.

(e) cyclo (lower) alkyl = cycloalkyl ring in the (lower) alkyl group, contains 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples of these groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclopropylmethyloxy, cyclopropylethyloxy, cyclobutylmethyloxy, cyclobutylethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, hexyloxy

Particularly preferred compounds and salts of formula I are those wherein R 1 is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropylmethoxy, and R is methoxy, ethoxy , n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy, cyclopropylmethoxy, nitro, amino or dimethylamino.

Because the compounds of this invention are amphoteric in nature, they can be converted into salts with either acids or bases by treating these compounds with a substantially equimolar amount of the selected acid or base in aqueous solution or in a suitable organic solvent such as methanol or ethanol. When such salts are intended for human consumption, the acids and bases used in the preparation of pharmaceutically acceptable salts must, of course, be those which form non-toxic salts. Examples of suitable acids are hydrogen chloride, hydrogen bromide, hydrogen iodide, type, sulfur, phosphorus, vinegar, milk, lemon, tartaric, oxalic, succinic, maleic, gluconic, ascorbic and -toluenesul-p-sulfonic acid. Pharmaceutically acceptable salts can be prepared with the following bases: ammonia, organic amines and metal salts, e.g. metal salts containing sodium, potassium, magnesium, barium and aluminum cations. Such bases include ammonia, primary amines such as n-propylamine, n-butylamine, ethanolamine, ethylenediamine, cyclohexylamine, benzylamine, ethylamine, octylamine and tris (hydroxymethyl) aminomethane, secondary amines such as diethanolamine, such as triethanolamine, N-methylpyrrolidone, N-methylmorpholine and 1,5-diazabicyclo [3.0.0] -5-nonene, and metal compounds such as sodium hydroxide, potassium hydroxide, ammonium 6 of: 7 7

. · '.? O S

umhydroxide, sodium ethoxide, potassium methoxide, magnesium hydroxide, calcium hydroxide and aluronium hydroxide,

The compounds of formula I have, as will be appreciated by those skilled in the art, two tautomeric hydrogen atoms, and the compounds may thus exist in the forms shown in formulas 1-6. All forms may be present to a greater or lesser extent with each other in dynamic equilibrium. The invention encompasses all such forms, but for convenience, structure 1 is arbitrarily selected to represent all compounds.

r Ο ΓΓ 7 7 7 a] Γί o, R2 T 2 ΛγΜ '

V / χΛ NJ Η R. 1 J H

| i _ ^ A II

R1 Ί ~ /

N = N

B? 1 HO N— “

A \ X ^ NH X I M

2 N 'χΝ

R ^ n 2 I N

A R I I. B

r it N _ ^ lX ^ V ^ - kA * i - 3 / /

N = M

Ai l S N =?

M / Y ^ N / A ^ X NH

2 || HN

VY "^ <^ xJ

Χ ^ Λ1 ^ - L JL

1 6 8 s rs r Τ '* 7 6 /, j>' j

The compounds of formula I are prepared according to the invention in such a way that a substituted benzamidine of formula nh2 kJvR1 (VII) 1 2, in which R and R are as defined above in connection with formula I and

CoHc0., C ___CN

2 5 2

Ethyl ethoxymethylene acetate according to C 1 H 5 O is reacted in an inert organic solvent with sodium azide and ammonium chloride. These four reagents are used in approximately equimolar amounts in a reaction-inert organic solvent which is a good solvent for sodium azide. Suitable solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide and hexamethylphosphoramide. The most preferred solvent is dimethylformamide. · The best results in the reaction are obtained when it is carried out, preferably at temperatures from about 100 ° C to the reflux temperature of the solvent. Upon completion of the reaction, the desired product can be isolated by adding sufficient water and then acidifying the mixture to precipitate Compound I.

This process has the advantage that compound I can be prepared directly in one step from the starting materials, basic benzamidine and ethyl ethoxymethylene cyanoacetate without first having to prepare and isolate one or more intermediates. The advantages obtained by the method in terms of overall yield and simple work are apparent from the following illustrative examples.

The starting materials are either known or prepared by methods known in the art. A preferred process for the preparation of substituted benzamidines can be described by the following series of reactions (describing the case where R 1 = -OC 2 H 2): 9 62533 srycom ^ (c2h5) 3o + B? 4- r- ~ \ * · 2 5 Γ j | IIL] 2

2> J S! T

1. HH3 in CjHjOH KH

-> r ^ \ TA

Γ if m

2. NoOH L jL

^ CC2H5.

In this method, described in U.S. Patent 3,819,631, and J. Org. Chem., 33, 1679 (1968), the above-mentioned triethyloxonium fluoroborate reactant can be replaced by alkyl fluorosulfonates (e.g. methyl fluorosulfonate), dimethyl sulfate or other alkyloxonium fluoroborates. The most preferred process uses low cost dimethyl sulfate as the alkylating agent instead of the more expensive alkyl fluorosulfonates and triethyloxonium fluoroborate. This process, described in the following reaction scheme, yields benzamidine methyl sulfate.

OCTL · rnvu ^ 1 »HOSO.jCHo (CH30) 2SO2 • ^ T ^ COoH- C1CH2CH2C1 c reflux ^ -> m2 T · hoso3ch3 ra C2H OH [£ ™ ---> OCgR ^ 10 62533

An alternative process for the preparation of the benzamidine compound of formula VII is described by the following reaction (shown the case where R 1 = -CX 2 H 2).

NHO

CN j

^ | NH 2 OH * HCl 2 ^ NH

L ^> / ^ OC2H5 ^^ OC2H5 nk2

^ NH

'Οο., Η ,.

2 5 2

In the preparation of compounds of formula I wherein R is di (lower) alkylamino, the corresponding amino-substituted compound can thus be prepared, which is thus alkylated internally by known methods. Alternatively, dialkylamino substituted compounds are prepared directly from the appropriate benzamide starting materials.

As mentioned above, the compounds of formula I have been found to inhibit the formation of toxic products, i. the release of mediators that result from a combination of certain types of antibodies and certain antigens. The compounds of formula I are particularly important in preventing the symptoms of allergic asthma in mammals when administered to a patient at a dose sufficient to inhibit the neurotransmitter. The compounds may also be useful in alleviating and preventing other allegational reactions, such as allergic rhinitis.

The compounds of the invention may be administered as medicaments either alone or in admixture with other therapeutic agents. They may be administered as such, but are usually administered in the form of pharmaceutical compositions, i. as mixtures of active substances with suitable pharmaceutical carriers or diluents. Examples of such compositions are tablets, lozenges, capsules, powders, aerosol sprays, aqueous or oily suspensions, syrups, elixirs and aqueous solutions for injection. The compounds are most preferably administered in oral dosage forms.

The nature of the pharmaceutical composition and the pharmaceutical carrier and diluent will, of course, depend on the desired route of administration, which is oral, parenteral or inhalation. Oral compositions may be in the form of tablets or capsules and may contain drugs such as binders (e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone), excipients (e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol, glycine), lubricants (e.g. magnesium stearate, talc, polyethylene glycol or silicic acid), disintegrants (e.g. starch) or wetting agents (e.g. sodium lauryl sulphate). Oral liquid preparations may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or may be presented as a dry product for constitution with water or other suitable vehicle. Such liquid preparations may contain conventional additives such as suspending agents, flavoring agents, diluents or emulsifying agents. For parenteral administration or inhalation, solutions or suspensions of the compounds of formula I in a suitable pharmaceutical medium may be used, e.g. aerosol sprays for inhalation, aqueous solutions for interventional injection and oily suspensions for intramuscular injection. The compounds may also be administered as a medicament by means of inhalation devices or other devices which bring the active compound in direct powder contact with the lungs.

The compounds of the invention or pharmaceutical compositions thereof may be administered to human patients suffering from asthma in single oral doses of about 1 to 500 mg of active ingredient, or in multiple oral doses up to a total of about 1000 mg of active ingredient per day. When used by inhalation, the compounds are generally administered in lower doses, i. at doses approximately 1/10 of the normal oral dose of the compound. These dosages are merely exemplary, and the more appropriate dose for each patient will, of course, be determined by the physician based on factors such as the age, weight, severity of symptoms and the particular drug being used in the 12,62533 patients.

The in vivo animal experiments described below show that the compounds of formula I are highly effective antiallergic agents.

Biological activity

The reagent-mediated rat skin anaphylaxis screening test (PCA) used to evaluate the compounds of the invention is generally considered to be one of the best animal experiments for predicting the antiallergic activity of test compounds in humans.

Briefly, in the method, the skin sites of experimental animals are passively sensitized with reagent antibodies, after which the test compound and antigen are administered after 24 hours. The allergic response is measured using Evans blue and assessed by measuring the diameter of the injection site. Details of the experiment are presented below.

materials

Egg albumin (5 times crystallized)

Na + salt of dinitrobenzenesulfonic acid

Bordetella pertussis vaccine - stage I 10-20 x 10 killed organism / ml

Aluminum hydroxide gel - 10 mg / ml

Potassium carbonate

Male Sprague-Dawley (S / D) rats - 200 g

Sprague-Dawley female rats - 100 g

Tris-buffered saline (TBS) - 0.02-m 2-amino-2-hydroxymethyl-1,3-propanediol (tris), 0.15-m NaCl, pH 8.2.

Antigen Preparation - DNP-d EA

Substituted egg albumin is used as both an immunogen and an antigen. The antigen is prepared as follows: 500 mg of egg albumin (EA) and 500 mg of K 2 CO 3 and dissolved in 25 ml of distilled water, and the solution is stirred at room temperature for 5 minutes. 500 mg of the Na salt of dinitrobenzenesulfonic acid (crystallized beforehand from hot absolute ethanol) are then added slowly and with constant stirring. The reaction mixture is then immediately taken to dark, where the reaction is allowed to proceed with stirring for 2 hours. After 2 hours, the mixture is transferred to a suitable dialysis tube and dialyzed at 5 ° C against 5 exchanges (4 L each) of distilled water. After dialysis, the product is lyophilized and stored at room temperature in a brown or amber jar. The resulting antigen is a pale yellow, amorphous solid that is highly soluble in water and saline. It is called DNP = denatured egg albumin (DNP-d ES).

Immunization Method for IgE Production The male Sprague-Dawley rat is used as a source of reagent-rich antisera in the PCA assay. Immunization is performed with a combination of DNP-d EA on an Al (OH) 2 gel and an E. pertussis vaccine. The DNP-d EA gel immunogen is prepared as follows: DNP-d EA is dissolved in TBS to a solution of 10 mg / ml. 1 ml of this solution is slowly added at room temperature to 10 ml of Al (OH) 2 gel (10 mg dry matter / ml) with constant stirring. Stirring is continued for 30 minutes to ensure even absorption of the antigen onto the gel.

The resulting preparation is then used in combination with pertussis vaccine stage IB to immunize male S / D rats as follows: Each rat is administered intramuscularly on each hind leg 0.1 ml of DNP-d EA gel suspension (200 μg DNP-d EA and a total dose of 2 mg gel). ). Following these injections, 1.0 ml of B. pertussis vaccine (10-20 x 10 organisms) is administered intraperitoneally. Injections should be given under mild ether anesthesia to ensure a proper intramuscular and intraperitoneal injection. 9 days after immunization (not more than 10 days), animals are bled with a needle from the heart or abdominal aortic cannula under ether or pentobarbital anesthesia. The collected whole blood is allowed to clot, the serum is separated by centrifugation, and the serum samples are kept refrigerated until their IgE content is determined.

Selection of high titer serum samples to be pooled «* 1 K‘ '* - II' · II "'i» -> i ^ - —I 1 1 1

Individual serum samples should be screened for reactive antibody levels prior to pooling, as not all rats respond to immunization by producing 14,62533 reagent. For this purpose, a 1:50 dilution of the serum of each immunized rat is prepared with saline. The shaved back of one small recipient rat (100-120 g) is injected intradermally with 0.05 diluted sera. Recipient animals can be tested for multiple serum samples simultaneously. After a latency period of 24-48 hours, the antigen is injected intravenously by administering 1 mg of DNP-D EA to each rat in 0.5 ml of 0.5% Evans M blue solution in saline. Samples that give a positive PCA reaction at a 1:50 dilution, measured 20-30 minutes after antigen injection, are pooled, divided into small aliquots, and stored at -70 ° C or below until use. Negative sera are discarded.

The IgE titer of the combined antiserum is determined. Prepare two-fold serial dilutions in saline (1: 5 -1: 160) of unheated seurums and seurums heated for one hour at 56 °, and each dilution is injected intradermally into the back of 0.05 ml female recipient rats. At least 4 animals should be used to determine the titre of both heated and unheated serum. After a latency period of 24 hours, each group receives a challenge injection of 1 mg DNP-d EA in 0.5 ml of 0.5% Evans1 blue solution. The reaction is read by measuring the reflection of the skin 20-30 minutes after the challenge. Intensity (blue staining) and spot diameter are measured and recorded. The titre is defined as the reciprocal of the maximum dilution of unheated serum, which gives a measurable PCA response (> 6 mm diameter) with at least an arrow from the recipient animals. Combined antisera with a titer of 50 or higher are acceptable for PCA screening. These antisera are sterile filtered and stored at -70 ° C or below until use. Alternatively, it can be lyophilized in small batches.

15 62533 PCA Screening Method 1. Animals - young female Sprague-Dawley rats, 90-110 g, are used. Rats are allowed to acclimate to their environment (acclimatized) for at least 5 days prior to the experiment, during which time they will receive food and water ad libidum.

2. Passive sensitization - Experimental animals are prepared for passive sensitization by carefully shaving both sides of the back with a fine-toothed cutter. Using a 27 gauge 1G mm needle in a 1 ml tubercle syringe, intradermal injections are performed with dilutions of pooled antiserum saline. Four dilutions (two on each side) of antiserum are used. The exact dilution depends on the titre of the antiserum. For example, if the pooled antiserum has a titer of 50, then dilutions of 1:10, 1:20, 1:30 and 1:40 are used; if the titer is 100, then dilutions of 1:20, 1:40, 1:60 and 1:80 and 1:80 are used. To facilitate evaluation of results, successive dilutions in series are placed either clockwise or counterclockwise. The latency period should be at least 24 hours and should not exceed 48 hours.

3. Administration of standard drug and unknown substances - 4 animals are used for each test compound. Disodium chromoglycate (DSCG) dissolved in saline is administered intravenously (i.v.) simultaneously with the antigen. The tetrazole test compounds are dissolved in aqueous sodium bicarbonate solution. ICoey compounds are administered i.v. or orally (p.o.), the former 1-5 minutes and the latter 10 minutes before the antigen.

4. Antigen and Evaluation of Reaction - To elicit a PCA response in the experiment, each test animal is finally administered 1 mg of DNP-d EA in 0.5 ml of 0.5% Evans blue solution in saline. PCA reactions are strongest 20-30 minutes after the challenge. The intensity of the reaction at each antiserum dilution site is assessed visually for color intensity and by measuring the average diameter of the spots. Both should be done by making the skin reflect. Control animals (untreated) should be used for comparison at least 5%, usually 10% of the total number of animals tested each day.

The observed inhibitory effect of the drug is expressed as the reduction (%) of the effective anti-sera Itter in the control group.

62533 16

Score

The results of some of the preferred compounds of the present invention, as well as the results obtained with DSCG when administered i.v. or p.o. as drug delivery are shown in Table 1 below. Results are expressed as ID ^ values, i. at a dose of the compound that inhibits the response by 50%.

Table Results of PCA screening experiments of 2-phenyl-5- (5-1H-tetrazolyl) pyrimidin-U (3H) -ones in rats

Compound

N-U

0 [I II

πν, Λ /:> '' N

Example ID mg / kg n: ° S1 Ha - - - · P o.

6 ocK7 K

n ~ 0.1

1 0C2H5 -H 0.02 o.OQ

2 OCH ^ CHj h - 0_0l 5 0CK (CK3) 2 H - "0.0 ;," OCHgCHj.CHgCHj H - ~ 0.07 5. OCHfCHjJCKgCK, H - 0.05 7 OCItjCHfCHj), h - - os :, 9 H - 0.07 10 OCKgCKjjCKj OCHj - 0-0 ·, 14 OCHjCHjCKj>! 02 - 5 15 CCHjCE.CH,: ¾ - „ca 15 CC. ^ C ^ CK-J r. (cK,) 2 - ^, 0., 22 0C5Hh “'- ~ 0.4 escc oj» jo 62533 17

The following examples are provided to illustrate the preparation of the starting materials and compounds of the present invention. All temperatures shown are in degrees Celsius. "Skellysolve B" is a petroleum ether fraction having a b.p. of 60-68 ° C and consisting mainly of n-hexane (trademark of Skelly Oil Oy).

Preparation of starting materials The substituted benzamidines (or benzamidine salts) used as starting materials can be prepared by the methods described below.

Preparation 1: 2-Ethoxybenzamidine hydrochloride In chilled (ice water) triethyloxonium fluoroborate. To a solution of 1 n (100 g, 0.53 mol) in 226 mL of methylene chloride was added a single portion of a suspension of 2-ethoxybenzamide (87 g, 0.53 mol) in 915 mL of methylene chloride. The resulting solution was stirred at room temperature for 36 hours. The solution was evaporated to 1/3 volume and diluted with about 600 ml of diethyl ether to precipitate crude ethyl 2-ethoxybenzimidate fluoroborate (130 g, mp 116-133 °).

The salt obtained above was suspended in 500 ml of cold 10 "ethanolic ammonia ethanolic solution, and the solution was stirred at room temperature for 36 hours. The solution was evaporated to dryness and the residue partitioned between ethyl acetate and 5N NaOH. The ethyl acetate layer was dried to give a viscous oil. about 200 ml of acetonitrile was added to separate and 36 g of solid was collected, mp 180-183 ° The solid was dissolved in about 60 ml of methanol and the solution was acidified with hydrogen chloride, about 1 liter of dry ether was added to give the desired hydrochloride salt. (31.2 g, mp 198-199 °) precipitated.

Preparation 2: 2-Ethoxybenzamidine hydrochloride (alternative method) To a solution of 2-ethoxybenzamide (20.0 g, 0.121 mol) in methylene chloride (324 mL) was added methyl fluorosulfonate (14.5 g, 0.127 mol). After 3 hours, the solvent was removed under reduced pressure. The residue was triturated with diethyl ether, and the mixture was filtered. The resulting crude ethyl 2-ethoxybenzimidate trifluorosulfonate (28.5 g, mp 83-110 °) was added to saturated ethanolic ammonia solution (120 mL). The mixture was stirred for 4 days at 62533 at 18 room temperature. The mixture was filtered and the filtrate was evaporated. The residue was triturated with 2N sodium hydroxide, and the resulting mixture was extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated to dryness. A solution of the residual oil in acetonitrile (50 ml) was treated with hydrogen chloride. Upon addition of diethyl ether (700 mL), 2-ethoxybenzamidine hydrochloride (11.0 g, mp 193-196 °) precipitated.

Preparation 3: 2-Ethoxybenzamidine To a solution of 2-ethoxybenzamide (13.0 g, 0.0785 mol) in 34 mL of dry methylene chloride was added in one portion a suspension of triethyl oxonium fluoroborate (15.0 g, 0.0785 mol) in 137 mL: methylene chloride. Immediately after the addition of fluoroborate, the resulting solution was stirred for 19 hours at room temperature. The solution was evaporated to about 1/3 volume and diluted with 100 mL of diethyl ether to precipitate ethyl 2-ethoxybenzimidate fluoroborate. It was collected and dried to give 19.2 g, m.p. 113-110 °.

The imidate fluoroborate obtained above was then added to 100 ml of ethanol containing 1.4 g of NH 4. The resulting solution was stirred in a tightly closed bottle for 78 hours at room temperature. The solvent was removed under reduced pressure to give a colorless solid which was dissolved in a small amount of water and basified with 6N NaOH. The solution was extracted with ethyl acetate, the extract evaporated to dryness to give 7.4 g of the title product, m.p. 78-84 °.

Replacing the 2-ethoxybenzamide used above with an equimolar amount of 2-isopropoxybenzamide or 2-n-propoxybenzamide gives 2-isopropoxybenzamidine and 2-n-propoxybenzamide, respectively.

Preparation 4: 2-Ethoxybenzamidine fluorosulfonate X Method A) To a suspension of 2-ethoxybenzamide (500 g, 3.03 mol) in dry methylene chloride (8 L) was added methyl fluorosulfonate (256 mL, 3.17 mol). The resulting solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The residue was triturated with diethyl ether, and the mixture was filtered. The resulting solid was washed with ether and then added to a cold (ice-water) solution of ammonia (500 g) in ethanol (3 L). The mixture was stirred cold for 0.5 hours and then at room temperature for 16 hours.

19 62533

The solution was evaporated and the residue was crystallized from 1,2-dichloroethane to give 2-ethoxybenzamidine fluorosulfonate (517 g, 55%), m.p. 98-99 °.

Analysis calculated for C 9 H 5 O 2 O 2. HFSO 4: C 40.90 H 4.96 N 10.60 found: found: C 40.95 H 4.83 N 10.73.

Preparation 5: 2-Ethoxybenzamidine fluorosulfonate (Method B) To a suspension of 2-ethoxybenzamide (1 kg, 6.05 moles) in methylene chloride (12.5 L) was added methyl fluorosulfonate (538 mL, 6.66 moles). The mixture was stirred at room temperature for 18.5 hours. Ammonia gas was then bubbled into the mixture for 8 hours, keeping the temperature below 26 °. The mixture was stirred for another 16 hours at room temperature. The solvent was evaporated in vacuo to give crude 2-ethoxybenzamidine fluorosulfonate (1.7 kg).

Preparation 6: 2-Ethoxybenzamidine methyl sulfate A solution of 2-ethoxybenzamide (16.5 kg, 0.1 mol) and dimethyl sulfate (19.0 mL, 0.2 mol) in 1,2-dichloroethane (60 mL) was heated to reflux. 17 hours while stirring.

The solvent was removed under reduced pressure. The residual oil was stirred in diethyl ether (200 mL) for 0.5 h. Methyl 2-ethoxybenzimidate methyl sulfate was collected by filtration, dried and then added to a stirred, saturated solution of ammonia in ethanol (150 mL). The solution was allowed to stand at room temperature for 18 hours. The solution was filtered and the filtrate was evaporated. The residue was triturated with diethyl ether, after which 2-ethoxybenzamidine methyl sulfate (19.9 g, 72% relative to 2-ethoxybenzamide) was filtered off.

Preparation 7: 2-n-Propoxybenzamidine hydrochloride A. Ethyl 2-n-propoxybenzimidate fluoroborate A solution of triethyloxonium fluoroborate (33.0 g, 0.175 mol) in methylene chloride (75 mL) was added over 10 minutes to a stirred solution of 2-n-propoxybenzamide (75 mL). 31.3 g, 0.175 mol) in methylene chloride (150 ml). The solution was stirred for another 18 hours at room temperature. The solution was evaporated to about 1/5 volume, diluted with diethyl ether to give ethyl 2-n-propoxybenzimidate fluoroborate (44.0 g, 85% yield), m.p. 108-112 °, precipitated.

62533 20 B. 2-n-Propoxybenzamidine hydrochloride 6.5 g of ammonia-containing ethanol (100 ml) were added over 5 minutes with stirring to a suspension of ethyl 2-n-propoxybenzimidate fluoroborate (44.0 g) in ethanol (25 ml). The resulting solution was stirred at 25 ° for 20 hours. The solution was evaporated to dryness and the residue partitioned between diethyl ether and 5N sodium hydroxide. The ether layer was washed with brine, dried over sodium sulfate and evaporated. A solution of the residue in ether (500 ml) and ethanol (50 ml) was treated with hydrogen chloride to precipitate 2-n-propoxybenzamidine hydrochloride (28.8 g, 76.6% yield), m.p. 184 to 186.5 °.

Preparation 8: 2-n-Propoxybenzamidine methyl sulfate To a warm, stirred solution of 2-n-propoxybenzamide (896 g, 5.0 mol) in 1,2-dichloroethane (5 L) was added dimethyl sulfate (950 mL, 10 mol) over about 0.5 h. .0 moles). The mixture was stirred and refluxed for 17 hours. The solvent was removed. The residual oily solid was filtered, washed with ethyl acetate and dried to give methyl 2-n-propoxybenzimidate methyl sulfate (403 g), m.p. 79-82 °. The combined filtrate and washings were left at 0 ° for 18 hours to give a second crop (503 g) of benzimidate, m.p. 81-83 °. A slurry of 2-n-propoxybenzimidate methyl sulfate (906 g) in ethanol (11) was previously added to ethanol (4 L) saturated with ammonia gas. The mixture was allowed to stand at room temperature for 17 hours. The mixture was filtered. The filtrate was evaporated to dryness to give 2-n-propoxybenzamidine methyl sulfate (872 g, 60%), m.p. 86-88 °.

.Preparation 9: 2-Isopropoxybenzamidine hydrochloride

A solution of triethyloxonium fluoroborate (38.4 g, 0.202 mol) in methylene chloride (75 mL) was added over 15 minutes to a stirred solution of 2-isopropoxybenzamide (36.2 g, 0.202 mol) in methylene chloride (100 mL). The mixture was stirred for 18 hours at room temperature. The solution was evaporated to about 1/5 volume and diluted with diethyl ether to give crude ethyl 2-isopropoxybenzimidate fluoroborate (60 g, mp 90-110 °) as colorless crystals. Recrystallization of this material from methylene chloride-diethyl ether gave 55 g of a colorless substance, m.p. 114-120 °.

21 62533

To a stirred suspension of the fluoroborate (55 g) obtained above in ethanol (50 ml) was added 150 ml of an ethanolic ammonia solution (8%). The mixture was stirred for 64 hours at 25 °. The solution was evaporated to dryness and the residue was basified with 100 ml of 5N NaOH. The basic mixture was extracted with ether and the ether extract was evaporated. A solution of the residue in ether (500 ml) and ethanol (50 ml) was treated with hydrogen chloride to precipitate 24.1 g of colorless 2-isopropoxybenzamidine hydrochloride, m.p. 162-164 °.

Preparation 10: 2-n-Butoxybenzamidine hydrochloride

A solution of triethyloxonium fluoroborate (32.4 g, 0.171 mol) in methylene chloride (75 mL) was added 2-n-butoxybenzamide / J. Pharm. Pharmacol., 4, 872 (1952) / (33.0 g, 0.171 mol) in a stirred solution of methylene chloride (200 ml) at 25 °. The mixture was stirred for 20 hours at 25 °. The solution was evaporated to about 1/5 of its original volume and then diluted with diethyl ether.

The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-n-butoxybenzimidate fluoroborate (28.7 g), m.p. 82-88 °. To a stirred, cooled (ice water) suspension of fluoroborate (28.7 g) in ethanol (75 mL) was added 8% ethanolic ammonia solution (150 mL). The mixture was stirred for 20 hours at 25 °. The ethanol was removed and the residue partitioned between ether and 5N sodium hydroxide (100 ml). The ether layer was washed with brine, dried over sodium sulfate and evaporated to dryness. A solution of the residual oil in ether was treated with hydrogen chloride to precipitate the title compound (16.8 g), m.p. 150-155 °.

Preparation 11: (-) - 2-sec-Butoxybenzamidine hydrochloride

In a similar manner to the preparation of 2-n-butoxy-benzamidine hydrochloride described in Preparation 10, (-) - 2-sec-butoxybenzamide was obtained from J. Pharm. Pharmacol, 9, 855 (1957), (-) - 2-sec-butoxybenzamidine hydrochloride, m.p. 142-144 °.

Preparation 12: 2-Isobutoxybenzamidine

A cold (ice water) solution of 2-isobutoxybenzamide (70.1 g, 0.363 mol) in methylene chloride (800 mL) was added to a cold solution of triethyloxonium fluoroborate (69.0 g, 0.363 mol) in methylene chloride (175 mL). The resulting solution was stirred at room temperature for 6 hours. About 2/3 of the solution was evaporated and the residue was diluted with diethyl ether (500 ml). The mixture was filtered.

The obtained ethyl 2-isobutoxybenzimidate fluoroborate1 (76.5 g), m.p. 110-112 °, was added to ethanol (350 ml) saturated with ammonia gas. After standing for 67 hours at room temperature, the solution was evaporated to dryness. The residue was treated with 5N sodium hydroxide (160 mL). The mixture was extracted with methylene chloride (3 x 200 ml), and the combined extracts were washed with water, dried (sodium sulfate) and evaporated. The residue was recrystallized from cyclohexane to give 2-isobutoxybenzamidine (0 + 2.9 g, 61.5% overall yield), m.p. 49-51 °.

Analysis calculated for C 11 H 16 N 2 O: C 68> 72 H 8.39 N 14.57 Found: C 68.60 H 8.42 N 14.28.

Literature Reference 1. B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain and K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).

Preparation 13: 2-Isobutoxybenzamidine fluorosulfonate

Methyl fluorosulfonate (5.65 g, 0.0495 mol) was added to a stirred solution of 2-isobutoxybenzamide (8.6 g, 0.0445 mol) in methylene chloride (100 mL) under nitrogen. The solution was stirred at room temperature for 18 hours. Ammonia gas was then bubbled into the solution for 3 hours with stirring. The solution was evaporated and the residue was crystallized from 1,2-dichloroethane to give the title compound (1.1 g, 8.5% yield).

Literature Reference 1. B.J. Broughton, B.J. Large, S.M. Marshall, D.L. Pain and K.R.H. Wooldridge, U.S. Patent 3,819,631 (1974).

Preparation 14: 2-Ethoxy-5-methoxybenzamidine hydrochloride A. 2-Ethoxy-5-methoxybenzamide 5-Methoxysalicylamide (41.8 g, 0.250 mol) was dissolved in a solution of sodium (6.37 g, 0.277 g) in ethanol (250 mL). To the resulting cooled (ice water) solution was added iodoethane (38.9 g, 0.250 mol) over 20 minutes. The reaction mixture was allowed to warm to room temperature over 45 minutes, then heated to reflux for 19 hours. The mixture was evaporated and the residue 23 62533 was triturated with water. The mixture was filtered and the resulting solid was recrystallized from acetonitrile to give 2-ethoxy-5-methoxybenzimide (34.5 g, 70.7%), m.p. 128-130 °.

Analysis calculated for C 10 H 13 NO 3: C 61.52 H 6.71 N 7.18 Found: C 61.45 H 6.51 N 6.93.

B. 2-Ethoxy-5-methoxybenzamidine hydrochloride

Methyl fluorosulfonate (28.4 g, 0.248 mol) was added to a cooled solution of 2-ethoxy-5-methoxybenzamide (33.5 g, 0.172 mol) in methylene chloride (450 mL) over 20 minutes. The mixture was stirred at room temperature for 4 hours. 2/3 of the solvent was evaporated and the residue was diluted with diethyl ether. Precipitated crude methyl 2-ethoxy-5-methoxybenzimidate fluorosulfonate (50.0 g), m.p. 144-152 °, dissolved in cold ethanol (300 mL) saturated with ammonia. The mixture was stirred under cooling (ice water) for 2 hours, and then for 17 hours at room temperature. The ethanol was evaporated under reduced pressure to give a semi-solid which was treated with 5N sodium hydroxide (200 ml).

The mixture was extracted with ethyl acetate. The extract was dried (sodium sulfate) and evaporated. A solution of the residue in acetonitrile-acetone (2: 5) was treated with HCl gas to precipitate 2-ethoxy-5-methoxybenzamidine hydrochloride (10.5 g, 26.5%), m.p. 166-167 °.

Preparation 15: 5-Carbomethoxy-2-ethoxybenzamidine A. 5-Carbomethoxy-2-ethoxybenzamide 5-Carbomethoxy-2-ethoxybenzamide (m.p. 159-161 °) was prepared from 5-carbomethoxysalicylamide, iodoethane and sodium methoxide in methanol analogously to 2 described in Preparation 14A. with the preparation of -ethoxy-5-methoxybenzamide.

B: 5-carbomethoxy-2-ethoxybenzamidine 5-carbomethoxy-2-ethoxybenzamidine, m.p. 133-135 °, was prepared from 5-carbomethoxy-2-ethoxybenzamide in analogy to the preparation of 2-isobutoxybenzamidine described in Preparation 12.

Preparation 16: 5-Chloro-2-ethoxybenzamidine hydrochloride A: 5-Chloro-2-ethoxybenzamide 5-Chlorosalicylamide (16.0 g, 0.093 mol), iodoethane (31.8 g, 0.204 mol) and potassium carbonate (13 , 1 g, 0.095 mol) in ethanol (225 ml) was heated at reflux for 20 hours. The hot mixture was filtered. The filtrate was evaporated to dryness.

24 62533 The residue was triturated with water. The mixture was filtered and the resulting solid was recrystallized from acetonitrile to give 5-chloro-2-ethoxybenzamide (6.8 g, 36.6%), m.p. 136-139 °.

Analysis calculated for C 9 H 11 ClNO 2: C 54.15 H 5.05 Cl 17.76 N 7.02 Found: C 54.25 H 4.85 Cl 17.42 N 6.89.

B. 5-Chloro-2-ethoxybenzamidine hydrochloride

When Preparation 10 is repeated using an equimolar amount of 5-chloro-β-ethoxybenzamide instead of the 2-n-butoxybenzamide used therein, the title product is obtained, m.p. 227 ° (decomposes).

Analysis calculated for C 9 H 9 Cl 2 O 2. HCl: C 45.97 H 5.15 N 11.91 found: C 46.23 H 5.20 N 11.87.

Preparation 17: 2,5-Dimethoxybenzamidine hydrochloride

Repeat Preparation 10 using an equimolar amount of 2,5-dimethoxybenzamide instead of the 2-n-butoxybenzamide used therein to give the title product, m.p. 170-172 °.

Preparation 18: 2-Cyclopropylmethoxybenzamidine hydrochloride A: 2-Cyclopropylmethoxybenzamide

A stirred mixture of salicylamide (10.02 g, 0.074 mol), potassium carbonate (10.24 g, 0.074 mol) and bromomethylcyclopropane (10.0 g, 0.074 mol) in ethanol (15 ml) was heated at reflux for 19 hours. The mixture was evaporated and the residue was treated with water. The mixture was filtered and the resulting solid was recrystallized from benzene-Skellysolve B to give 2-cyclopropylmethoxybenzamide (10.0 g, 71.6%), m.p. 102-105 °.

B: 2-Cyclopropylmethoxybenzamidine hydrochloride

A solution of triethyloxonium fluoroborate (99.1 g, 0.522 mol) in methylene chloride (225 mL) was added to a stirred solution of 2-cyclopropylmethoxybenzamide (99.2 g, 0.518 mol) in methylene chloride (450 mL). The mixture was stirred at 22 ° for 18 hours.

The solution was evaporated to about 1/5 volume and then diluted with diethyl ether. The precipitated solid was recrystallized from methylene chloride-diethyl ether to give ethyl 2-cyclopropylmethoxybenzimidate fluoroborate (104.7 g, 65.7%), m.p. 120-121 °. To a stirred, cooled (ice water) mixture of fluoroborate (104.7 g) in ethanol (100 ml) was added 400 ml of a 6% ethanolic solution of ammonia. The mixture was stirred for 18 hours at 20 °.

The mixture was evaporated and the residue partitioned between diethyl ether and 3N sodium hydroxide. The ether layer was washed with brine and dried over sodium sulfate. The dried solution was treated with hydrogen chloride. The precipitate was recrystallized from methylene chloride-diethyl ether to give 2-cyclopropylmethoxybenzamidine hydrochloride (71.5 g, 92.5% based on fluoroborate), m.p. 166-171 °.

Preparation 19: 5-Methoxy-2-n-propoxybenzamidine hydrochloride A: 5-Methoxy-2-n-propoxybenzamide 5-Methoxysalicylamide (56.0 g, 0.335 mol) was added to cooled, stirred sodium (8.55 g, 0.372 mol). g) in ethanol (335 ml). To the resulting suspension was added 1-bromopropane (41.3 g, 0.335 mol) dropwise over 20 minutes. The mixture was stirred at room temperature for one hour, and then heated to reflux for 19 hours. The solvent was removed under reduced pressure. The residue was treated with cold water (500 mL). The solid was filtered and recrystallized from acetonitrile to give 5-methoxy-2-n-propoxybenzamide (29.0 g, 41.4%), m.p. 83-87 °.

Analysis calculated for C 13 H 14 N 2 O 3: C 63.14 H 7.23 N 6.69 Found: C 63.28 H 7.43 N 6.47.

B: 5-Methoxy-2-n-propoxybenzamidine hydrochloride To a solution of 5-methoxy-2-n-propoxybenzamide (29.0 g, 0.139 mol) in methylene chloride (200 mL) at 5 ° was added methyl fluorosulfonate (15.8 g). , 0.139 mol). The solution was stirred at room temperature for 5 hours. Most of the solvent was evaporated and the residue was diluted with diethyl ether (500 ml). The precipitated methyl 5-methoxy-2-n-propoxybenzimidate fluorosulfonate (35.4 g, mp 117-126 °) was collected and added to cold, saturated ethanolic ammonia solution (220 mL). The mixture was stirred at room temperature for 19 hours. The solution was evaporated and the residual oil was dissolved in a mixture of acetonitrile and ether. The resulting solution was treated with hydrogen chloride to precipitate 5-methoxy-2-n-propoxy-benzamidine hydrochloride (31.5 g) as an oil which was separated by decantation of the solvents.

62533 26

Preparation 2Q-1: 2-Methoxybenzamidine hydrochloride

In a similar manner to the preparation of 2-n-propoxy benzamidine hydrochloride described in Preparation 7 was obtained. 2-methoxybenzamide 2-methoxybenzamidine hydrochloride, m.p. 150-152 °.

Preparation 20-2: 2-Ethylthiobenzamidine hydrochloride A. 2-Ethylthiobenzamidoxime 2-Ethylthiobenzonitrile (29.0 g, 0.178 mol) / K. Brand et al., J. Prakt. Chem., 108, 19 (1924) / solution in ethanol was added over 30 minutes to a solution of hydroxylamine hydrochloride (4.47 g, 0.64 mol) and sodium carbonate (31.2 g, 0.29 mol) in water (474 ml). The mixture was heated to reflux for 1.75 hours. The cooled solution was evaporated to 1/3 volume. The residue was partitioned between diethyl ether and 1N hydrogen chloride. The ether and water layers were separated. The ether layer was extracted twice with a new portion of 1N HCl. The pH of the combined aqueous layers was adjusted to 5.5 with sodium bicarbonate. The mixture was extracted with ether (3 x 200 mL). The combined ether extracts were dried (sodium sulfate) and evaporated to give 2-ethylthiobenzamidoxime (12.5 g, 36%), m.p. 72-78 °. Recrystallization from 2-propanol-ether gave an analytically pure product, m.p. 79-83 °.

Analysis calculated for C 9 H 18 N 2 O 2: C 55.09 H 6.17 N 14.28 Found: C 54.92 H 6.27 N 14.08.

B. 2-Ethylthiobenzamidine hydrochloride To a solution of 2-ethylthiobenzamidoxime (6.0 g, 30.6 mmol) in ethanol (200 mL) was added Raney nickel, and the mixture was shaken for 3 hours under an atmosphere of hydrogen at an initial pressure of 3.5 kg / cm 3. The mixture was filtered and the filtrate was evaporated. The residual oil was dissolved in a mixture of ethanol (30 ml) and diethyl ether (400 ml). The solution was treated with hydrogen chloride. Precipitated 2-ethylthiobenzamidine hydrochloride, m.p. 290-291 ° (2.4 g, 36.2%), recrystallized from 2-propanol-ether to give an analytical sample, m.p. 296-297 °.

1,6-Dihydro-6-oxo-2-phenylpyramidine-5-carboxylate esters (general formula V) can be prepared as follows: 27 6 2 5 3 3

Preparation 21: Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate (illustrates the use of benzamidine as the free base)

To a cooled solution of sodium (1.0 * 4 g, 0.0 * 45 g) in 35 mL of ethanol was added 2-ethoxybenzamycline (7.3 g, * 45 mmol) in one portion. To this suspension was then added over 5 minutes a solution of diethyl ethoxymethylene malonate (9.7 g, * 4 b mmol) in 20 mL of ethanol, which soon formed a pale yellow precipitate. An additional 25 mL of ethanol was added to the reaction mixture, which was then heated to reflux for 2 L / 4 hours. The cooled solution was poured into about 500 mL of ice water, and the mixture was acidified with 6N HCl to precipitate a pale yellow solid. It was dried to give 10.2 g of the title compound, m.p. 1 * 4-1 * 4 * 49 °. Recrystallization from acetonitrile gave 9.8 g of pure product, m.p. * 1 47-150 °.

Analysis calculated for C 15 H 16 N 2 O 1 +: C 62 • 49 H 5.60 N 9.72 Found: C 62.23 H 5.57 N 9.63.

Preparation 22: Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyramidine-5-carboxylate (illustrates the use of the benzamidine hydrochloride salt

To a cooled solution of sodium (8.2 g, 0.356 g) in 300 mL of ethanol was added 2-ethoxybenzumidine hydrochloride (35.7 g, 0.178 mol) in one portion. A solution of diethylethoxymethylene malonate (38.7 g, 0.178 mol) in 80 ml of ethanol was added to the suspension, and the mixture was heated under reflux for 2 l / 4 hours. The cooled solution was added to 2,800 ml of ice water, and the mixture was acidified to pH 5 with glacial acetic acid. The precipitated title compound was dried to give * 47 g of an off-white solid, m.p. * 1 47-150 °.

Preparation 23: Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate (illustrates the use of benzamidine fluorosulfonate)

To a solution of sodium ethoxide in sodium (* 41 g, 1.78 g) and ethanol (1 L) at 18 ° was added a solution of 2-ethoxybenzamidine fluorosulfonate (206.5 g, 0.78 mol) in ethanol (500 mL). . The resulting solution was cooled to 13 ° and then treated with a solution of diethyl ethoxymethylene malonate (180 mL, 0.89 mol) in ethanol (400 mL). The mixture was heated to reflux for 2.25 hours. The mixture was cooled to 10 ° and then poured into cold water (5 L) with good stirring. Ice was added to the mixture as needed to keep the temperature below 20 °. The mixture was acidified to pH 5 with glacial acetic acid. The solid was collected by filtration, washed with water and dried to give the title compound (218.7 g, 97%). Recrystallization from acetonitrile gave the product, m.p. was 144-147 °.

Preparation 24: Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate (illustrates the most preferred method using benzamidine methyl sulfate)

To a stirred solution of sodium (3.3 g, 0.144 g) in ethanol (150 mL) was added 2-ethoxybenzamidine methyl sulfate (19.9 g, 0.072 mol) followed by diethyl ethoxymethylene malonate (17.0 g, 0.079 mol). . The mixture was heated to reflux for 2.25 hours. The cooled solution was poured into ice water (250 ml), and the mixture was acidified with glacial acetic acid. The title compound was filtered, washed with water and dried. The compound (16.0 g, 77%) had m.p. 138-140 °.

Preparation 25: Ethyl 1,6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carboxylate (benzamidine hydrochloride) 2-n-propoxybenzamidine hydrochloride (12.0 g, 0, 0558 mol) was added to a stirred, cooled (ice water) solution of sodium (2.57 g, 0.112 g atoms) in ethanol (50 ml). To this cooled, stirred solution was added a solution of diethyl ethoxymethylene malonate (12.1 g, 0.0558 mol) in ethanol (50 mL) over 10 minutes. The mixture was heated to reflux for 2.5 hours. The cooled solution was poured onto ice and acidified with 6N hydrochloric acid. Precipitated ethyl 1,6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carboxylate (16.2 g, 96%) had m.p. 111-113 °. Recrystallization twice from cyclohexanone gave the title compound, m.p. 112-113 °.

Analysis calculated for the formula (p0 ^ p3 ^ 2 ° u: ^ 63.56 H 6.00 N 9.27 found: C 63.59 H 6.15 N 9.47.

29 62533

Preparation 26: Ethyl dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carboxylate (Benzamide dimethyl sulfate and sodium ethoxide)

To a warm solution of sodium (181.7 g, 7.9 g) in ethanol (5 L) was added, with stirring, a slurry of 2-n-propoxybenzamidine methyl sulfate (1115.7 g, 3.95 mol) in ethanol (1.6 L). ).

After 2-3 minutes, diethyl ethoxymethylene malonate (815 g, 3.95 mol) was added and the mixture was stirred and refluxed for 2.25 hours. The mixture was cooled and then added to cold water (13 L). The mixture was acidified to pH 5-6 with glacial acetic acid. The solid was filtered, washed with water and dried to give the title compound (937.8 g), m.p. 102-101 °.

An additional portion of product (101.5 g, mp 105-107 °) was obtained from the filtrate and washings. The total yield was 1039.1 g (87%).

Preparation 27: Ethyl 1'6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carboxylate (benzamidine methyl sulfate and CO 2) 2-n-propoxybenzamidine methyl sulfate ( A mixture of 7.1 g, 0.0255 mol), potassium carbonate (3.53 g, 0.025 mol) and diethylethoxymethylene malonate (5.99 g, 0.0277 mol) in ethanol (80 ml) was heated to reflux with stirring for 17 hours. The cooled solution was added to ice water (160 mL), which was then acidified with glacial acetic acid. The precipitate was collected by filtration, washed with water and dried to give the title compound (6.55 g, 89%), m.p. 106-107 °.

Preparation 28: Ethyl 1,6-dihydro-6-oxo-2- (2-isopropoxyphenyl) -pyrimidine-5-carboxylate (benzamidine hydrochloride) 2-isopropoxybenzamidine hydrochloride (10.0 g, 0.0165 mol) ) was added to a stirred, cooled (ice water) solution of sodium (2.11 g, 0.093 g atoms) in ethanol (100 mL). To this cooled, stirred solution was added dropwise over 10 minutes a solution of diethyl ethoxymethylene malonate (10.1 g, 0.0165 mol) in ethanol (30 mL). The mixture was refluxed for 2 hours and then left at 22 ° for 18 hours. The mixture was then poured into ice water containing acetic acid (10 mL) and concentrated HCl (10 mL), whereupon the desired product precipitated. The precipitate was washed and dried to give 15.5 g of the title product, m.p. 123-121 °. Recrystallization from ethyl acetate and then cyclohexane gave the ester as colorless crystals, m.p. 128-130 °.

Analysis calculated for C 63 H 18 N 2 O 2: C 63.56 H 6.00 N 9.27 Found: C 63.60 H 5.93 N 9.29

Preparation 29: Ethyl 1,6-dihydro-6-oxo-2- (2-allyloxyphenyl) pyramidine-5-carboxylate (benzamidine hydrochloride) 2-allyloxybenzamidine hydrochloride (U.S. Pat. No. 3,819,631 ) (19.07 g, 0.0896 mol) was added to a cooled (ice water), stirred solution of sodium ethoxide (12.25 g, 0.18 mol) in ethanol (100 ml). To this cooled, stirred mixture was added a solution of diethyl ethoxymethylene malonate (19.4 g, 0.0896 mol) in ethanol (15 mL). The mixture was heated to reflux for 2.5 hours and then left at room temperature for 18 hours. The mixture was poured into ice water containing acetic acid.

The resulting precipitate was collected and recrystallized from cyclohexane to give the title compound (24.0 g, 89), m.p. 118-120 °. Recrystallization from cyclohexane gave a melting point of 118.5-120.5 °.

Analysis calculated for C 16 H 16 N 2 O 4: C 63.99 H 5.37 N 9.33 Found: C 63.93 H 5.42 N 9.36.

Preparation 30: Ethyl 1,6-dihydro-6-oxo-2- (2-n-butoxyphenyl) pyrimidine-5-carboxylate (benzamidine hydrochloride)

Repeating Preparation 29 except using an equimolar amount of 2-n-butoxybenzamidine hydrochloride instead of the 2-allyloxybenzamidine hydrochloride used therein gave the title compound, m.p. 123-125 °.

Analysis calculated for C 17 H 20 N 2 O 4: C H 6.37 N 8.86 Found: C 64.41 H 6.29 N 9.07.

Preparation 31: Ethyl (-) - 1,6-dihydro-6-oxo-2- (2-sec-butoxyphenyl) pyrimidine-5-carboxylate (benzamidine hydrochloride)

In analogy to the preparation of ethyl 1,6-dihydro-6-oxo-2- (2-n-butoxyphenyl) pyrimidine-5-carboxylate described in Preparation 30, ethyl (-) - 1,6-dihydro-6-oxo-2 - (2-sec-butoxy-31,62533 ciphenyl) pyrimidine-5-carboxylate, m.p. 134-136 °, from (-) - 2-sec-butoxybenzamidine.

Analysis calculated for C 7 H 20 N 2 O 4: C 64.54 H 6.37 N 8.86 Found: C 64.31 H 6.12 N 8.82.

Preparation 32: Ethyl 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carboxylate (benzamidine free base)

To a stirred solution of sodium (3.15, 0.137 g) in ethanol (250 mL) was added 2-isobutoxybenzamidine (26.3 g, 0.137 mol) followed by diethyl ethoxymethylene malonate (29.6 g, 0.137 mol). The mixture was heated to reflux for 3 hours. The cooled mixture was added to ice water (300 mL), which was then acidified to pH 5 with glacial acetic acid. The crystalline product formed on cooling (36.4 g, 85%), m.p. 89-91 °, collected and some of it was crystallized from 50% ethanol-water to give the title compound, m.p. 92-93 °.

Analysis calculated for C 64.54 H 6.37 N 8.86 Found: C 64.66 H 6.64 N 8.69.

Preparation 33: Ethyl 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyramidine-5-carboxylate (benzamidine fluorosulfonate)

To a solution of sodium (161 mg, 7 mg) in ethanol (10 mL) was added 2-isobutoxybenzamidine fluorosulfonate (1.02 g, 3.5 mmol). The mixture was heated to give a clear solution to which was added diethyl ethoxymethylene malonate (765 mg, 3.5 mmol) in ethanol (2 mL). The solution was heated to reflux for 3 hours. The cooled solution was added to ice water (50 mL) and acidified to pH 5 with glacial acetic acid. After stirring for a while, the solid was filtered, washed with water and dried to give the title compound (0.94 g, 86%), m.p. 90-91 °.

Preparation 34: Ethyl 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carboxylate (1 CO 2 was used instead of alkali metal alkoxide)

Diethyl ethoxymethylene malonate (6.42 g, 0.03 mol) was added to a stirred mixture of 2-isobutoxybenzamidine (5.76 g, 0.03 mol 32,62533) and potassium carbonate (4.14 g, 0.03 mol) in ethanol (70 ml). ). The mixture was heated to reflux for 4 hours. The cooled solution was added to water (100 ml), to which was then added 6-hydrochloric acid to pH 8 and then acetic acid to pH 5. The title compound was filtered, washed with water and dried. The product (6.76 g, 71%) had m.p. 88-90 °.

Preparation 35: Ethyl 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carboxylate (condensation reaction without condensing wave)

The experiment of Preparation 34 was repeated without potassium carbonate. The title compound was obtained in 69% yield, m.p. 89-91 °.

Preparation 36:

The following ethyl 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylates were prepared from the corresponding benzamidine hydrochlorides by the general method described in Preparation 29.

, A. Ethyl 1,6-dihydro-6-oxo-2- (2,5-dimethoxyphenyl) pyrimidine-5-carboxylate, m.p. 149-150 °.

Analysis calculated for C 18 H 18 N 2 O 2: C 59.20 H 5.30 N 9.21 Found: C 59.07 H 5.27 N 9.23.

B. Ethyl 1,6-dihydro-6-oxo-2- (5-chloro-2-ethoxyphenyl) pyrimidine-5-carboxylate, m.p. 209-212 °.

Analysis calculated for C 18 H 28 Cl 2 N 2 O 2: C 55.82 H 4.68

Cl 10.99 N 8.68 found: C 55.66 H 4.76 Cl 10.87 N 8.78.

C. Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxy-5-methoxyphenyl) pyrimidine-5-carboxylate, m.p. 149-152 °.

Analysis calculated for C 60 H 27 N 2 O 2: C 60.37 H 5.70 N 8.80 Found: C 60.31 H 5.68 N 9.09.

D. Ethyl 1,6-dihydro-6-oxo-2- (2-methoxyphenyl) pyrimidine-5-carboxylate, m.p. 148-150 °.

Analysis calculated for the formula ^ μ, Η - ^^ Ομ: C 61.31 H 5.14 N 10.21 found: C 61.38 H 5.05 N 10.23.

33 6 2 5 3 3 E. Ethyl 1,6-dihydro-6-oxo-2- (2-chlorophenyl) pyramidine-5-carboxylate, m.p. 139-1 * 41 °.

Analysis calculated for C 18 H 19 Cl 2 O 3: C 56.02 H 3.98 Cl 12.72 N 10.05 Found: C 55.90 H 3.83 Cl 12.34 N 10.16.

F. Ethyl 1,6-dihydro-6-oxo-2- (3-methoxyphenyl) pyridimidine-5-carboxylate, m.p. 169-170 °

Analysis calculated for C 61.31 H 5.14 N 10.21 Found: C 60.96 H 5.13 N 10.16.

G. Ethyl 1,6-dihydro-6-oxo-2- (3-trifluoromethyltenyl) -pyrimidine-5-carboxylate, m.p. 151-152 °

Analysis calculated for C 23 H 19 F 3 O 3 O 3 C 53.85 H 3.55 N 8.97 Found: C 53.84 H 3.70 N 8.71.

H. Ethyl 1,6-dihydro-6-oxo-2- (4-methoxyphenyl) pyrimidine-5-carboxylate, m.p. 230-232 ° I. Ethyl 1,6-dihydro-6-oxo-2- (4-chlorophenyl) pyrimidine-5-carboxylate, m.p. 245-247 °

Analysis calculated for C 18 H 12 Cl 2 O 2: C 56.02 H 3.98 Cl 12.72 N 10.05 Found: C 55.94 H 4.06 Cl 12.46 N 9.86.

J. Ethyl 1,6-dihydro-6-oxo-2- (4-trifluoromethylphenyl) pyrimidine-5-carboxylate, m.p. 225 to 226.5 °

Analysis calculated for C 53.85 H 3.55 N 8.97 Found: C 54.00 H 3.62 N 9.05.

Preparation 37: Ethyl 1,6-dihydro-6-oxo-2- (5-carboethoxy-2-ethoxyphenyl) pyrimidine-5-carboxylate (benzamidine free base)

Diethyl ethoxymethylene malonate (1.18 g, 5.45 mmol) was added to a cold, stirred mixture of sodium ethoxide (0.37 g, 5.45 mmol) and 5-carbomethoxy-2-ethoxybenzamidine (1.21 g, 5.45 mmol) in ethanol ( 15 ml). The mixture was heated to reflux for 0.5 hours. The cooled solution was poured into ice water and acidified with acetic acid. The precipitate was filtered and recrystallized from ethanol to give the title compound (1.49 g, 76%) as colorless crystals, m.p. 180 to 181.5 °.

62533 34

It should be noted that in the coupling reaction of carbomethoxybenzamidine and ethoxymethylene malonate, an ester exchange takes place (under the action of NaOC 2 Hg / H 2 O 2) to give a 5'-carboethoxy compound.

Preparation 38: Ethyl 1,6-dihydro-6'-oxo-2- (5-amino-2-ethoxyphenyl) pyrimidine-5-carboxylate A. Ethyl 1,6-dihydro-6-oxo-2- (2- ethoxy-5-nitro-phenyl) -pyrimidine-5-carboxylate

Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate (1.0 g, 3.46 mmol) was added over 20 minutes to a cooled (ice water) stirred mixture of 70% nitric acid. (1.7 ml, d = 1.42) and 96% sulfuric acid (0.29 ml, d = 1.84). The mixture was stirred at room temperature for 19 hours. The solution was poured into ice water (300 ml). The mixture was triturated and then filtered. The resulting solid was recrystallized from acetonitrile to give the title compound (0.64 g, 55%), m.p. 222-224 °.

Analysis calculated for C 15 H 15 N 3 O 3: C 54.05 H 4.54 N 12.61 Found: C 54.32 H 4.71 N 12.56.

B. Ethyl 1,6-dihydro-6-oxo-2- (5-amino-2-ethoxyphenyl) pyrimidine-5-carboxylate

Ethyl 1,6-dihydro-6-oxo-2- (2-ethoxy-5-nitrophenyl) pyrimidine-5-carboxylate (0.42 g, 1.26 moles) and 10% palladium on carbon ( A mixture of 0.07 g) in ethanol (200 ml) was treated with hydrogen 2 at a pressure of about 3.5 kg / cm until hydrogen bonding ceased. The mixture was filtered and the filtrate was evaporated to dryness. The residue was recrystallized from water and then aqueous ethanol to give the title compound (0.12 g, 31.6%), m.p. 107-110 °.

f i Analysis calculated for Ng04. ^ 0:! C 56.07 H 5.96 N 13.08 H 2 O 5.62 found: C 56.37 H 5.70 N 13.32 HyO 5.82.

Preparation 39: Ethyl 1,6-dihydro-6-oxo-2- (2-cyclopropylmethoxy-phenyl) -pyrimidine-5-carboxylate The title compound was prepared from 2-cyclopropylmethoxybenzamidine hydrochloride as described in Preparation 29, ethyl-1,6-dihydro-6-oxo. 2- (2-allyloxyphenyl) pyrimidine-5-carboxylate. The melting point of the product was 104-105 °.

Analysis calculated for C 64 H 18 N 2 O 2: C 64.95 H 5.77 N 8.91 Found: C 64.66 H 5.93 N 8.87.

35 62533

Preparation 40: Ethyl 1,6-dihydro-6-oxo-2- (5-methoxy-2-n-propoxyphenyl) pyrimidine-5-carboxylate The title compound was prepared from 5-methoxy-2-n-propoxybenzamidine hydrochloride in a similar manner. by a method other than ethyl 1,6-dihydro-6-oxo-2- (2-allyloxyphenyl) pyrimidine-5-carboxylate in Preparation 29. The melting point of the compound was 124-1.26 °.

Preparation 41: Ethyl 1,6-dihydro-6-oxo-2- (2,4-dimethoxyphenyl) pyrimidine-5-carboxylate A solution of diethyl ethoxymethylene malonate (8.4 g, 0.0388 mol) in ethanol (20 ml) was added dropwise. to a cooled (ice water), stirred mixture of 2,4-dimethoxybenzamidine (7.0 g, 0.0388 mol) in ethanol (50 mL) containing sodium (0.89 g, 0.0388 g). The mixture was heated to reflux for 2 hours. The cooled solution was poured into ice water and acidified with dilute hydrochloric acid. The precipitate was recrystallized from 95% ethanol to give ethyl 1,6-dihydro-6-oxo-2- (2,4-dimethoxyphenyl) pyrimidine-5-carboxylate (9.0 g, 63.5 %), m.p. 190-192 °.

Analysis calculated for C 59.20 H 5.30 N 9.21 Found: C 59.15 H 5.22 N 9.19.

Preparation 42-1:

The following ethyl 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylates were prepared by reacting the appropriate benzamidine with diethyl ethoxymethylene malonate according to the general procedure set forth in Preparation 41.

Ethyl 1,6-dihydro-6-oxo-2- (2-fluorophenyl) pyrimidine-5-carboxylate, m.p. 151-153 °.

Analysis calculated for C 59.54 H 4.23 N 10.68 Na: C 59.69 H 4.15 N 11.05.

Ethyl 1,6-dihydro-6-oxo-2- (2-benzyloxyphenyl) pyrimidine-5-carboxylate, m.p. 156.5 to 157.5 ° C.

Analysis calculated for C 20 H 18 N 2 O 4: C 68> 56 H 5> 18 N 8> 00 Found: C 68.27 H 4.99 N 8.01.

62533 36

Preparation 42-2: Ethyl 1,5-dihydro-6-oxo-2- (2-ethylthiophenyl) pyrimidine-5-carboxylate 2-Ethylthiobenzamidine hydrochloride (2.12 g, 10.0 mmol) was added to the cooled (ice water). ) to a solution of sodium (0.46 g, 20 mg) in ethanol (12 mL). To this mixture was added a solution of diethyl ethoxymethylene malonate (2.16 g, 10.0 mmol) in ethanol (4 mL). The mixture was heated to reflux for 3.5 hours. The cooled mixture was poured into ice water (400 ml) and acidified to pH 6 with glacial acetic acid. The precipitate was collected and recrystallized from acetonitrile to give the title compound (2.04 g, 64.6%), m.p. 117-120 °.

Analysis calculated for C 19 H 19 N 2 O 2 S: C 59.19 H 5.30 N 9.20 Found: C 59.42 H 5.31 N 9.37.

Preparation 42-3: Ethyl 1,6-dihydro-6-oxo-2- (2-methylthiophenyl) pyrimidine-5-carboxylate

The title compound was prepared as described in Preparation 42-2 from 2-methylthiobenzamidine hydrochloride (disclosed in U.S. Patent 3,819,631). Recrystallized from benzene, the compound had m.p. 155-156 °.

Analysis calculated for C 11 H 12 N 2 O 2 S: C 57.92 H 4.86 N 9.65 S 11.04 Found: C 57.93 H 4.76 N 9.71 S 11.01.

Preparation 42-4: Ethyl 1,6-dihydro-6-oxo-2- (2-nitrophenyl) pyrimidine-5-carboxylate

Diethyl ethoxymethylene malonate (0.73 g, 3.44 mmol), potassium carbonate (0.95 g, 6.88 mmol) and ethanol (11 mL) were added to 2-nitrobenzamidine hydrochloride (0.69 g, 3.44 mmol) (prepared According to the general method of U.S. Patent 2,450,386). The mixture was heated to reflux for 3.5 hours. The cooled mixture was filtered. The filtrate was poured into ice water (150 ml) and the pH was adjusted to 6.0 with acetic acid. The precipitate was collected and dried to give the title compound (0.20 g, 20.2%), m.p. 171-175 °. Recrystallization from acetonitrile gave the analytically pure product, m.p. 175-177 °.

Analysis calculated for C 13 H 18 N 2 O 9: C 53.98 H 3.83 N 14.53 Found: C 53.62 H 3.90 N 14.35.

37 62533

Preparation 42-5: Ethyl 1,6-dihydro-6-oxo-2- (2-aminophenyl) pyrimidine-5-carboxylate

Ethyl 1,6-dihydro-6-oxo-2- (2-nitrophenyl) pyrimidine-5-carboxylate (0.91 g, 3.14 mmol), 10% palladium on carbon (0.34 g) and a mixture of ethanol (200 ml) was shaken under a hydrogen atmosphere at an initial pressure of 3.5 kg / cm 3. When the hydrogen uptake was complete, the mixture was filtered and the filtrate was evaporated. The residue was recrystallized from acetonitrile to give the title compound (0.445 g, 54.5%), m.p. 228-230 ° (decomposes).

Analysis calculated for C 18 H 28 N 2 O 2: C 60.22 H 5.05 N 16.21 Found: C 58.89 H 4.98 N 16.51.

1,6-Dihydro-6-oxo-2-phenylpyrimidine-5-carboxamides (general formula III) can be prepared as follows:

Preparation 43: 1,6-Dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxamide

A mixture of ethyl 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate (10.0 g) and ammonium hydroxide (120 ml, d = 0.90) was heated in a sealed vessel with a steam bath 4.5 hours. The solution was partially evaporated and then acidified to pH 3 with 6N hydrochloric acid. The collected solid was washed with water, dried and recrystallized from N, N-dimethylformamide to give the title compound (6.93 g, 77%), m.p. 236-238 °.

Analysis calculated for C 19 H 19 N 2 O 9: C 60.22 H 5.05 N 16.21 Found: C 60.15 H 5.11 N 15.77.

Preparation 44:

The following carboxamides were prepared from the corresponding 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylates by the method described in Preparation 43.

A. 1,6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyramidine-5-carboxamide, m.p. 225-226 °.

Analysis calculated for C 18 H 18 N 2 O 9: C 61.53 H 5.53 N 15.38 Found: C 61.76 H 5.56 N 15.14.

B. 1,6-dihydro-6-oxo-2- (2-methoxyphenyl) pyrimidine-5-carboxamide, m.p. 218-219 °.

62533 38

Analysis calculated for C 25 H 27 N 3 O 3 • C 58.77 H 4.52 N 17.14 obtained; C 59.17 H »4.48 N 16.87.

C. 1,6-dihydro-6-oxo-2- (2-isopropoxyphenyl) pyrimidine-5-carboxamide, m.p. 200-201 °.

Analysis calculated for C 61 H 23 N 3 O 2: C 61.53 H 5.35 N 15.38 Found: C 61.42 H 5.53 N 14.99.

D. 1,6-dihydro-6-oxo-2- (2-n-butoxyphenyl) pyrimidine-5-carboxamide, m.p. 181-183 °.

Analysis calculated for C 18 H 18 N 2 O 9: C 62.70 H 5.96 N 14.63 Found: C 62.71 H 5.94 N 14.61.

Preparation 45: (-) - 1,6-Dihydro-6-oxo-2- (2-sec-butoxyphenyl) -pyrimidine-5-carboxamide

Ethyl (-) - 1,6-dihydro-6-oxo-2- (2-sec-butoxyphenyl) pyrimidinecarboxylate (3.76 g) and liquid ammonia (about 45 ml) were heated in a steel tank on a steam bath for 4 hours. Ammonia was removed. The residue was dissolved in ice water and acidified with concentrated hydrochloric acid. The precipitate was recrystallized from methanol to give the title compound (2.99 g, 87.7%), m.p. 183-185 °.

Analysis calculated for C 62 H 27 N 2 O 2 • C 62.70 H 5.96 N 14.63 Found: C 62.37 H 5.95 N 14.50.

Preparation 46: 1,6-Dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carboxamide

A mixture of ethyl 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carboxylate (10.0 g, 0.0316 mol) and ammonium hydroxide (110 ml, d = 0.9) heated in a sealed steel bomb for 4.5 hours. The solution was partially evaporated and acidified with 6N hydrochloric acid. The mixture was filtered and the solid was recrystallized from Ν, Ν-dimethylformamide to give the title compound (7.5 g, 83%), m.p. 230-231 °.

Analysis calculated for C 62.70 H 5.96 N 14.63 Found: C 62.58 H 5.91 N 14.23.

39 62533

Preparation 47: 1,6-Dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidin-5-carboxamide (illustrates the use of ΝΗ ^ ΟΗίη at room temperature)

To a slurry of ethyl 1,6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carboxylate (1811.4 g) in ammonium hydroxide (12 L, d = 0.9) was added tetrahydrofuran. (800 ml). The solution was allowed to stand at room temperature for 64 hours. Partial evaporation of the solvents under reduced pressure gave a thick slurry which was cooled and acidified to about pH 3 with 6N hydrochloric acid. The solid was filtered, washed with water, dried and recrystallized from N, N-dimethylformamide to give the title compound (1407.7 g, 86%), m.p. 227-229 °.

Preparation 48:

Following the general procedures of Preparations 43-47, the following carboxamides can be prepared from the appropriate 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxylates: A. 1,6-Dihydro-6-oxo-2- (2-chlorophenyl ) pyrimidine-5-carboxamide; B. 1,6-dihydro-6-oxo-2- (3-methoxyphenyl) pyrimidine-5-carboxamide; C. 1,6-dihydro-6-oxo-2- (3-trifluoromethyl) pyrimidine-5-carboxamide; D. 1,6-dihydro-6-oxo-2- (4-methoxyphenyl) pyrimidine-5-carboxamide; E. 1,6-Dihydro-6-oxo-2- (4-trifluoromethyl) pyrimidine-5-carboxamide ·, F. 1,6-Dihydro-6-oxo-2- (2,4-dimethoxyphenyl) pyrimidine-5 -carboxamide; 6. 1,6-dihydro-6-oxo-2- (2-fluorophenyl) pyrimidine-5-carboxamide; H. 1,6-dihydro-6-oxo-2- (2-benzyloxyphenyl) pyrimidine-5-carboxamide; I. 1,6-dihydro-6-oxo-2- (2-ethylthiophenyl) pyrimidine-5-carboxamide; J. 1,6-dihydro-6-oxo-2- (2-methylthiophenyl) pyrimidine-5-carboxamide and K. 1,6-dihydro-6-oxo-2- (2-aminophenyl) pyrimidine-5-carboxamide.

62533 40

Preparation 49; 1.6-dihydro-6-oxo-2- (2-allvvlioksifenvvli) pyrimidine-pyrimidine-5-carboxamide

A mixture of ethyl 1,6-dihydro-6-oxo-2- (2-allyloxyphenyl) pyrimidine-5-carboxylate (5.0 g) and liquid ammonia (50 ml) was kept in a steel bomb at 25 ° for 18 hours and then heated on a steam bath for 2.5 hours. Ammonia was removed. The residue was dissolved in water and the solution was acidified with acetic acid. The precipitated title compound (4.4 g, 97%) had a melting point of 21) 2-204 °, and solidified again and melted again at 275-280 °. Recrystallization from ethanol gave the analytically pure compound, m.p. 205-207 °.

Analysis calculated for C 22.4 13 H 3 4.83 N 15.49 Found: C 61.97 H 4.79 N 15.30.

Preparation 50: 1,6-Dihydro-6-oxo-2- (2-cyclopropylmethoxyphenyl) -pyrimidine-5-carboxamide.

In a similar manner to the preparation of 1,6-dihydro-6-oxo-2- (2-allyloxy-phenyl) -pyrimidine-5-carboxamide in Preparation 49, the title compound ethyl 1,6-dihydro-6-oxo-2- ( 2-cyclopropyl-pyylimetoksifenyyli) pyrimidine-5-carboxylate. The product (100%) m.p. was 215-217 ° (recrystallization from ethanol).

Analysis calculated for C 18 H 19 N 2 N 2 O 3: C 63.15 H 5.30 N 14.73 Found: C 63.00 H 5.46 N 14.62.

Preparation 51: 1,6-Dihydro-6-oxo-2- (5-methoxy-2-n-propoxyphenyl) -: pyrimidine-5-carboxamide

A mixture of ethyl 1,6-dihydro-6-oxo-2- (5-methoxy-2-n-propoxyphenyl) pyrimidine-5-carboxylate (10.0 g) and concentrated ammonium hydroxide (100 ml) was heated in a sealed steel bomb. on a steam bath for 4.5 hours. The reaction mixture was concentrated and then acidified to pH 3 with 6N hydrochloric acid. The collected solid was partially dried and recrystallized from acetonitrile to give the title compound (3.8 g, 41.6%), m.p. 206-207 °.

Analysis calculated for C 18 H 19 N 2 O 2: C 59.39 H 5.65 N 13.86 Found: C 59.17 H 5.81 N 13.69.

1,6-Dihydro-6-oxo-2-phenylpyrimidine-5-carbonitriles (general formula II) can be prepared by the methods described below.

41 62533

Method A (from carboxamides)

Preparation 52: 1,6-Dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carbonitrile 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyramidine-5-carboxamide ( A solution of 5.5 g) in phosphorus oxychloride (160 ml) was heated at reflux for 3.5 hours. The solution was evaporated under reduced pressure to a thick oil which was treated with water (150 ml) with vigorous stirring. The mixture was filtered. The resulting solid was washed with water, dried and recrystallized from glacial acetic acid to give the title compound (3.48 g, 68%), m.p. 186-187 °.

Analysis calculated for C 13 H 30 N 3 O 2: C H 4.60 N 17.42 Found: C 65.09 H 4.84 H 17.75.

Preparation 53:

The following carbonitrites were prepared from the corresponding 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxamides by the method of Preparation 52 described above.

A. 1,6-Dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carbonitrile, m.p. 171-172 °.

Analysis calculated for C 12 H 12 N 2 O 3: C 65.87 H 5.13 Found: C 65.82 H 5.22.

B. 1,6-Dihydro-6-oxo-2- (2-methoxyphenyl) pyrimidine-5-carbonitrile, m.p. 245-246 °.

Analysis calculated for C 12 H 9 N 9 O 3: C 63.43 H 3.99 N 18.49 Found: C 63.09 H 4.09 N 18.22.

C. 1,6-Dihydro-6-oxo-2- (2-isopropoxyphenyl) pyrimidine-5-carbonitrile, m.p. 174-175 °.

Analysis calculated for C 18 H 13 N 3 O 2: N 16.46 Found: N 16.53.

D. 1,6-Dihydro-6-oxo-2- (2-n-butoxyphenyl) pyramidine-5-carbonitrile, m.p. 171.5 to 173.5 ° C.

Analysis calculated for 5N 3 O 2: C 66.90 H 5.61 N 15.61 Found: C 66.58 H 5.62 N 15.46.

E. (-) - 1,6-dihydro-6-oxo-2- (2-sec-butoxyphenyl) pyrimidine-5-carbonitrile, m.p. 152-158 °.

Analysis calculated for C 15 H 15 N 3 O 2: C 66 → 90 H 5.61 N 15.61 Found: C 66.59 H 5.43 N 15.77.

42 6 2 5 3 3

Preparation 54; 1,6-Dihydro-6-oxo-2- (2-isobutoxyphenylpyrimidine-5-carbonitrile 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyramidine-5-carboxamide (7,4-g) and phosphorus oxychloride (150 ml) was heated at reflux for 3.5 hours Excess phosphorus oxychloride was removed under reduced pressure Water (150 ml) was added to the residue The mixture was stirred for some time, cooled and filtered The collected solid was recrystallised from 50% acetic acid. from aqueous solution to give the title compound (3.9 g, 58%), mp 186-187 °.

Preparation 55:

Following the general procedures of Preparations 52-54 above, the following carbonitriles were prepared from the appropriate 1,6-dihydro-6-oxo-2-phenylpyrimidine-5-carboxamides: A. 1,6-Dihydro-6-oxo-2- (2- chlorophenyl) pyrimidine-5-carbonitrile; B. 1,6-dihydro-6-oxo-2- (3-methoxyphenyl) pyrimidine-5-carbonitrile; C. 1,6-Dihydro-6-oxo-2- (3-trifluoromethylphenyl) -pyrimidine-5-carbonitrile; D. 1,6-dihydro-6-oxo-2- (4-methoxyphenyl) pyrimidine-5-carbonitrile; E. 1,6-dihydro-6-oxo-2- (4-trifluoromethyl) pyrimidine-5-carbonitrile; F. 1,6-dihydro-6-oxo-2- (2,4-dimethoxyphenyl) pyrimidine-5-carbonitrile; G. 1,6-dihydro-6-oxo-2- (2-fluorophenyl) pyrimidine-5-carbonitrile; H. 1,6-dihydro-6-oxo-2- (2-benzyloxyphenyl) pyrimidine-5-carbonitrile; I. 1,6-dihydro-6-oxo-2- (2-ethylthiophenyl) pyramidine-5-carbonitrile; J. 1,6-dihydro-6-oxo-2- (2-methylthiophenyl) pyrimidine-5-carbonitrile and K. 1,6-dihydro-6-oxo-2- (2-aminophenyl) pyramidine-5-carbonitrile.

43 6 2 5 3 3

Preparation 56: 1,6-Dihydro-6-oxo-2- (2-allyloxyphenyl) pyrimidine-5-carbonitrile 1,6-dihydro-6-oxo-2- (2-allyloxyphenyl) pyrimidine-5-carboxamide (3, 58 g) A solution in phosphorus oxychloride (60 ml) was heated at reflux for 2 hours. The solution was evaporated to dryness. The residue was cooled in an ice bath, and then ice water was carefully added thereto. The mixture was warmed to 25 ° and then heated on a steam bath for 15 minutes. The solid was collected, washed with cold water and crystallized from benzene-Skellysolve B to give the title compound (2.3 g, 69%), m.p. 162-164 °.

Analysis calculated for the formula (-: ΐ4ΗχιΝ302: ^ 66> 39 H 4.38 N 16.59 found: C 66.36 H 4.45 N 16.53.

Preparation 57: 1,6-Dihydro-6-oxo-2- (2-cyclopropylmethoxyphenyl) -pyrimidine-5-carbonitrile 1,6-dihydro-6-oxo-2- (2-cyclopropylmethoxyphenyl) pyramidine-5-carboxamide (13.6 g, 0.0476 mol) was added with stirring to a cold solution of pyridine (18.9 g, 0.24 mol) in phosphorus oxychloride (136 ml), and the mixture was then heated to reflux for 15 minutes. The mixture was evaporated to dryness and the residue was added to ice-methylene chloride. The mixture was neutralized with sodium bicarbonate. The methylene chloride layer was dried (sodium sulfate) and evaporated. To the residual oil were added 1N sodium hydroxide (15 ml) and tetrahydrofuran (10 ml). The mixture was allowed to stand at 25 ° for 18 hours. The mixture was washed with diethyl ether, filtered, and the filtrate was acidified with acetic acid. The resulting bag was recrystallized from toluene to give the title compound (7.6 g, 59.6%), m.p. 188-190 °. Crystallization twice from ethyl acetate gave the analytically pure product, m.p. 187-189 °.

Analysis calculated for the formula ^ 15 ^ 3 ^ 3 () 2: ^ H 4.90 N 15.72 found: C 67.00 H 4.96 N 15.50.

Preparation 58: 1,6-Dihydro-6-oxo-2- (5-methoxy-2-n-propoxyphenyl) -pyramidine-5-carbonitrile

The title compound was prepared in 82.5% yield (m.p. 192-194 °) from 1,6-dihydro-6-oxo-2- (5-methoxy-2-n-propoxyphenyl) pyrimidine-5-carboxamide in Preparation 56 by the method described.

Crystallization was performed from 2-propanol.

44 6 2 5 3 3

Analysis calculated for C 12 H 13 N 2 O 2: C 63.15 H 5.30 N 14.73 obtained; C 62.87 H 5.28 N 14.74.

Method B (from an acrylate intermediate of formula VI)

Preparation 59: 1,6-Dihydro-6-oxo-2- (2-isopropoxyphenyl) pyrimidine-5-carbonitrile

A solution of ethyl 2-cyano-3- (2-isopropoxybenzamidino) acrylate (0.60 g, 1.99 mmol) (prepared as described in Preparation 60) in dimethyl sulfoxide (15 mL) was heated on an oil bath at 100 ° for 18 h. The cooled mixture was poured into ice-water (400 ml). The mixture was filtered to give the title compound (0.40 g, 78.7%), m.p. 182-184 °.

By repeating the above procedure using toluene instead of dimethyl sulfoxide, the crude product was obtained in 81.7% yield.

By repeating the above procedure using N, N-dimethylformamide instead of dimethyl sulfoxide, the title compound was obtained in 74% yield, m.p. 184-188 °.

Acrylate intermediates of formula VI can be prepared as follows:

Preparation 60: Ethyl 2-cyano-3- (2-isopropoxybenzamidino) acrylate Ethyl ethoxymethylene cyanoacetate (0.95 g, 5.61 mmol) was added to an ice-cooled solution of 2-isopropoxybenzamidine (1.0 g, 5.61 mmol) in ethanol. (7.1 ml). The mixture was stirred at 5 ° for 1.5 hours. The mixture was filtered to give the title compound (1.2 g, 71%), m.p. 118-122 °. The m.p. was 123-124 ° (decomposes).

Analysis calculated for C 63.77 H 6.36 N 13.95 Found: C 63.57 H 6.25 N 14.02.

In a similar manner, but using Ν, Ν-dimethylformamide instead of ethanol, ethyl 2-cyano-3- (2-isopropoxybenzamidino) acrylate was obtained by the above method, m.p. 118-120 °, in 76.2% yield.

45 6 2 5 3 3

Example 1 2- (2-Ethoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4- (3H) -one 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5-carboxylate a mixture of nitrile (2.17 g, 9.0 mmol), sodium azide (0.645 g, 9.9 mmol) and ammonium chloride (0.53 g, 9.9 mmol) in dry N, N-dimethylformamide (18 mL) stirred at 125 ° for 16 hours. The solvent was evaporated under reduced pressure. The residue was treated with water, and the resulting slurry was acidified with 1N hydrochloric acid.

The mixture was filtered. The collected solid was washed with water, dried and recrystallized from glacial acetic acid to give the title compound (1.28 g, 50%). The assay sample had m.p. 289-290 ° (decomposes).

Analysis calculated for C 27 H 19 N 2 O 2: C 54.92 H 4.26 N 29.57 Found: C 55.09 H 4.32 N 29.29.

Example 2 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyramidin-4 (3H) one

The procedure of Example 1 was repeated using 1,6-dihydro-6-oxo-2- (2-n-propoxyphenyl) pyrimidine-5-carbonitrile using the 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine used therein. Instead of 5-carbonitrile. The title product was obtained, m.p. 247-248 °.

Analysis calculated for N 28.17 Found: N 28.27.

Example 3 2- (2-Isopropylphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one

The procedure of Example 1 was repeated using 1,6-dihydro-6-oxo-2- (2-isopropoxyphenyl) pyrimidine-5-carbonitrile using the 1,6-dihydro-6-oxo-2- (2-ethoxyphenyl) pyrimidine-5- instead of carbonitrile. The title compound was obtained, m.p. 275-276 ° (decomp.).

Analysis calculated for C 18 H 18 N 2 O 2 C 56.37 H 4.73 N 28.17 Found: C 56.22 H 4.75 N 28.13.

Example 4 2- (2-n-Butoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one

The procedure of Example 1 was repeated using an equimolar amount of 1,6-dihydro-6-oxo-2- (2-n-butoxyphenyl) pyrimidine-5-carbonitrile as used in 1,6-dihydro-6-oxo-2- (2- ethoxyphenyl) instead of pyri-46 62533 mididine-5-carbonitrile. The title compound was obtained, m.p. 244-247 ° (decomposes).

Analysis calculated for C 15 H 15 N 2 N 2 O 2: C 57.68 H 5.16 N 26.91 Found: C 57.41 H 5.13 N 27.09.

Example 5 (-) - 2- (2-sec-butoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one

The procedure of Example 1 was repeated using an equimolar amount of (-) - 1,6-dihydro-6-oxo-2- (2-sec-butoxyphenyl) pyramidine-5-carbonitrile in the 1,6-dihydro-6-oxo-2- Instead of (2-ethoxyphenyl) pyrimidine-5-carbonitrile. The title compound was obtained, m.p. 240-242 ° (decomposes). It should be noted that the compound of this example has an asymmetric carbon atom and can thus be a racemate, i. contains equal amounts of optical (+) and (-) isomers as a mixture, from which mixture the (+) and (-) isomers may be separated by methods known per se.

Analysis calculated for C 15 H 18 N 2 O 2: C 57.68 H 5.16 N 26.91 Found: C 57.49 H 5.09 N 26.66.

Example 6 2- (2-Methoxyphenyl) -5- (5-1H-tetrazolyl) Dvrimidin-4 (3H) -one

Sodium azide (283 mg, 4.35 mmol) was added to a solution of Aluminum Chloride (193 mg, 1.45 mmol) in tetrahydrofuran (8 mL). The mixture was stirred at reflux for 0.5 hours. To the mixture was then added 1,6-dihydro-6-oxo-2- (2-methoxyphenyl) pyrimidine-5-carbonitrile (300 mg, 1.32 mmol), and the mixture was stirred at reflux for 24 hours. The cooled mixture was diluted with water (15 mL) and acidified with 6N hydrochloric acid. The mixture was filtered. The resulting solid was recrystallized from glacial acetic acid to give the title compound (130 mg, 36.4%), m.p. 282-283 ° (decomposes).

Analysis calculated for C 12 H 10 N 6 O 2: C 53> 33 H 3> 73 N 31.10 Found: C 53.20 H 3.74 N 31.50.

47 62533

Example 7 2- (2-Isobutoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4- (3H-one 1,6-dihydro-6-oxo-2- (2-isobutoxyphenyl) pyrimidine-5-carbonitrile (3.78 g, 0.014 mol), a mixture of sodium azide (1.0 g, 0.0154 mol), ammonium chloride (0.824 g, 0.0154 mol) in N, N-dimethylformamide was heated at 125 ° with stirring for 19 hours. The solvent was removed under reduced pressure, and the residue was treated with water (40 mL), acidified with 6N hydrochloric acid with stirring, filtered and the resulting solid recrystallized from glacial acetic acid to give the title compound (2.4 g, 55%), mp 230-. 231 °.

Analysis calculated for C 57.68 H 5.16 N 26.91 Found: C 57.52 H 5.27 N 26.72.

Example 8 2- (2-Allyloxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one To ice-cold stirred tetrahydrofuran (100 ml) was added aluminum chloride (1.71 g, 0.0128 mol) and then caution with sodium azide (2.5 g, 0.0384 mol). The mixture was heated to reflux for 0.5 hours. To the mixture was added 1,6-dihydro-6-oxo-2- (2-allyloxyphenyl) pyrimidine-5-carbonitrile (3.23 g, 0.0128 mol) and heating at reflux was continued for 18 hours. The cooled mixture was diluted with water and acidified with 6N hydrochloric acid. The precipitate was collected and recrystallized from 95% ethanol to give the title compound (1.4 g, 37%), m.p. 221-225 °. Crystallization twice from acetic acid gave an analytical sample, m.p. 230.5-232 ° (decomposes).

Analysis calculated for C 41 H 12 N 2 O 2: C 56.75 H 4.08 N 28.37 Found: C 56.71 H 4.24 N 24.40.

Example 9 2- (2-Chloropropylmethoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one 1,6-dihydro-6-oxo-2- (2-cyclopropylmethoxyphenyl) pyrimidine-5-carbonitrile (4.5 g, 0.0168 mol), a mixture of sodium azide (1.2 g, 0.0184 mol) and ammonium chloride (0.99 g, 0.0185 mol) in N, N-dimethylformamide (45 ml) was stirred and heated in a 125 ° oil bath for 20 hours. The mixture was evaporated. The residue was diluted with water, and the mixture was acidified with 1 + 8 625 33 concentrated hydrochloric acid. Precipitated title compound (4.7 g, 90%), m.p. 237-243 ° (decomposes), recrystallized from acetic acid and then from 2-methoxyethanol to give an analytical sample, m.p. 252-254 ° (decomposes).

Analysis calculated for C 18 H 18 N 2 O 3: C 58.0 H 4.55 N 27.09 Found: C 58.16 H 4.66 N 27.04

Example 10 2- (5-Methoxy-2-n-propoxyphenyl) -5- (5-1H-tetrazotyl) -pyrimidin-4 (3H) -one

In a similar manner to 2- (2-cyclopropylmethoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one described in Example 9, the title compound 1,6-dihydro-6-oxo-2- (5 methoxy-2-n-propok sifenyyli) pyrimidine-5-carbonitrile. The crude product was recrystallized from 2-methoxyethanol to give the analytically pure product (65%), m.p. 257-260 ° C.

Analysis calculated for C 11 H 12 N 2 O 9: C 54.87 H 4.91 N 25.60 Found: C 54.92 H 4.90 N 25.69.

Example 11 2- (2-Isopropoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one (from the acrylate intermediate)

To a solution of ethyl 2-cyano-3- (2-isopropoxybenzamidino) acrylate (0.60 g, 1.99 mmol) in N, N-dimethylformamide (15 mL) was added sodium azide (0.159 g, 2.44 mmol) and ammonium. chloride (0.131 g, 2.44 mmol). The mixture was heated at 127 ° C for 21 hours. The cooled solution was poured into ice water (400 ml) and acidified to pH 2 with 6N hydrochloric acid. The mixture was filtered and the precipitate was recrystallized from 2-methoxyethanol to give the title compound (0.06 g, 10%), m.p. 274-277 °.

Example 12 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one (Example illustrates a one-step process) 2-n-propoxybenzamidine (1.00 g, 5.61 mmol) To a cooled (ice bath) solution of dry N, N-dimethylformamide (4 mL) was added ethyl ethoxymethylene cyanoacetate (0.94 g, 5.61 mmol). After 2 G minutes, sodium azide (0.447 g, 6.88 m-mole) and ammonium chloride (0.368 g, 6.88 mmol) were added. The ice bath was removed and the mixture was heated in an oil bath (127 °) for 30 hours. The cooled mixture was poured into ice water (400 ml) and acidified with 6N hydrochloric acid. The solid obtained (0.93 g), m.p. 245-248 ° (decomposes), recrystallized from 2-methoxyethanol to give the title compound (0.69 g, 41%), m.p. 256-267 ° (decomposes).

Example 13 2- (2-Isopropoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one (one step process)

Substitution of 2-n-propoxybenzamidine in Example 12 with 2-isopropoxybenzamidine gave the title compound by a similar method. The recrystallized product (38%) had a m.p. 282-283 ° (decomposes).

Example 14 2- (5-Nitro-2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one 2- (2-n-propoxyphenyl) -5- (5- 1H-Tetrazolyl) pyrimidin-4 (3H) -one (1.03 g, 3.46 mmol) is added over 20 minutes to cooled (5 °) 70% nitric acid (1.7 mL, 26.9 mmol) and concentrated to a mixture of sulfuric acid (2 ml). The mixture was allowed to stand at room temperature for 2 hours. The mixture was poured into ice water (200 ml). The precipitate was recrystallized from 2-methoxymethanol to give the title compound (0.73 g, 61.3%), m.p. 251-252 ° (decomp.).

Analysis calculated for C 18 H 28 N 2 O 2: C 48.98 H 3.82 N 28.56 Found: C 48.76 H 3.71 N 28.47.

Example 15.

2- (5-amino-2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one 2- (5-nitro-2-n-propoxyphenyl) -5- ( A mixture of 5-1H-tetrazolyl) -pyrimidin-4 (3H) -one (5.0 g) and 10% palladium on carbon (4.0 g) in 2-methoxyethanol (900 ml) was shaken under hydrogen gas for 2 hours. at a pressure of 3.5 kg / cm for 19 hours. The mixture was filtered and the filtrate evaporated to dryness to give the title compound (3.6 g, 79%), m.p. 250-253 ° (decomposes). Recrystallization from 2-methoxyethanol gave the analytically pure product, m.p. 261-262 °.

Analysis calculated for C 24 H 24 N 2 O 2 • 2 H • 4.83 Found: C, 53.92 H 5.041.

50 6 2 5 3 3

Example 16 m (t- * n ι * ι i 2- (5-dimethylamino-s'2 «nT'propoxyphenyl) * -5 ^ (S, 1H-tetrat-11 * i 19 1 f 1 Ml H'T I Ι · Ι '1 III ^ I * ^' 1 I 1 '<f «' ITI" Il I · η 'Ψ »ν · Ψ ί <II' 1 1 '1»' solyl) pyrimidine ^ 4 (3H- ^ onion to a suspension of 2- (5-amino * -2-n-propoxyphenyl) -5 - [(5H-tetrazosyl) pyrimidin-4 (3H) -one (0.50 g, 1.6 IOM) in acetonitrile (40 mL) was added 37% formaldehyde in water (1.32 mL, 16.0 mmol), then sodium cyanoborohydride (0.302 g, 4.8 mmol) and glacial acetic acid (1.67 mL) were added. The mixture was cooled to reflux for 3 hours, cooled in an ice bath, and the resulting precipitate was recrystallized from acetonitrile to give the title compound (0.19 g, 35%), mp 258-259 ° C.

Analysis calculated for C 18 H 19 N 7 O 2: C 56.29 H 5.61 N 28.73 Found: C 55.92 H 5.42 N 28.63

Example 17 1 <I I j '9! Sodium salt of 2- (2-n-propoxyphenyl) -5- (5'-tetrazoyl) pyrimidin-4 (3H) -one 2- (2-n-propoxyphenyl) -5- (5-1H- To a slurry of tetrazolyl) pyrimidin-4 (3H) -one (298 mg, 1 mmol) in water (10 mL) was added 1N sodium hydroxide (1 mL). The resulting solution was filtered. The filtrate was evaporated to a smaller volume and acetone was added. The resulting slurry was stirred for 20 minutes. The sodium salt was filtered, washed with acetone, dried and left to stand freely in air for a week.

Analysis calculated for C 12 H 12 N 3 NaCl 2 * 2H 2 O: C 47.19 H 4.81 N 23.59 H 2 O 10.11 Found: C 47.37 H 4.55 N 24.54 H 2 O 11.70 si 62533 Using the above in the present process, instead of 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4- (3H) one, an equimolar amount of something else is prepared from the compounds prepared in Examples 1, 3-11 and 13-17. 5- (5-1H-Tetrazolyl) pyrimidin-4 (3H) one gives the corresponding sodium salt of each of the above compounds.

By using another base instead of sodium hydroxide in the above method, e.g. KOH, Ca (OH) 2, Mg (OH> 2 or NH 2 UH), the corresponding base salts are obtained.

The 5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one compounds prepared in Examples 1-17 can be converted to the acid addition salts of the desired pyrimidin-4 (3H) -one compound by adding a stoichiometrically equivalent amount of a suitable acid to the methanol solution, e.g. HCl. , HBr, HJ, CH3C00H or H3PO4.

Example 18 2- (2-n-Propoxyphenyl) -5- (5-ΙΗ-tetrazolyl) pyrimidin-4 (311) -one ethanolamine salt monohydrate

Freshly distilled ethanolamine (141.6 g, 2.32 moles) was added with stirring to micronized 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one (671.4 g). , 2.25 moles) in a suspension in distilled water (7 L). Stirring was continued at 40 ° until almost all had dissolved. The mixture was filtered and the filtrate was lyophilized to give the title compound (831.4 g, 98%), m.p. 145-148 °.

Analysis calculated for C 20 H 18 N 2 O 2 .C 2 H 7 NO .H 2 O: C 50.92 H 6.14 N 25.98 H 2 O 4.77 Found: C 50.71 H 6.09 N 26.18 H 2 O 5.64 .

Example 19 2- (2-n-Propoxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one ethylenediamine salt dihydrate

Ethylenediamine (0.625 g, 0.0104 mol) was added to 2- (2-n-propoxyphenyl) -5- (5-ΙΗ-tetrazolyl) pyrimidin-4 (3H) -one (2.98 g, 0.010 mol) to the stirred mixture. suspension in water (30 ml). Gentle heating caused everything to dissolve. The solution was lyophilized to give the title compound in quantitative yield, m.p. 177-180 ° and was allowed to reach equilibrium with air humidity for a month.

52 62533

Analysis calculated for C 14 H 14 N 6 O 2. C 2 H 9 N 2 · 2H 2 O: C 48.72 H 6.64 N 28.41 H 2 O 9.13 found: C 48.98 H 6.21 N 29.25 H 2 O 8.75.

Example 20

Following the general procedure of Example 19 but substituting diethanolamine, triethanolamine and tris (hydroxymethyl) aminomethane for the ethanolamine used therein, the following 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) -pyrimidin-4 (3H ) -one water-soluble salts: diethanolamine salt · ^ 4 ^ 11 ^ 2 'SP * 138 + 3 ° triethanolamine salt C14H2N2O22.CgH1 & NO3, m.p. 146-199 ° tris (hydroxymethyl

the aminomethane salt C-, ..H-, hNcn „„ --. is mcO

14 14 8 2 * ^ 4H11NO3 'sP * 180-198 · Using 2- (2-n-propoxyphenyl) -5- (5-1H-tetrazolyl) -pyrimidin-4 (3H) -one instead of 2- (2-n-propoxyphenyl) in the methods of Examples 19-21 an equimolar amount of any of the 5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one compounds prepared in Examples 1, 3-11 and 13-17 gives the corresponding salt of each of said compounds.

Example 21 2- (2-n-Pentyloxyphenyl) -5- (5-1H-tetrazolyl) pyrimidin-4 (3H) -one Solution of ethyl ethoxymethylene cyanoacetate (24.6 g, 0.145 mol) in N, N-dimethylformamide (DMF, 50 mL) was added dropwise over 10 min. during stirring and cooling (ice / water mixture) to a solution of 2-n-pentyloxybenzamidine (30.0 g, 0.145 mol) in DMF (70ml). Stirring was continued while further cooling the mixture for 20 min. after which time sodium azide (11.5 g, 0.178 mol) and ammonium chloride (9.5 g, 0.178 mol) were added to the mixture. The mixture was heated for 24 hours. in an oil bath at 123-127 ° C. The mixture was poured into cold water and acidified with concentrated hydrochloric acid (50ml). The solid was collected and recrystallized from 2-methoxyethanol to give the title compound (18.1 g, 38%), m.p. 236-238 ° C (dec.). Recrystallization from 2-methoxyethanol followed by 2-propanol gave colorless needles, mp 236-238 ° C (dec.).

Analysis: Calculated for C 18 H 18 N 2 O 2: C 58.88 H 5.56 N 25.75 Found C 58.77 H 5.69 N 25.55

Claims (2)

53 6 2 5 3 3 1. A process for the preparation of 2-phenyl-5- (5-1H-tetrazolyl) pyrimidin-4- (3H) -one derivatives of the formula I and their pharmaceutically acceptable salts, which inhibit allergic reactions, 0 N_N r2 (I ) wherein R 1 is hydrogen, C 1 -C 6 alkoxy, cyclo- (lower) alkyloxy 2 (lower) alkoxy or (lower) alkenyloxy and R is hydrogen, C 1 -C 6 alkoxy, nitro, amino or di (lower) alkylamino, characterized in that the substituted benzamidine of the formula NH R2 I XX "· 1 2 in which R and R have the same meaning as above and the ethyl ethoxymethylene cyanoacetate of the formula C2H5 ° 2C The reaction is carried out in an inert organic solvent with an equimolar amount of sodium azide and ammonium chloride, and, if desired, the compound thus obtained is converted into the corresponding pharmaceutically acceptable salt. A process according to claim 1, characterized in that preparing a compound of formula 1 wherein R 1 is methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, allyloxy or cyclopropylmethoxy, and R is hydrogen, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec, -butoxy, amino, nitro or dimethylamino, or pharmaceutically acceptable salts thereof. Process according to Claim 1, characterized in that 2- (2-n-propoxyphenyl) -5r (5-1H-tetrazolyl) -pyrimidin-4 (3H) one, or a pharmaceutically acceptable salt thereof, is prepared. Process according to Claim 3, characterized in that the sodium salt of the compound of the formula I is prepared. Process according to Claim 3, characterized in that an ethanolamine salt of a compound of the formula I is prepared. Process according to Claim 3, characterized in that an ethylenediamine salt of a compound of the formula I is prepared. 55 Patentkrav 625 33 A compound for the further preparation of an allergic reaction with 2-phenyl-5 - ((5H-1H-tetrazolyl) pyrimidine-4- (3H) -derivates of formula I, which is a pharmaceutically acceptable salt, and N-'N XA J (I) i flash formula C 1 -C 6 alkoxy, C 1 -C 6 alkoxy, C 1-6 alkyl, (alkoxy) or (alk) alkenyl-Oxy and formula, C 1 -C 6 alkoxy, nitro, amino or di (alkyl) alkylamino, on the other hand, with the addition of benzamide with NH-NH NH2 A (VII> 1 2 color R and R is an anhydrous betehyde, and ethyl ethoxymethylene cyanoacetate with the formula C0H_0, C CN 2 5 2 C2H50 / ^ i and inert organic solvents with an equimolar amount of sodium azide and ammonium chloride, and if the self-contained manure are present in a suitable form for the use of a pharmaceutical formulation site.