JPS5818363A - Heterocyclic substituted aminopyrazolines and use as drug - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION It, U.S. Patent No. 4,1 by Hide Battisti
No. 49,005 (dated April 10, 1979), in the formula, R is H or Or (, X is HlBr, C
I is an alkyl, alkoxy or carboxyalkyl group of 1-41+5 carbon atoms or Or8; and n is 1 or 2. These products are made of 1-phenyl-3-aminopyrazole as a coupling component when producing azo dyes.
It has been clarified that it can be used as an intermediate for

Related foreign % photo 2 German patent application publication details 2
, 72 Otsu No. 706: French Patent No. 9-2, 355.834; British Patent No. 1,515
, 500/j; Belgian Patent No. 855.944; Dutch Patent No. 7,70 to 760 and Japanese Patent No. 2
No. 8,168.

G. A. Higgs et al. (Wellcome Rea
searchLaboratories): Bioc
Chemical Pharmacology.

28 1959 (1979) is 6-amino-1-[m~
(trifluoromethyl)phenyl]-2-pyrazoline (
BW 7550): This compound has been reported to have anti-inflammatory activity.

The present invention relates to pyrazolines which have pharmaceutical activity and are represented by the following general formula: 10 = A where A is a group, R8 is
-tolyl; and R8 is -00-R, where R4 is 0. -04 is alkyl; or where A is a group, R6 and R6 are the same or different and H,01,
F, 0. ~0. Full Kill, -OF.

or 0OOFs, 11-, R5 is H or 01-c4 alkyl; R9 is H,0□-0. and FLB is 10HO1-000FII or 100R8, where R8 is 0. ~04 is alkyl; alternatively, A is a group R9 in which Ro and rt. are the same or different, and are ■ or halogen, provided that both cannot be H, then R1 is H or O1-C4 alkyl12-; R1 is 0. ~0. In the alkyl, phenyl or group formula, R11 and Rlt are the same or different, H%
Halogen or 0. ~04 alkyl, but they cannot both be H. , and R3 is H; or A is a group, J, and R84 are HlOlf, or F, then R1 and R1 are H or 0. ~0°7/l
/kyl; and R1 is 01-04 alkyl, 0)
or when A is a group; Ro is H or 01-C, alkyl; R9 is C1-C, alkyl or phenyl; and R8 is H; Or, in the radical formula of A, 2 is N or OH, and R4 is H, halogen or 0.-0.alkyl, then R and R9 are the same or different (rjt)
, H, O, ~04 alkyl, phenyl, or 14-substituted phenyl; and R, is H, provided that when both R□ and R1 are H, A further represents fIJ' flucoquine, di Hello Mojiku Hanitoro,
or (2) the group or -I-, the heterocycle described above can be a methyl-substituted heterocycle; or where A is a group 15, J is Hlo , ~C, alkyl, HO, 0-1O
L(,0-1-000F, or phenyl, R, is H or 01-0.alkyl; R1 is H, 0,-0, alkyl, phenyl, or , and R18 are the same or different, H1
Halogen or 0□~0. alkyl, but they cannot both be H; and R, is H; or if A is 16, X is herogen or =OF, then R, and R8 is H or O, ~04 alkyl;
And R8 is 1000H or 10HO.

The above compounds are all active as anti-inflammatory agents, analgesics or as anti-bacterial agents and bactericidal agents, in which case they are active in one or more of this range α. Furthermore, compounds of the present invention are useful in inhibiting the progression of arthritis, such as rheumatoid arthritis, inhibiting deterioration of joints, or preventing the onset of asthma and other allergic diseases. It has also been found that the present compounds are effective in improving or preventing pathological reactions such as osteoarthritis, gout, acute synovitis, and dry feeding. The invention includes pharmaceutical compositions comprising a compound of the invention as an active ingredient.

Further, the present invention has the formula (■): 17, in which R is 0. -0. alkyl; R and R1 are hydrogen or OI to 0. alkyl; and X is a herogen. It has been found to be highly useful for drug therapy when administered in amounts in the range of . Preferred dosages for optimal results are from about 5 to about 100 mg/day of body weight, such dosage units containing about 0.359 to about 0.359 to about 90 mg/day of total active ingredient for a patient of about 70 cm. 7.0 g is 2
Used to be administered within 4 hours. The dosage of 18- above can be adjusted to obtain the optimal therapeutic response. For example, several divided doses may be administered during the day, or the dosage may be reduced proportionately, as indicated by the exigencies of the therapeutic situation. A clear practical advantage of the present invention is that all of the active ingredients can be administered in any convenient manner, eg, orally, parenterally, or by the interstitial route. Of course, the active ingredients can also be administered by inhalation to treat asthma and allergy anti-Lδ.

The compounds according to the present invention having the desired clarity, stability and suitability for parenteral use contain the active compounds 010-100 in a vehicle consisting of half aliphatic alcohol or mixtures thereof. Obtained by dissolving the amount%. Glycerin, propylene glycol and polyethylene glycol are particularly preferred. Polyethylene glycol consists of a mixture of non-volatile, normally liquid polyethylene glycols that are compatible with both water and organic liquids and have a molecular weight of about 200-1500.

The amount of active compound dissolved in the above excipients is between 0.1 and 10.
．． Although it can range from 0% by weight, it is preferred that the amount of active compound used is from about 30% to about 90% by weight. Various mixtures of the non-volatile flexible polyethylene golicols described above may be used, with average molecular weights ranging from about 200 to about 4.
Preference is given to using a mixture having 0.00.

In addition to the active compound, parenteral solutions can also contain various preservatives, which can be used to protect against bacterial and fungal contamination. In practice it is also advantageous to use antioxidants. Generally, antioxidant concentrations of about 0.05% to about 0.2% are used.

For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.501 n9 per 1 of the final composition.

The compounds of the invention are suitable for intravenous administration as well as for intravenous administration when diluted in appropriate amounts with water or diluents used in intravenous therapy. For intrastatic pancreatic applications, the active injection compound approx.
It is preferred to reduce the initial concentration to ~0.251 ng/-.

The active compounds of the invention can be administered orally, for example, with an inert diluent or an assimilable edible carrier.

These can be enclosed in hard or soft gelatin capsules, compressed into tablets, or incorporated directly into food. For oral therapeutic administration, the active compound can be formulated with excipients and presented in tablets, troches,
It can be used as capsules, elixirs, suspensions, syrups, wafers, etc. Take/fill IE
Products and preparations should contain at least 0.1% of active compound. The percentages of the compositions and preparations can vary and range from about 2 to about 60% by weight of the units. Kagaru therapeutically useful p44 set 1 to 2
The amount of active ingredient administered is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the invention contain about 50 to 250 m9 of active compound in oral dosage unit form.
K # jt T so that it contains.

Tablets, troches, pills, capsules, etc. may also contain: binders; excipients; disintegration; lubricants; and sweetening or flavoring agents.

When the dosage unit form is a capsule, it can also contain a liquid carrier such as a fatty oil. Various other materials may be present as coatings or agents that modify the physical form of the dosage unit. The syrup or elixir can also contain dyes. All materials used in preparing all dosage unit forms should be pharmaceutically pure and practically non-toxic in the amounts used.

For multi-person routes, the active 22-component in a suitable form, eg a powder or solution with a suitable pharmaceutical carrier, can be used in an inhaler.

The production of the compound of the present invention exhibiting the above-mentioned medicinal properties is l1u.
ffin, G.E', and Kendall, J.D.
,,J.

Ohem, Soe, 1954, gd+ in 408
This is done by applying the tili method. The invention is illustrated by the following examples.

28 g of sodium metal was dissolved in 125 g of absolute ethanol, and then 21.29 g of m-)lifluoromethylphenylhydrazine hydrochloride was added, followed by 5.5 g of acrylonitrile. The solvent was removed in vacuo and water was added to give a sticky solid. This solid was poured into dichloromethane. The solution was dried over anhydrous magnesium sulfate and passed through a short column of anhydrous magnesium butyrate. The eluent was collected and condensed to separate yellow-brown crystals. This material was recrystallized from acetone-hexitine with a melting point of 104-105
Desired formation as light yellow needles of 'c'19/J14.
I got 8 shi.

Practical υ0Σ1 Nri 2 Dissolve 07 of sodium purine metal in 650 of absolute ethanol, gradually add 569 of m-trifluorometherphenyllehydrazine hydrochloride, and then gradually add 9 of methacrylonitrile 1,79.
I blurted it out. The reaction mixture was refluxed for 18 hours and a solid was obtained by overriding the procedure of Example 1.

This solid was recrystallized from ether-hexane and r”)i
Desired generation @'9/J 3.6'; Obtained l. 209 mg of this product was recrystallized again from ether-hexane to give 138'''9 white crystals with a melting point of 69-70°C.

1]3 Lazolin A solid was obtained according to the method of Example 2, replacing methacrylonitrile 179 with cinnamonitrile 6.2. This solid was recrystallized from ether-hexane to give the desired product 4,
3g was obtained. This raw material, 200 parts, is reheated into ether.
Recrystallization from hexane gave the product as white needles with a melting point of 124-125°C.

Example 4 Sodium metal 289 was dissolved in anhydrous ethanol 125 and m-trifluorometherphenylhy25 = drazine hydrochloride 2129, then crotononitrile 6,7
The reaction mixture was refluxed for 6 hours.

The solvent was removed under JlGl air and water was added to separate an orange oil. This oil was dissolved in dichloromethane. The organic solution was washed with water and dried over anhydrous magnesium sulfate. Evaporate this to obtain a light orange oil. This oil was dissolved in dichloromethane and lN41'1! Extracted with. The aqueous solution was washed once with dichloromethane and then made basic to separate the dark brown oil. This oil was dissolved in dichloromethane. The orange solution was washed, dried over anhydrous magnesium sulfate, filtered and evaporated to give 8.59 of a pale yellow solid.

This solid was recrystallized three times from acetone-hexitine to yield the desired product as yellow crystals with a magnetic field of 61-63'C.

Example 5 145 g of 26-trifluoro-m-)lyl)-2-pyrazoline metal sodium was dissolved in 75 vt of absolute ethanol,
m-) Lifluoromethylphenylhydrazine hydrochloride 10
Then 4.09 g of α-methylcrotononitrile was added. The reaction mixture was refluxed for 18 hours and then the procedure of Example 1 was continued to give an orange oil which was partially crystallized. This mixture was heated to give chitin. The solution was cooled and seeded. The resulting crystals were collected and washed with cold hexane to obtain 5.49 pale yellow crystals.

300 μl of the crude product was recrystallized from hexane, melting point 7.
Desired product as white crystals at 9-80°C 200”9
I got it.

Example 6 2.09 ml of sodium metal was added to 100 tnl of absolute ethanol
40.0-1 of phenylhydrazine and 260-1 of theacrylonitrile were added. The reaction mixture was refluxed for 6 hours, resulting in exothermic crystallization of the product. The product was collected by filtration and washed with 95% ethanol. This material was recrystallized from dichloromethane-hexane to yield the desired product*43 as a solid with a melting point of 168-1705°C.
．． I got 69.

Example 7 Acid acid 3-amino-1-phenyl-2-pyrazoline (Example 6
) 2.09 was dissolved in concentrated hydrochloric acid 15- and then poured into anhydrous ethyl ether to crystallize the product. The product was collected by one filtration and recrystallized from acetone-hexane to yield the desired product as a white solid with a melting point of 94-96°C.
I got a 9.

Example 8 2.09 ml of pyrazoline gold 114 potassium was dissolved in 200 ml of absolute ethanol, 32.49 ml of phenylhydrazine in 5 ml of ethanol was added over 10 minutes, followed by 201 g of crotononitrile. The reaction mixture was refluxed for 5 hours. Most of the ethanol was removed under vacuum, water was added and the product was collected by filtration. The solid was dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The column eluent was refluxed on a steam bath with gradual addition of hexane to crystallize the product. The product was collected and recrystallized from acetone-hexane to yield product 269q of this example as colorless prismatic crystals with a melting point of 1035-106°C.

Example 9 Pyrazoline 29 - 2.09 g of sodium metal was dissolved in 200 g of absolute ethanol, 674 g of phenylhydrazine was added over 10 minutes, and then 201 g of methacrylonitrile was added. The reaction mixture was refluxed for 4 hours and then brought to near dryness under vacuum F. Water was added to the residue and the oil was separated. This oil crystallized upon standing.

This solid was dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate.

The column eluent was evaporated to give an oil. This oil was crystallized from acetone-hexitine and then recrystallized from the same solvent to give the desired product 2088 as colorless crystals, mp 83-84°C.

Example 10 3-Amino-4-methyl-1-phenyl-2-pyrazoline (Example 9) 6.09 and 60-120 of methyl iocodide were heated in a reflux oven for 2 hours. The reaction mixture was cooled and filtered to collect 112 grams of Japanese product. this(
F8 solution of Matsushima in water, recrystallized from 95% ethanol,
The product of this example, 4.59, was obtained as colorless needles with a melting point of 1685-170''C.

Example 11 Sodium metal 209 was dissolved in 150 ml of absolute ethanol, then 40.0 ml of phenylhydrazine was added over 5 minutes, and then 480 ml of phenylhydrazine was added. anti [6
The mixture was refluxed for 3 hours, resulting in exothermic crystallization of the product. The product was collected by filtration and washed with water. This material was recrystallized from absolute ethanol with a melting point of 195-19
56.09 of the desired product was obtained as a 7"c solid.

Example 12 5-amino-1-phenyl-5-p-tolyl-dissolve 1.09 of sodium metal in 100 of absolute ethanol, add 200 of phenylhydrazine for 5 minutes, then (mixed ance and trans) 4-Methylcinnamonitrile24.
0- was added. The reaction mixture was refluxed for 4 hours, then cooled. The precipitate was collected by filtration, treated with activated carbon, and then recrystallized from acetone-hexitine, melting point 165-1.
Desired product 14 as pale orange needles at 665 °C
．． I got 259.

Example 13 2.89% of sodium metal was dissolved in 150% of absolute ethanol, and then 15% of p-methylphenylhydrazine hydrochloride was added.
．． 86 g over 5 minutes followed by 5.5 g of acrylonitrile.
5 g was added. The reaction mixture was refluxed for 18 hours and evaporated to dryness under vacuum. Water was added and the solid that separated was collected by filtration. Dissolve this solid in dichloromethane and
Passed through a short column of hydrous magnesium silicate. The eluent was refluxed with gradual addition of hexane to separate the crystalline product. The entire crystallization process was repeated to obtain product 6.4 of this example as colorless platelets with a melting point of 142-143°C.

Example 14 3-Amino-1,5-diphenyl-2-pyrazoline (Example 11) 509 and trifluoroacetic anhydride 20 were heated until they went into solution. The reaction mixture was allowed to stand for 30 minutes and then the precipitate was filtered off. Solution f was allowed to stand for 15 hours, and the precipitate that settled was collected and dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The eluent was evaporated to dryness under vacuum. The residue was poured into acetone and refluxed with gradual addition of hexane until crystallization occurred. The mixture was cooled and filtered as yellow needles.
2.2-)lifluoro-N-[5-phenyl-1-(
5.39 g of p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide was obtained.

The above product 559, acetone 1oJ, water 100-
and 5.09 g of powdered potassium hydroxide was refluxed for 1.5 hours. The reaction mixture was evaporated to dryness under vacuum. Water was added to the residue, the mixture was extracted with dichloromethane,
Acidification with 5% hydrochloric acid produced a precipitate, which was collected by filtration and dried.

The solid was treated with ammonium hydroxide and activated carbon, filtered through a sieve. The P solution is made acidic with acetic acid, and the melting point is 245-248.
The raw 34-acid 023 of this example was obtained as a yellow solid at 10°C.

Example 15 2.2-Trifluoro-N-(5-phenyl-1-1p-trifluoroacetylphenyl)-2-pyrazolin-6-yl]acetamide (in Example 14) in 100 mal of tophenonemethanol What was left behind by the weir as described) 10
The solution of g was saturated with ammonia gas and then stored in the refrigerator for 16 hours. The solution was evaporated to dryness under vacuum. The residue was dissolved in acetone:hechitin 5 using silica gel.
The product was subjected to preparative column chromatography at a ratio of 0:50 to collect most of the polar product. The product was recrystallized from dichloromethane-hexitine and had a melting point of 2
0.259 of the product of this example was obtained as yellow needles at 14-216°C.

Example 16 Rhoamin-1-(4-biphenylyl)-5-methyl-
5.09 grams of 2-pyrazoline 4-amino-biphenyl was suspended in a stirred solution of 400 grams of concentrated hydrochloric acid and 270 grams of water held at 5'C. Continue stirring and keep the temperature below 10°C.
During this time, a solution of 80 g of sodium nitrate in 1&ml of water was slowly added. The reaction mixture was stirred at 5°C for 15 more minutes and then added slowly to a cold solution (0-5°C) of 530 g of stannous chloride in 530° of concentrated hydrochloric acid. The resulting mixture was diluted with water and treated with a 40% solution of sodium hydroxide until alkaline. The resulting solid was collected by filtration, taken up in dichloromethane, dried over magnesium sulfate, and filtered. The P solution was passed through a short column of hydrous magnesium silicate. The eluent was evaporated in vacuum F to give a solid. This solid was diluted with dichloromethane. The solution was heated to boiling and hexane was added until it became cloudy. The mixture was cooled and filtered, melting point 135-138
5 g of 4-piphenylhydra iyys were obtained as orange crystals at 50°C (min wI).

43 g of the above compound were added to a solution of 0.19 g of sodium metal dissolved in 100 g of absolute ethanol. Then 154 g of crotononitrile were added and the mixture was refluxed for 6 hours and poured into water to separate the dark solid. This solid was collected, dissolved in dichloromethane and heated to boiling while hexane was added until cloudiness occurred. The mixture was cooled and filtered to obtain 3.6 g of product as a solid. The recrystallization process was repeated to obtain the product of this example with a melting point of 174-176°C.

Example 17 57- 6-Amino-5-isopropyl-1-phenyl-2-pyrazoline Isobutyraldehyde 189 in dry benzene 500
A mixture of Caltriphenyl Phosphoranf 509 and Caltriphenyl Phosphoranf 509 was refluxed for 6 hours with stirring under nitrogen. The reaction mixture solvent was removed under vacuum on a water bath maintained at 46-50°C. The solid was separated from P and washed with ether and then hexane.

The 1st solution and the washing solution were combined and concentrated to leave a liquid and a solid. This material was distilled through a Vigreaux column to give 11.059 4-methyl-2-pentenonitrile as a colorless liquid with a boiling point of 70-72°C/45M.
I got it.

0.319 g of sodium metal was dissolved in 150 g of absolute ethanol, and 6.39 g of phenylhydrazine and then 5.5 g of 4-methyl-2-pentenonitrile were added. The reaction mixture was refluxed for 16 hours. Solvent = 68- was removed under vacuum, water was added to the residue and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and evaporated to give a gum. This rubber was chromatographed on a column containing 400 parts of magnesium silicate and 400 parts of magnesium silicate.

The column was first eluted with 21% acetone-hexane and 5% acetone-hexane to remove colored material, then eluted with 25% and 10% acetone-hexane to separate the product. The product fraction was evaporated and a dark colored rubber 2
．． 79 was obtained, which solidified upon standing. This material was recrystallized twice from ether-hexane and had a melting point of 1
Product 17 of this example was obtained as tan crystals at 15-117°C.

Example 18 Acid acid (2°1) 6-amino-1-phenyl-2-pyrazoline (Example 6
) was dissolved in 200 mj of absolute ethanol, and then 4.0 tnt of a 10 W/W% sulfuric acid solution was added with stirring. This anti-161 compound was left at room temperature for 2 hours,
Then it was filtered. The precipitate was refluxed with 100° of acetone, cooled and filtered to give 1.40° of the desired product, melting point 181-183°C.

Example 19 A mixture of 108 g of freshly distilled butyraldehyde, 309 g of malonomonoamide, 251 nt of pyridine and 5 drops of piperazine in a round bottom flask with a capacity of 85
In an oil bath maintained at ~95°C @ flowing down 24) ￥j
1... Heated. This mixture was evaporated to dryness under vacuum. The residue was diluted with 10° of water and 50° with ether trough 504.
Extracted twice. The extracts were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to give a gummy solid. This solid was recrystallized from ether-hexitine, melting point 115~
2-hexenamide 469 as white crystals at 117 °C
I got it.

A mixture of 59 g.
Heated to °C. The mixture was heated to 200°C for 1 hour, then the pressure was reduced to 50°C and heating continued, gradually increasing the pressure to 15°C. The distillate was collected in a flask cooled with dry ice to yield 2-hechitin carbonitrile 279 as a colorless liquid.

0.29 g of sodium metal was dissolved in 100 g of absolute ethanol, 5.19 g of phenylhydrazine, and then 267 g of 2-hexanecarbonitrile were added. The 41-reaction mixture was refluxed for 18 hours and then evaporated to dryness on a vacuum gage. The residue was taken up in dichloromethane @Ml.

The solution was washed with water, dried over anhydrous magnesium Wc acid, passed through a column of hydrous magnesium silicate, and evaporated to dryness under vacuum to give a tan gum. Hexane was added and the rubber solidified.

The sticky solid was collected and dried. This solid was dissolved in ether and concentrated with the addition of hexane, mp 1
Product 639 of this example was obtained as light tan crystals at 18-120°C.

Example 20 2.8 g of sodium metal was dissolved in 100 g of absolute ethanol, 158 g of m-)lylhydrazine hydrochloride, and then 5 g of m-)
99 g of β-ethquin propionitrile was added over a period of minutes. The reaction mixture was refluxed for 16 hours and then evaporated to dryness under vacuum. Water was added and the precipitate was collected by filtration. The solid was dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. The column distillate was refluxed on a steam bath with gradual addition of hexane to crystallize the product. The mixture was cooled and heated to give product 10.1 of this example 1+ll as colorless crystals with a melting point of 119-120°C.

Example 21 3-amino-5-(3,4-dichlorophenyl)-1-
Phenyl-2-pyrazoline gold 1^sodium o, iog in absolute ethanol 25. 〇-, 2.169 g of phenylhydrazine was added, and then 3.969 g of IKK 5.4-dichlorocinnamonitrile was added for 5 minutes. The reaction mixture was refluxed for 5 hours and then evaporated to dryness in vacuo F. The procedure as described in Example 20 is repeated, a second recrystallization is carried out from the same solvent pair and treated with hydrous magnesium silicate, melting point 150-
Desired product 13 as colorless needles of 151.5'C
I got 59.

Example 22 A mixture of absolute ethanol 5QQmj, 50% choline 50- in methanol, phenylhydrazine 32.49 and p-chlorocinnamonitrile 49.089 was refluxed for 7 hours, then left at room temperature for 16 hours and evaporated under vacuum. It was evaporated to dryness. Following the method of Example 21, melting point 1835-18
Product 12 of this example as colorless needles at 5.5°C.
．． I got 09.

Example 23 4.429 grams of sodium metal was dissolved in 300 grams of absolute ethanol, and 27 grams of p-methoxyphenylhydrazine hydrochloride was dissolved.
89 and then cinnamonitrile 20.649 was added over 5 minutes. The reaction mixture was refluxed for 7 hours and then evaporated to dryness under vacuum. Water was added to the residue to form a sludge. The mixture was filtered once and the residue was evaporated to dryness. The solid was dissolved in dichloromethane and crystallized as described in Example 21 to give the desired product 4.759 as colorless needles, mp 1635-166°C.

Example 24 026 g of pyrazoline metal sodium was dissolved in 750 g of absolute ethanol, 10.8 g of phenylhydrazine was added, and then α-
3.69 g of mecalcrotononitrile was added over 5 minutes. The reaction mixture was refluxed for 18 hours and then evaporated to dryness under vacuum. Water was added to form a gum which solidified upon standing for 16 hours. Solid 45- was collected and dissolved in dichloroethane. The procedure of Example 20 was continued to give 186 g of the desired product as light yellow crystals, mp 123-125'C.

Example 25 4'-(3-amino-4-methyl-2-pyrazoline-1
-yl) -2,2,2-trifluoroacetophenone 3-amino-4-methyl-1-phenyl-2-pyrazoline (Example 9) 5.09 was combined with trifluoroacetic anhydride 25- to exothermic reaction. occurred.

The reaction mixture was left at room temperature for 24 hours. The precipitate was collected by filtration, dissolved in dichloromethane and evaporated to dryness under vacuum. The residue was dissolved in dichloromethane and the solution was passed through a short column of hydrous magnesium silicate.

The column eluent was refluxed on a steam bath with gradual addition of hexane to give 46-2,2.2-)lifluoro-N-(6-mete-1 -trifluoroacetyl-2-pyrazolin-3-yl)acetamide 529 crystallized.

2.09 of the above compound in 150° of anhydrous methanol was saturated with ammonia gas at room temperature and then stored in the refrigerator for 16 hours. The reaction mixture was evaporated to dryness under vacuum. The residue was dissolved in dichloromethane and treated with hydrous magnesium silicate and hexane as above to give the crude product 1.6
I got a 9. This material was subjected to preparative column chromatography using silica gel, and acetone:hexane 50%
:50 and the most polar product was collected. This product was recrystallized from dichloromethane:hexane to give 62 g of the product α of this example as orange needles with a melting point of 159-160°C.

Example 26 = 0.6 kg of phenyl-2-pyrazoline metal sodium in anhydrous ethanol 100''Km
14,769 ml of m-chlorophenylhydrazine was added, followed by 1292 ml of cinnamonitrile over 5 minutes. The reaction mixture was refluxed for 6 hours and then cooled in a water bath. The resulting precipitate was collected by filtration and dissolved in dichloromethane.

This solution was passed through a short column of hydrous magnesium silicate. The eluent was heated to reflux on a steam bath and hexane was added until precipitation occurred. The product was collected and recrystallized from dichloromethane to yield 755 g of the product of this example as salmon-colored needles with a melting point of 164-165°C.

Example 27 3-amino-1-C3,4-dichlorophenyl)-2-
Dissolve 2.8 g of sodium pyrazoline metal in 200 g of absolute ethanol, and dissolve 21 g of 3,4-dichlorophenylhydrazine hydrochloride.
．． Add 359, then add 5 acrylonitrile, 59 10
Added in minutes. The reaction mixture was refluxed for 4 hours and most of the ethanol was removed under vacuum. Water was added and a solid separated. This solid was collected by filtration and dried. The solid was dissolved in methanol, treated with activated charcoal, filtered and filtered.

The P liquid was evaporated to obtain a solid. This solid was recrystallized from methanol to give the desired product as tan crystals with a melting point of 182-1835°C.

Example 28 4-Methyl-2-pyrazoline metal sodium 1389 was added to absolute ethanol 150911
K. was dissolved, 81 g of m-fluorophenylhydrazine hydrochloride was added, and then 59 q of methacrylonitrile was added. The reaction mixture was refluxed for 5 hours, 49- then evaporated to dryness under vacuum. Addition of water resulted in a dark semi-solid precipitate. The aqueous phase was decanted, more water was added, and the solids were collected by filtration.

The solid was dissolved in dichloromethane and the solution was passed through a short column of hydrous magnesium butate. The syneresis was evaporated to give an oil. This oil was dissolved in hexane, treated with activated charcoal, filtered and evaporated to give a solid. This solid was recrystallized from hexane to give 0.659 g of the desired product as light orange prismatic crystals with a melting point of 78-80°C.

Example 29 2-pyrazoline metal sodium 1389 was added to 150 dKi of absolute ethanol
@m'L, , m -Add 8.1 g of fluorophenylhydrazine hydrochloride, then add 2.75 g of acrylonitrile.
Q was added over 15 minutes. The reaction mixture was refluxed for 5 hours at 50°C and then evaporated to dryness under vacuum. Water was added and the solid that separated was collected by filtration. The solid was dissolved in dichloromethane and the solution passed through a short column of hydrous magnesium silicate. The eluent was heated to reflux on a steam bath;
Hexane was added to precipitate the product. Collect solids,
Dissolved in acetone, treated with activated carbon and dried.

Addition of hexane to Part 1 gives 2.95% of the product of this example as off-white needles with a melting point of 146-147°C.
g crystallized.

Example 60 According to the method of Example 29, 275 g of acrylonitrile was replaced with cinnamonitrile 6,469, and the melting point was 165 to 1.
Desired product as pale yellow prismatic crystals at 66°C 4.7
I got 59.

Example 61 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline (prepared as described in Example 1 pH 27) 1.652 was dissolved in 50 portions of concentrated hydrochloric acid, then methanol was added and the solvent was evaporated under vacuum. The residue was triturated with ether several times and acetone was added to crystallize the product. The product of this example was collected by one filtration and washed with ether to give 165 as colorless crystals, mp 170-175'C (decomposed).

Example 62 248 g of sodium methylate was dissolved in a solution of 8289 methanol diluted with 102 parts of N,N-dimethylformamide. This solution was poured through a droplet funnel into a stirred solution of 150 ml of N,N-dimethylborumamide, 200 g of dimethylcyanometerbosphonate and 70.09 g of propionaldehyde, cooled to 40-45°C in a water bath. added to the solution. After the addition is complete, heat the mixture to 50°C.
Stirring was continued for 1 hour without further warming or cooling.

The reaction mixture was a 50:50 mixture of methane-)v:water.
0- and then the pH value of the solution was adjusted to ZO with glacial acetic acid. The neutral solution was extracted with a large amount of ether, and the combined ether extracts were backwashed with water. The organic solution was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo F to give an oil. This oil was distilled through a column packed with 24-inch saddles, boiling point 50'C/9-10
When heated (oil bath temperature 135-145°C), a colorless liquid was obtained. The crude product was dissolved in ether and washed 6 times with water.

The organic solvent was evaporated under vacuum to give 53- as a colorless liquid. 26.09 of the desired product was obtained.

Example 55 To 50 Qlnt of freshly distilled hot benzene were added 14.3 g of valeraldehyde and 500 q of (triphalphosphoranylidene)acetonitrile.

The stirred mixture was heated to reflux under nitrogen for 6 hours and then left at room temperature for 48 hours. The reaction mixture was washed twice with 100ml each of 5% sodium sulfate, followed by 5% sodium bicarbonate and water. The solution was dried over anhydrous magnesium sulfate and then evaporated to dryness leaving a solid and a thin oil. The solids were extracted several times with hexane. I combined the liquid~
The xane extract was heated at 25-60° under reduced pressure (160 m).
Distilled at a temperature of 70-75 °C/17
- and collected 12.6 g of the desired product as a colorless liquid nD 1.4382.

-54 = Example 34 A mixture of 340 g of dimethylamine hydrochloride, 31.89 g of 37% formaldehyde and 350 g of n-hexanal was stirred at 70°C for 24 hours. The reaction mixture was then steam distilled for 3 hours. The organic distillate was dried over anhydrous magnesium sulfate and filtered to give the desired product 6 as a colorless liquid.
I got 179.

Example 35 To 135.2 g of xyamine trifluoroacetic anhydride was added 140 g of hydroxylamine salt. The mixture was refluxed for 2 hours and then cooled. Excess amount of reaction solvent was removed, and the residue was diluted with hegisan for 2 portions.

The organic solvent was removed under vacuum. The product was recrystallized from dichloromethane to give the desired product 35.4 t as white crystals of 59-60'C (sublimation). The product was stored dry in a vacuum tin booter.

Example 66 To 500 fnl of ti-benzene were added 62.0% of 2-methylene hexacal (Example 34), 96% of pyridine, and 35.09% of N,0-bis(trifluoroacetyl)hydroxylamine (Example 55). Ta.

The reaction mixture was refluxed for 3 hours and then cooled.

This solution was washed six times with saturated sodium chloride, each 50-
It was dried over anhydrous magnesium sulfate, filtered and filtered. f
The solution 5 was concentrated under vacuum on a water bath maintained at 40-50°C. This rubber is distilled in a Vigreux column and has a boiling point of 7.
The 2-76°C 150mm fraction was collected to give 3.89% of the desired product as a colorless liquid.

Examples 67-6B Additional 3-amino-1-halogenated phenyl-2-pyrazoline compounds shown in Table 1 were prepared in the following general manner. At this time, 01 mol of sodium 2+ metal was dissolved in absolute ethanol (50-200 vnl). To this solution was added the appropriate hydrazine salt or free base (01 mol). The warp mixture was refluxed (4-20 hours) after which the solvent was removed under vacuum. Addition of water produced a filtrate solid, which was dissolved in dichloromethane. This solution is passed through an adsorbent column to remove impurities,
The eluate was then refluxed with gradual addition of ~gisan until crystallization was observed. Recrystallization from the same solvent pair (with or without other adsorption processes) or from acetone-hexitine and/or ether-hexitine afforded the desired product.

57- Example 69 3-Amino-1-(p-fluorophenyl)-5-mecal-2-pyrazoline (prepared as described in Example 51) 4.09, 250 water and 10 fn concentrated sulfuric acid
The mixed proboscis of t was refluxed for 6 hours. Cool this mixture and
The precipitate was collected and the solid was recrystallized first from acetone-hexane and then from acetone to give a melt of 4164.5-166
The desired product @ 1.09 was obtained as prismatic crystals at 5°C.

Example 70 3-amino-1-(3,4-dichlorophenyl)-5-
A precipitate formed immediately from a mixture of 10 g of methyl-2-pyrazoline (manufactured by JR as described in Example 45), 10 and 65 of water, and 05 of concentrated sulfuric acid.

The precipitate was collected and washed with dichloromethane. This material was then recrystallized from acetone-hexitine, melting point 160.
Desired product 060 as prismatic crystals at 5-163 °C
I got g.

Example 71: 2,4-dichlorohydrazine (prepared from 2,4-dichlorohydrazine hydrochloride by treatment with 1N sodium hydroxide) 789, crotononitrile 299 and 3 drops of choline (45% in methanol) The mixture was heated on a steam bath for 18 hours. This solution was mixed with 2001 rLt of water and then made basic with concentrated hydrochloric acid 204 and 10% sodium hydroxide to yield a gummy solid. This solid was loaded into a chromatography column containing a 200 mesh synthetic buoy containing 300 ml of magnesium oxide nitrogen absorbent. The column was eluted with 1% acetone-hexane, 5% acetone-hexane, and 10% acetone-hexane to remove most of the less polar materials. The separation process was monitored by thin layer chromatography using the upper phase of a mixture of 2 parts benzene, 1 part acetone and 2 parts water; the column was then filled with acetone to give the crude product as a dark oil. When I removed it and left it unattended, some parts came out. This material was rechromatographed using magnesium silicate adsorbent (200%) to elute visible impurities with 5% acetone-hexane. The column was then eluted with 50% acetone-hexane to collect a tan oil that solidified on standing. This solid was recrystallized three times from ether to chitin,
5 g of the product α of this example was obtained as yellow-brown crystals with a melting point of 109-111°C.

Example 72 0.589 g of sodium monopyridine metal was dissolved in 150 g of absolute ethanol, 140 g of 2-hydrazinopyridine was added, and then 127 g of β-ethoxypropionitrile was added. The reaction mixture was refluxed on a steam bath for 16 hours, then the solvent was removed under vacuum. Water was added and the solids were collected by filtration. The solid was recrystallized twice from acetone, melting point 1685~
Product 55 of this example as tan crystals of 171'C
I got 5 points.

EXAMPLE 73 A mixture of 100 g of 2,6-dichloropyridine in hydrazine hydrate 200 was stirred and refluxed for 5 hours. The mixture was cooled, filtered and filtered. The product was washed with water, dried and converted into 2-
417 g of chloro-6-hydrazinopyridine was obtained.

0.329 ml of sodium metal to 1 oz. of absolute ethanol.

- and 100 g of the product of Example 72 were added, followed by 40 g of acrylonitrile. The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added to the residue to separate the solids. The solid was collected by filtration, dissolved in dichloromethane, dried over magnesium sulfate,
It was filtered through magnesium silicate and concentrated with the addition of hexane to separate the crystals. Cool this mixture and
As a result, 95 g of the product of this example was obtained as a pale yellow solid with a melting point of 143-145°C.

Example 74 A mixture of 16.1 2,5-dichloropyridine, P in 69--2-pyrazoline hydrazine hydrate 52 me was stirred and refluxed for 15 hours. The reaction mixture was cooled and water was added. The precipitate was collected by filtration, washed with water and dried, melting point 127-1
5-chloro-2-hydrazinopyridine 127I was obtained as a white solid at 28°C.

Sodium o, o a g was dissolved in 1° of absolute ethanol, and 5-chloro-2-hydrazinopyridi>2.
5,1it1 then β-ethoxypropionitrile1,
70 II was added. The method of Example 72 was carried out to obtain a melting point of 2.
1.40 g of the product of this example was obtained as yellow crystals at 03-204.5°C.

Example 75 As in Example 73, metallic sodium 0.3270-I was dissolved in 100+ml of absolute ethanol, 100 g of 2-po-6-hydrazinopyridine was added, and then methacrylonitrile 489 was added in place of acrylonitrile. added. Following the method of Example 76, crude product 9.4.9 was obtained. This material was recrystallized from dichloromethane-hexane to give the product of this example as pale yellow crystals with a melting point of 175-176°C.

Example 76 As in Example 75, 02 g of sodium metal was dissolved in 501 d of absolute ethanol, 5.0.9 g of 5-chloro-2-hydrazinopyridine (Example 74) was added, and then 4.0 g of methacrylonitrile was added. Added 8g.

The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added resulting in a gum that solidified.

This solid was collected by filtration and washed with water.

This solid was dissolved in dichloromethane, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The p-liquid was evaporated and the residue was triturated with hexane to give a brown solid. This solid was dissolved in dichloromethane and hexane was added while concentrating to separate the solid. The mixture was cooled and filtered to give a gray solid 3.4, ? I got it.

The desired product was recrystallized from dichloromethane-hexane to give a white solid with a melting point of 159-160°C.

Example 77 Sodium metal 0.3 g @ absolute ethanol 100-
and add 545g of 2-hydrazinopyridine,
Then 3.359 g of crotononitrile (mixture of cis or trans isomers) was added. The reaction mixture was refluxed for 6 hours, then the solvent was removed under vacuum. Add water;
The solid content was collected by filtration. This solid was recrystallized from dichloromethane-hexane and then from a7ton-hexane to give product 3.1.9 of this example as yellow crystals with a melting point of 154-157°C.

Example 78 Kinko sodium 023y was dissolved in anhydrous ethanol 7576--, and 2-chloro0-6-hydrazinopyridine 7,
After 21 s, the residual crotononitrile 34I/ was added. The reaction mixture was refluxed for 18 hours and passed through an anhydrous siliceous magnesium filtration step according to the method of Example 76. Evaporation of the p-liquid yielded a dark orange gum which crystallized on standing.

The residue was dissolved in needles, treated with activated carbon and filtered through diatomaceous earth. The p solution was concentrated under reflux without adding hexane to obtain an oil. The oil was seeded and cooled. Ether was added and cooling continued to give light yellow crystals. The mixture was filtered, melting point 105-107°C.
52 g of the desired product were obtained as pale yellow crystals.

Example 79 Sodium 74 dissolved in 50 tnl of absolute ethanol
- Ao, 20. A mixture of 50 g. According to the method of Example 76, the borderline magnesium p liquid was evaporated to obtain a yellow rubber. Disintegration with hexane gave a yellow solid. This solid was dissolved in dichloromethane. The solution was concentrated by heating on a steam bath without the addition of hexane, then cooled in a refrigerator and the product of this example 3,51 was isolated as pale yellow crystals with a melting point of 168-170°C. .

Example 80 2,6-dichloropyrazine 4 in warm methanol 150
5Ii was slowly treated with hydrazine (95+%) 30-. The mixture was refluxed for 2 hours and then evaporated under vacuum. The sapon was shaken with 200 ml of water and filtered. The precipitate was washed with water and air dried to give the crude product 33
0 g of this product 709 was recrystallized from ethanol 100 cooled to -10°C. The face piece was collected, washed with ether, dried under a violet at room temperature, and had a melting point of 136.
2-chloro-6-hydrazinopyrazine at ~137°C2.
I got 8.9.

060g of metallic sodium in absolute ethanol 100+yf
672 g of 2-chloro-6-hydrazinopyrazine (prepared as described above) was added to the solution, and after 5 minutes,
4.6 ml of distilled crotononitrile was added. The reaction mixture was refluxed for 6 hours and 1 hour.

The solvent was removed under vacuum and water was added to the residue to separate the gum. The gum was dried over St., km magnesium dissolved in dichloromethane and filtered.

The p liquid was evaporated to obtain rubber. The rubber was treated with benzene to separate yellow crystals. The crystals were collected, dried and crystallized from a7ton-hexane, melting point 147-
1.4 g of the desired product was obtained as yellow crystals at 148°C.

Example 81 Sodium methylate 124J9 in methanol 4149 diluted with 51 ml of N,N-dimethylformamide
A stirred solution of diethyl cyanomethyl phosphorate i 0017 and freshly distilled propionaldehyde in N,N-dimethylformamide 75me maintained at 40-45°C in a water bath was added via a dropping funnel. added to. After the addition was complete, the reaction mixture was warmed to 50'0: and stirring was continued for 1 hour without external heating or cooling.

The reaction mixture was diluted with 270 ml of 50:50 methanol-water, then the pH value of the mixture was adjusted to ZO with glacial acetic acid,
This neutral solution of 77- was thoroughly extracted with ether. The combined ether extracts were washed with dilute acetic acid and then with water.

The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give an oil. This oil was distilled through a 2 foot Zadol packed column to give 3-methoxyvaleronitrile 2901/3; boiling point 4225°C/3, n 1.4190 Sodium metal 026I was dissolved in 100 ml absolute ethanol and 2- 8.1 g of chloro-6-hydrazinopyridine (Example 73) was added, followed by 64 g of 3-methoxyvaleronitrile. The reaction mixture was refluxed for 16 hours and then evaporated under vacuum to give a solid. This solid is mixed with water/
Dissolved in dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered through anhydrous magnesium silicate and concentrated with the addition of hexane to give pale yellow crystals Z.
Obtained Og. The crude product was dichloromethane-Hegyi 78
- Recrystallization from Sun gives the product of Example 171~ as pale yellow crystals with a melting point of 131-163°C.

Example 82 β-ethoxypropionitrile5. O,? 1 Anhydrous tanol 100m, 2-hydrazinobenzothiazole 8
25g and 50% W/V choline in methanol 2.5.
The mixture of 9 was refluxed on a steam bath for 16 hours, then the solvent was removed under vacuum. Water was added and the solids were collected by filtration. The solid was recrystallized twice from ethanol, melting point 2315.
Product 5 of this example as a gray prism group at ~265°C
75g was obtained.

Example 86 05 g of sodium metal was dissolved in 100 me of absolute ethanol, and 16.51 g of 2-hydrazinobenzothiazole was dissolved in 100 me of absolute ethanol.
Then 6.717 g of methacrylonitrile was added. The reaction mixture was refluxed for 4 hours and then cooled. Part of the ethanol is removed under vacuum and the precipitate is collected by filtration;
206 g of the desired product were obtained as colorless prismatic groups with a melting point of 207 DEG -209 DEG C.

Example 84 Crotononitrile 20.1,9. Anhydrous ethanol 80m
, 2-hydrazinobenzothiazole 487I and 50%
The mixture of methanol and choline 15 was refluxed for 16 hours. The solvent was removed under vacuum and water was added. The separated solid was collected by filtration, dissolved in dichloromethane, and passed through a short column of hydrous magnesium silicate. The eluent was refluxed while gradually adding hexane to obtain a crystalline product.

The crystallization step was repeated to obtain 0.5 g of the product of this example as grayish plate crystals with a melting point of 212-215°C.

Example 85 3.28 g of p-chlorocinnamonitrile, 50 m of water x 50 m of ethanol, 3.1 g of 2-hydrazinobenzotheasole
1I and 50% W/V Choline 1,0.9 in methanol
The mixture was refluxed on a steam bath for 16 hours.

The reaction mixture was cooled and the precipitate was collected by filtration.

The solid was washed with ethanol to obtain crude product 3211. This material was crystallized from acetone and had a melting point of 276-2.
165 g of the product of this example was obtained as yellow crystals at 75°C.

81 Example 86 050g of metallic sodium and 250rnl of absolute ethanol
Dissolved in 2-hydrazinothiazole 84.9. Next 4
- 74.9 ml of methylcinnamonitrile was added. The reaction mixture was refluxed for 4 hours, then cooled to 1. The resulting precipitate was collected by filtration, washed with ethanol and then with water,
137 g of Japanese product were obtained. This material was recrystallized from 2-methoxyethanol, filtered, washed with hexane,
855 g of the desired product were obtained as colorless prismatic groups with a melting point of 282 DEG-285 DEG C.

Example 87 Kinpo Sodium 046y was dissolved in absolute ethanol 82-150-, and 2-hydrazinobenzothiazole 1
6.5F, then 129g of cinnamonitrile was added. The reaction mixture was refluxed for 16 hours, then cooled. Part of the solvent was removed under vacuum and the mixture was filtered. The precipitate was washed with hexane to obtain 25.67 g of crude product. This thing g3. oy was recrystallized from acetone-hexane to obtain product 235.9 of this example as yellowish brown prismatic crystals with a melting point of 270-2715°C.

Example 88 1/4 H20 2-(3-amino-5-phenyl-2-pyrazoline-1
-yl)benzothiazole (Example 77) 2,0.9 was dissolved in 20.0 ml of N,N-dimethylformamide. The solution was made acidic with 5N ethanolic hydrogen chloride. The solvent was removed under vacuum and the residue was crystallized from ether-methanol at 5°C to give the product of this example 2.0.9 as green crystals with a melting point of 275-285°C.

Example 89 05 g of sodium gold phase was dissolved in 150 g of absolute ethanol, and 5-chloro-2-hydrazinopyridine (Example 74) was dissolved in 150 g of absolute ethanol.
14.36. Next, cinnamonitrile 12.92F was added. 1 of the reaction mixture
It was refluxed for 6 hours. The solvent was removed under vacuum, water was added to the residue and a solid separated. This solid was collected by filtration and dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate and filtered through hydrous magnesium silicate. Pg was concentrated and crystals were separated while adding hexane. This material was recrystallized from ethyl acetate to give a light yellow crystalline product 11. <S8. Obtained li+. This material was dried under vacuum to give the product of this example as yellow crystals with a melting point of 142-147°C.

Example 90 Two hundred grams of hydrazine hydrate were added to 100 J of 6-chloro-2-picoline (98%) and the mixture was refluxed for 16 hours.

Excess hydrazine was removed under vacuum and the remaining oil was dissolved in dichloromethane and extracted with Sphagnum moss 100-. The ti layer was dried over anhydrous sodium sulfate and evaporated under vacuum. Steaming) was repeated until crystals formed, then hexane was added to separate the crystalline mass. This substance,
After treatment with activated carbon, recrystallization from hexane gave 2-hydrazino-6-methylpyridine 26.57, li+, melting point 53-56°C.

051 g of Sodium Kinki in 150 mIV of absolute ethanol
Dissolve in 2-hydrazino-6-metherpyridine 12.
32,9. Then 6.7 g of methacrylonitrile was added. The reaction mixture was refluxed on a steam bath for 16 hours and then evaporated under vacuum to give an oil. Water was added to separate the solids. The solid was collected, treated with activated carbon, and then recrystallized from ethyl acetate to give the desired product 10.12.9 as white crystals with a melting point of 181-185°C.

Example 91 Metallic sodium 1.02.9 in absolute ethanol 250+
++e, 86-21.8 g of 2-hydrazinopyridine, then 13.4 Jil of methacrylonitrile.
I added wo. The reaction mixture was refluxed for 16 hours, then the solvent was removed under vacuum. After treatment with activated carbon, it was recrystallized twice from 3A ethanol to obtain 430 g of yellow-brown face pieces. The above recrystallized p liquids were combined and evaporated under vacuum to obtain a solid. This solid was dissolved in dichloromethane and passed through hydrous magnesium silicate. The p solution was concentrated under reflux with the addition of hexane to give additional 164I of the desired product (total 20.79
g) was crystallized.

Example 92 1.02 N of Kinpo Sodium was added to 2501 N of absolute ethanol
2-hydrazinopyridine 21.8
2.9° Then 25.8 N of cinnamonitrile was added.

The reaction mixture was refluxed for 16 hours, then the solvent was removed under vacuum. Water was added and the solids were collected by filtration.

The solid was recrystallized from 3A ethanol, melting point 203-20
Desired product as yellow crystals at 6°C 20,32,! 9
I got it.

Practical IM Example 93 A mixture of 100 g of 2,6-dichloropyridine in 2 ml of doamidohydrazine hydrate was stirred and refluxed for 5 hours. The reaction mixture was cooled and filtered.

The product was washed with water and dried [7, melting point 117-119°C
477 g of 2-chloro-6-hydrazinopyridine was obtained.

Kanata Sodium 5001119 and absolute ethanol 100
2-chloro-6-hydrazi/pyridine dissolved in m1
5. OF was added followed by methachloronitrile 7211.

The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum, water was added to the residue and the solid was separated. The solid was collected by filtration, dissolved in dichloromethane, dried over magnesium sulfate, and filtered through hydrous magnesium silicate. The eluent was concentrated while adding hexane, and 2-(3-amino-4-methyl-2-pyrazolin-1-yl)-6=chloropyridine 15.0& was crystallized as a yellow-brown isomer with a melting point of 170-175°C. did.

The above compound i0. Op, a mixture of 500 ~ 4-dimethylaminopyridine and 500 ~ acetic anhydride at room temperature
The solution was stirred for a minute. The solution was allowed to stand at room temperature for 18 hours to allow the solids to separate. The entire mixture was poured into water and allowed to stand for 1 hour before the solids were collected by filtration. This solid was dissolved in dichloromethane. Wash this solution with water and
Dry over Mag89-nesium sulfate and evaporate under vacuum to give a solid.

This solid was dissolved in 100° of methanol and 10.0° of 1N potassium hydroxide in methanol was added. After 1 hour at room temperature, the organic solvent was removed under vacuum and water was added to separate the homogens. The solid was collected, washed with water, and dried to yield 87 g of product.

500 ml of this solid was recrystallized from dichloromethane-hexane to obtain 408 ml of the product of this example as pink crystals with a melting point of 166-167°C.

Example 94 A solution of 124 g of sodium methylate in 414 y of methanol diluted with 51 ml of amide N,N-dimethylformamide was added via an addition funnel to 90-N,N-dimethylformamide maintained at 40-45°C in a water bath. Diethylated cyanomethyl phosphorate in Muamide 75 Biao and propionaldehyde distilled in new lanterns 5
577 to the stirred solution. After the addition was complete, the reaction mixture was warmed to 50° C. and stirring continued for 1 hour without further external heating or cooling.

This reaction mixture was mixed with 270 ml of 50:50 methanol-water.
and then bring the pH value of the mixture to 7.0 with glacial acetic acid.
The neutral solution was thoroughly extracted with ether. The combined ether extracts were washed with dilute acetic acid and then with water.

The organic layer was dried over magnesium sulfate, filtered, and concentrated under vacuum to give an oil. This oil was passed through a 2-foot saddle-packed Shida column, 290.9 μl of 3-methoxyvaleronitrile was mixed with 500 μl of sodium gold paulow, and 100 μl of absolute ethanol was added to 2-chloro-6-hydrazinopyridine (Example 93). 15.0 Ii and then 110 g of 6-methoxyvaleronitrile were added. The reaction mixture was refluxed for 18 hours and dried under vacuum to obtain a solid. This solid was dissolved in water/dichloromethane.

The organic layer was separated, dried over magnesium sulfate, filtered through a hydrous silicate column and concentrated without adding hexane to give 2-(3-amino-5) as light yellow crystals with a melting point of 125-127°C. -ethyl-2-pyrazoline-
146 g of 1-yl)-6-chloropyridine were obtained.

95 g of the compound of item 1, 4-dimethylaminopyridine 5
A mixture of 0.00 and 50.0 ml of acetic anhydride was stirred until the solids gradually dissolved. Bring this solution to room temperature for 1
It was held for 8 hours. The solution was then added to water to separate the solids. After standing for 1 hour, the solids were collected by filtration,
Dissolved in 50-methanol and then added 10-1N potassium hydroxide in methanol. After standing for 30 minutes at room temperature, the mixture was added to water and the solids were separated. This solid was collected and dried to yield 69 g of crude product. This product 63001119 was recrystallized from dichloromethane-hexane to give the desired product 252~ as white crystals with a melting point of 170-171°C.

Example 95 032g of metallic sodium was added to 1001nε of absolute ethanol
2-chloro-6-hydrazinopyridine (Example 93) 10. OIl, then 40g acrylonitrile
added. This anti-F6 mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added to the residue to separate the solids. The solid was collected by filtration, dissolved in dichloromethane, dried over magnesium sulfate, filtered through magnesium silicate, concentrated with hexane,
6- Separate the crystals. The mixture was cooled, filtered and 2-(6-amino-2-pyrazolin-1-yl)-6-chloropyridine 9 was obtained as a pale yellow solid with a melting point of 143-145°C.
3.9 was obtained.

The above compound 5.0i 4-dimethylaminopyridine 50
The mixture of 1 and 250 acetic anhydride was allowed to stand at room temperature for 16 hours, and the resulting solid was collected by filtration and washed with cold acetic anhydride and then with hexane to yield 225 g of crude product. This material was dissolved in acetone. The solution was passed through hydrous magnesium silicate and the p-liquid was concentrated with the addition of hexane, and 162 g of the desired product crystallized out as colorless needles with a melting point of 209-2115°C.

Experimental Example 96 50 g of 2-(3-amino-2-pyrazolin-1-yl)94--6-chloropyridine (prepared as described in Example 95) and a mixture of formic vinegar and acetic anhydride+ (Feiser and Fe1ser, Rea
gentsfor Qrganic 5ynthesi
s, Volume 1, 4) The mixture of 25〃i immediately formed a yellow precipitate at room temperature. This precipitate was collected by filtration and recrystallized from acetone-hexane, melting point 190-1.
Product 305y of this example was obtained as off-white crystals at 92°C.

Example 97 A) 2.8.9% sodium metal to 200% absolute ethanol
- dissolved in p-chloroleenyl hydrazi>mealy
, 911 then acrylonitrile 5.5.9 was added over 25 minutes. The reaction mixture was fast-flowed for 6 hours and heated. The p-liquid was evaporated to dryness, then water was added to separate the solids. This solid was collected by filtration and dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The eluent was heated to boiling and hexane was added to crystallize the product. The mixture was cooled, filtered and the 3-amino-1-(p-chlorophenyl)-2-pyrazoline 8
．． Got 75p.

B) A mixture of 690 g of the above product and 4.32 g of ethoxymethylene diethyl malonate, ii' was refluxed for 2 hours.
The solution was then evaporated to dryness to yield a solid. This solid was dissolved in methylene chloride and treated with hydrous magnesium silicate and hexane as described above, and the solid was collected. This solid was recrystallized from a7ton-hexane to obtain 478 g of the product of this example as yellow prism crystals with a melting point of 159-162°C.

Example 98 A) Gold formula sodium 1.72,! 9 in 110+J of absolute ethanol, 11.0# of p-chlorophenylhydrazine hydrochloride, and then 420 g of crotononitrile in 15
Added in minutes. The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum, water was added to the residue and the gum was separated. This gum was dissolved in dichloromethane and separated from the water. The organic layer was dried over anhydrous magnesium sulfate and filtered through a column of hydrous magnesium silicate.

Evaporation of the eluent gave a glass. A small amount of benzene and then hexane were added to this glass and it was gradually solidified.

The solid was collected, washed with hexane, dried and melted at mp 90~
81 g of 6-amino97--1-(p-chlorophenyl)-5-methyl-2-pyrazoline was obtained as a pink solid at 92°C.

B) 48 g of the above compound was mixed with formic acid and acid 1ψ anhydride (pe
iser and peacer, Reagent
s for Qrganic Synthesis, Vol. 1, p. 4) and kept at room temperature for 3 hours. Ice water was added to this mixture to form a gum.

The aqueous phase was decanted and the gum was dissolved in dichloromethane. The solution was dried over magnesium sulfate, filtered through hydrous magnesium silicate, and evaporated to leave 1 of gum. This material was dissolved in dichloromethane, heated to boiling and hexane was added until cloudy. The mixture was cooled, filtered and N-(1-(p-chlorophenyl)-5-
Methyl-2-pyrazolin-3-yl]formamide 36
g.

98- C) To a stirred solution under nitrogen of freshly distilled tetrahydrone run 250- is carefully added 3.3.9 liters of lithium aluminum hydride and then N-(1-(p-chlorophenyl) )-5-Methyl-2-pyrazolin-3-yl]formamide (33 g) was added and the mixture was refluxed under nitrogen for 4 hours. The reaction mixture was cooled. While stirring, water was carefully added. 15% hydroxide solution) and 10.0 ml of water. was dripped. The mixture was filtered and the residue was washed with ether. The combined p solution and washing solution were evaporated to dryness to obtain a solidified rubber. The facepiece was collected, washed with hexane, and dried. The product of this example was recrystallized from dichloromethane-hexane to obtain 2.3 g of white crystals with a melting point of 102-103°C.

Example 99 1-(3,4-dichlorophenyl)-3-methylamino-2-pyrazoline A) 99 g of sodium metal was dissolved in 450 m of absolute ethanol.
l-dissolved L, 3.4-dichlorophenylhydrazine salt #salt 75.0,9. Next, add 195g of acrylonitrile to 1
Added in 0 minutes. The reaction mixture was refluxed for 18 hours, then the solvent was removed under vacuum. Water was added to the residue to separate particulate solids. This solid was collected by filtration and dissolved in acetone. The solution was filtered and the p solution was evaporated to dryness. The resulting residue was triturated with ether, melting point 181-1
3-Amino-1-(
624 g of 3,4-dichlorophenyl)-2-pyrazoline
I got it.

B) 100 g of the above product was mixed with a mixture of formic acid and acetic anhydride (peiser and peiser, Rea
gentsfor Qrga old c 5ynthesis
, Vol. 1, p. 4) was dissolved in 50 ml and kept at 4 temperature for 2 hours. The resulting solid was collected by filtration and dissolved in dichloromethane. The organic solution was washed with water, dried over anhydrous magnesium sulfate, and filtered through a short column of hydrous magnesium silicate. The eluate was concentrated with the addition of hexane until cloudy. The mixture was cooled and filtered to give N-(1-(3,4-dichlorophenyl)-3-pyrazolin-6-yl)formamide 6,5.9, melting point 148-149°C.

C) To a stirred solution under nitrogen of freshly distilled tetrahydrofuran 250- was carefully added lithium aluminum hydride, then N-(1-(3,
4-dichlorophenyl)-6-pyrazolin-3-yl]
5°Og of formamide was added in portions and the mixture was refluxed under nitrogen for 6 hours.

1 oi- Cool the reaction mixture and carefully drain excess hydride with 5 ml of water.
0-1 then 15% hydroxide) IJum solution 50- and water 15Wd! , decomposed by dripping. The mixture was filtered and the p-liquid was evaporated to free the gums and solids. This material was dissolved in dichloromethane and passed through a short column of hydrous magnesium silica. Evaporation of the eluent gave a dark gum and solid. This mixture was treated with hydrous magnesium silicate as described above. The eluent was evaporated and the solid was recrystallized twice from ether-hexane to give the desired product 2.017 as white crystals, mp 68-70<0>C.

102- Example 100 A) 1.2 ml of metallic sodium to 110 ml of absolute ethanol
75 g of p-chlorophenylhydrazine hydrochloride was added, followed by 29 g of methacrylonitrile. The reaction mixture was refluxed for 18 hours. The solvent was removed with an empty F, and water was added to the residue to separate the rubber. This gum was collected and dissolved in dichloromethane. The organic solution was washed with water, dried over an anhydrous magnetic column, and passed through a short column of hydrous magnesium silicate. Evaporation of the eluent left a gum which solidified upon addition of hechitin. This solid was collected and recrystallized from ether-hexane to give 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline 469 as white crystals with a melting point of 107-108'C.

B) 2.29 of the above product was dissolved in 10.0 of a mixture of formic acid and acetic anhydride.

The mixture was kept at room temperature for 3 hours. Water was added and the yellow solid was collected by filtration. This solid was dissolved in dichloromethane. The solution was dried, filtered and concentrated as described in Example 99...), mp 172-
174'C N-[1-(p-chlorophenyl)-4-
Methyl-2-pyrazolin-3-yl]formamide2.
I got 19.

0) Freshly distilled tetrahydrofuran 1.99 from the above product 1 as described in Example 991(3)
It was added to a suspension of 19 ml of lithium aluminum hydride in 0.00-ml under a nitrogen atmosphere, and the mixture was refluxed for 4 hours.

The reaction mixture was cooled and excess water accumulated was destroyed with 1 liter of water and 15% sodium hydroxide.

The mixture was filtered once and the liquid f was evaporated. The residue was dissolved in dichloromethane and the solution was passed through a short column of hydrous magnesium silicate. The m#E solution was evaporated under vacuum to give a cloudy gum. Dissolve this rubber in ether and set it to 1
passed. The f solution was evaporated under vacuum and cooled. Addition of hexane produced crystals. The crystals were collected and dissolved in ether. The solution was filtered and then hexane was added until cloudiness appeared. The solution was cooled and seeded to give 1.189 of the product of this run IP11 as white crystals with a melting point of 70-72°C.

Example 101 A) Metallic sodium! i, 12g ■ water ethanol 2
209 g of m-chlorophenylhydrazine hydrochloride and then 76 g of methacrylic nitrile were added. The reaction mixture was passed through the inlet of Example 100), extracted, purified and purified to give a solid. This solid was recrystallized twice from ether-hexitine, As white crystals with a melting point of 84-85°C - Amino 1-
162 g of (m-chlorophenyl)-4-meru-2-pyrazoline was obtained.

B) The above product 3.09 was dissolved in a mixture of formic acid and acetic anhydride [Example 99(B)) 10- and kept at room temperature for 3 hours. The reaction mixture was poured into water to separate some of the gum and solids. This material was collected, dissolved in dichloromethane, and passed through a short column of hydrous magnesium silicate. The eluent was condensed while adding hexane, and the melting point was 14.
N-(1-(rn
-chlorophenyl)-4-methyl-2-pyrazoline-3
-yl]formamide 619 was isolated.

0) As per IM99(0), the above compound @2.
2.0g of lithium aluminum hydride in 200ml of tetrahydrofuran distilled from 100g of S-106
- Added to the solution under nitrogen and refluxed for 4118 hours. The reaction mixture was cooled and excess hydride was carried out.
(Ill<1.) and treatment to obtain a solid. This solid was recrystallized from ether-xane and
I got 13 pieces of crude raw rJ5. 200 ml of this material was purified from ether-hexitine through diatomaceous earth and then recrystallized twice to give 100 ml of the product as white crystals with a single point of 75-76°C.

Fruit 1 I) full 102 pyrazoline Δ) 6-amino-1-(p-chloro1]phenyl)-5-
Methyl-2-pyrazoline (produced by pounding ν1 on methyl-2-pyrazoline) 860 g was mixed with 25 g of dichloromethane. Dissolved in Ornt with stirring. The solution was gradually added to trifluoroacetic anhydride 250°C cooled to 10°C with stirring. The reaction mixture was heated at room temperature for 3 hours.
The mixture was stirred and then the common medium was removed under vacuum [J].

The residue was dissolved in dichloromethane and the solution was passed through a short column of hydrous magnesium silicate. The eluate was concentrated with hexane until cloudy.

The solution was cooled and filtered to form a white solid with a melting point of 170-172°C.
, 85 g of 2-trifluoroacetamide were obtained.

B) Tetrahydrofuran 25 freshly distilled under nitrogen
Lithium aluminum hydride 5 to the stirred clear liquid of 0-
PE;M 09 and say 0 mouth, then the above raw TFF 50
9 was added portionwise to this mixture. The reaction mixture was stirred under nitrogen and refluxed for 7R. The reaction mixture was cooled and the excess hydride was poured into 1:F water 5. Omt,
The mixture was then decomposed by dropwise addition of 50% of a 15% hydroxide fl.licum solution and 15% of water. The mixture was filtered once and the P liquid was evaporated leaving a thin oil. This oil was dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate, passed through hydrous magnesium silicate, and evaporated to yield a gum that solidified upon disintegration with hexane. One bottle of this solid was recrystallized from dichloromethane-hexitine to obtain 2.8 ml of the product of this sample as white crystals with a temperature of 66-64°C.

Fruit j Asahi 9'1J103 A) 70g of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline [produced by beating as described in Example row 100] was dissolved in dichloromethane 25.0-
The mixture was dissolved in water and cooled to 5°C. This solution of 109- was stirred and trifluoroacetic anhydride 14.0- was added. Stirring was continued for 3 hours at room temperature, then the solvent was removed under vacuum. The residue was poured into dichloromethane and the solution was concentrated with the addition of hexane until cloudiness appeared. The mixture was cooled, the solid collected, and the product 5,69
I got it. Ten volumes of this material were recrystallized from dichloromethane-hexitine as a white solid with a melting point of 181-183°C.
-pyrazolin-3-yl]-2,2,2-trifluoroacetamide 750~ was obtained.

B) Tetrahydrofuran 40 freshly distilled under nitrogen
Carefully add the lithium aluminum hydride 699 to the stirred solution of 0- and then mix! 69 portions of the above product (prepared as described above) were added to the snout. The reaction mixture was stirred under nitrogen and refluxed for 5 hours. Cool the reaction mixture and add 69 tons of water, being careful not to hydrogenate an excessive amount.
1st 69% 15% sodium hydroxide solution and 20% water.
Digested with a 7 tnl drop. The mixture is filtered and the liquid f is evaporated to leave a crude sticky tan solid. This product was diluted with ether and filtered through a finely divided synthetic silicate magnet column. The eluate was concentrated with hexane until it became cloudy.

The mixture was cooled in the refrigerator and then filtered once, melting point 84~
6.4 g of the desired product was obtained as a white solid at 86°C.

Example 11i104 3-Amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline [by mouth as described in Example 98(A),! 1! ! ! [What was left] A mixture of 400 m9 of 4-dimethylaminepyridine and 200 m9 of vinegar anhydride was left at room temperature for 48 hours. The resulting solid was collected by filtration, washed with cold acetic anhydride, then hexane, and dried to give a white solid. This solid was recrystallized from dichloromethane-hexitine as a white solid with a melting point of 167-169°C, N-1:1-(p-chlorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide 6.69
I got it.

Tetrahydrofuran 500w freshly distilled under nitrogen
6.0 g of lithium aluminum hydride was carefully added to the stirred solution of +t, and then 60 g of the above product was added in portions to the mixture. The reaction mixture was stirred under nitrogen and refluxed for 5 hours.

The reaction mixture was cooled and excess hydride was removed from Example 10.
The solution described in 3(B) was decomposed using 6.0 to 115% sodium hydroxide solution in water and 18.0 in water. The remaining solid was filtered and washed with tetrahydrofuran. The combined liquid 1 and washing liquid were evaporated to obtain a thin oil. This oil was dissolved in dichloromethane, passed through hydrated magnesium and evaporated to give a thin oil. The addition of hexane yielded 4.7 g of crystals per minute. 200 μm of this solid was recrystallized from ether-hexane with a melting point of 57.
168 .mu. of the desired product was obtained as a white solid at .about.58.degree.

Example 105 A) Dissolve 129 of sodium metal in 110 of absolute ethanol, and dissolve 15 of p-chlorophenylhydrazine hydrochloride,
Next, 2.99 g of methacrylonitrile was added. The reaction mixture was refluxed for 18 hours. A column packing step was carried out according to the method of Actual hlU column 9 a [a). Evaporation of the eluent left a gum that solidified when hexane was added. This solid was recrystallized from Ni-113-tyl-hexitine and had a melting point of 107-108'C.
6-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline 46 was obtained as white crystals.

B) The above compound (produced as in -H) 9
．． 09 to vinegar +'lk anhydrous @ 54.0-6%. The hot solution was left at room temperature for 16 hours, and some solids separated. Water was added to complete solid separation. This solid was collected by filtration and dissolved in methanol. 1N potassium hydroxide in methanol was added to make basic. 1 at room temperature
After 5 minutes, the solvent was removed under vacuum and water was added to separate the solids. This solid was collected and recrystallized from dichloromethane-hexitine, mp 172-17! N'-(1-(p-chlorophenyl)-4-methyl-
2-pyrazolin-3-yl]acetamyl! 6.59 was obtained.

114-0) Lithium aluminum hydride 6.5% in freshly distilled tetrahydrofuran 250% of the above compound m65
g of nitrogen F was added to the stirred suspension. The stirred reaction mixture was centrifuged for 5 hours under nitrogen. The mixture was then cooled and the excess hydride was decomposed as described in Example 103 using 6.5 ml of water, 5 ml of 15% sodium hydroxide solution/) and 16-ml of water. The remaining solid was filtered and washed with tetrahydrofuran. The combined liquid f and washing liquid were evaporated to obtain a thin oil that crystallized.

The solid was collected and recrystallized from dichloromethane-hexane to yield product @4.69. 115 ml of this product was recrystallized from ether-hexane to give 90 ml of the desired product as white crystals with a melting point of 63-64°C.

Example 106 Phosphorus 6-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline [Example 99 France]) 10. The Og was added in portions to 50 g Lt of trifluoroacetic anhydride while cooling and stirring, and a solid separated. The reaction mixture was stirred at room temperature for 3 hours, then the solid was collected by filtration and dried to yield product 12.29. 3.09 of this material was recrystallized from dichloromethane-hexitine, melting point 163-164°C.
N-(1-i,4-dichlorophenyl)=2-pyrazolin-3-yl)-2,2,2 as pale yellow needle-like crystals of
-Trifluoroacetamide 249 was obtained.

5.0 g of the above product was made into a solution as described in Example 102 (B) and refluxed with lithium aluminum hydride in tetrahydrofuran for 4 hours. The hydride was decomposed as before and the reaction mixture was filtered.

The P solution was evaporated to obtain a dark colored rubber. This gum was dissolved in dichloromethane and filtered through hydrous magnesium silicate. Evaporation of the e liquid gave a pale green oil which crystallized on standing.

This material was recrystallized twice from hexane and had a melting point of 93-94°.
3.69 of the desired product was obtained as a gray solid.

Example 107 A) 2.8 g of sodium metal in 200 d of absolute ethanol
K melt! m-fluorophenylhydracune hydrochloride 16
．． 2 g and then 15.4 g of methacrylonitrile were added.

The reaction mixture was refluxed for 18 hours, then the solvent was evaporated under vacuum. Water was added to obtain rubber. The gum was dissolved in dichloromethane and the solution passed through a short column of hydrous magnesium silicate. The eluate was concentrated with addition of hexane 117-ene until cloudiness occurred. The solution was cooled, a mercury crystal was added, and a pink solid was stirred for 1 minute, which was collected by filtration and dried. 4.2 parts of -2-pyrazoline were obtained.

B) 4.2g of the above compound was added to 1Q of acetic anhydride, Qwf
100 m9 of 4-dimethylaminopyridine were added and the reaction mixture was left at room temperature for 16 hours.

This mixing power was poured into water to separate the solidifying rubber.

The solids were collected by filtration and washed with water. Solid to methanol 50.0trLt? 1F in methanol
10.0-N sodium hydroxide was added. The mixture was left at room temperature for 60 minutes, then the solvent was partially removed under vacuum. A yellow solid separated upon addition of water. This solid was collected, dried, and N-[1-(m
-fluorophenyl)-4-mecal-2-pyrazoline-
4.1 g of 6-yl]ace118-doamide was obtained.

0) The above compound (produced as above) 4
．． 5 g of freshly distilled tetrahydrofuran 25
Added to a stirred suspension under nitrogen of 4.5 g of lithium aluminum hydride in 0frLt. The reaction mixture was stirred and refluxed under nitrogen for 5 hours.

The mixture was cooled and excess hydride was removed from Example 103 (B
) using 4.5 g Lt water, 4.5 Lt 15% sodium hydroxide solution and 14 v Lt water. The mixture was filtered and the liquid was evaporated under vacuum to yield a gum. This rubber is used as a synthetic magnesium silicate adsorbent.
into a column containing g. First, add hexane (
fractions 1 and 2), 2% acetone-hexane (combined fractions 3 and 4, and fractions 5.6 and 7), then 4%
Elution was performed with acetone-hexitine (combination of fractions 8.9 and 10).

This elution step was carried out using 2 parts of benzene, 1 part of acetone and 2 parts of water.
Spread it on a plate using the upper phase of the mixture and spread it thinly.
Monitored by fi chromatography. Distillate 5.6
and 7 were combined and the indicated fraction was evaporated,
The desired product 099 was obtained as a pink oil.

Example 108 2.09 g of sodium metal was dissolved in 200 g of absolute ethanol, and 37.49 g of phenylhydrazine and then 20.1 g of methacrylonitrile were added over 10 minutes.

The reaction mixture was refluxed for 4 hours and then evaporated to near dryness under vacuum. Water was added to the residue and the oil was separated.

This oil crystallized upon standing. This solid was dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The column eluent was evaporated to give an oil. This oil was crystallized from acetone-hexitine and then recrystallized from the same solvent pair to give colorless crystals of 3-amino-4-methyl-1-phenyl-2-pyrazoline 20, melting point 86-84°C. I got 889.

The above Kr2 product 1009 was converted into acetic anhydride'#l50frLt
500 m9 of 4-dimethylaminopyridine were added and the reaction mixture was left at room temperature for 18 hours. The mixture was poured into water and the solidifying rubber separated and was collected by one sieve. This solid was added to 150 g of methanol containing 10.0 g of sodium hydroxide with stirring. After 60 minutes, the solvent was removed in vacuo F and water was added to yield a gum which became a solid.

This solid was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and passed through a short column of hydrous magnesium silicate. The eluent was concentrated with the addition of hexane to form crystals. This +91J substance is collected, dried, and has a melting point of 1
A white solid of 49-150'C was reacted with 121- to give 3.3 g of N-(4-methyl-1-phenyl-2-pyrazolin-6-yl)acetamide.

The above compound (simulated as above) 6,09
was added to a stirred suspension under nitrogen of 6.0 g of lithium aluminum hydride in 250 ml of freshly distilled tetrahydrofuran. The reaction mixture was stirred and flushed with nitrogen F.
Refluxed for an hour. The mixture was cooled and the excess hydride was washed with 6 ml of water as described in Example 1 Blood 131103 (B).
6.0 g of 0-115% sodium hydroxide solution and 18 g of water
Decomposed with gLt. The mixture was filtered and the P solution was evaporated under vacuum F to obtain an oil. This oil was placed in a column containing a 200 mesh synthetic silicone It Magne column absorber 809.

This column was first washed with 2% acetone-hexitine (fraction 1).
It was then eluted with 4% acetone-hexano (fraction 2.3.4.5 and 6) and finally with 8% acetone-hexano (fraction 7). The elution process was monitored by thin 1-chromatography using a system as described in Example 122-107(0). Fractions 2.3.4.5 and 6
The fractions represented by were evaporated to give the desired product 463 as a pink oil.

Example 109 9.99% of sodium metal was dissolved in 450% of absolute ethanol, and 75% of 3.4-dichlorophenylhydracune hydrochloride was prepared by dissolving 9.99% of sodium metal in 45% of absolute ethanol.
0 g and then 195 g of acrylonitrile were added over 10 minutes. This reaction mix-example was run for 184 hours. The solvent was removed in vacuum F. Water was added and a granular solid separated.

The solid from 5 was dissolved in acetone and filtered to remove a small amount of insoluble material.

The P solution was evaporated to dryness, leaving a solid. This solid was triturated with ether to give 3-amino-1-(3°4-dichlorophenyl)-2-pyrazoline 624 as a tan crystalline solid with a melting point of 181-186°C.

100q of the above product was added in portions to 50-mL of trifluoroacetic anhydride while cooling and stirring, and a solid separated. The reaction mixture was stirred at room temperature for 6 hours, then the solid was collected by filtration and dried to yield 12.2 g of product. 6.02 of this material was recrystallized from dichloromethane-hexitine to give 424 samples of 11 colors of real fruit as pale yellow needles with a melting point of 166-164'C.

Example 110 3-Amino-1-(3,4-dichlorophenyl)-2-pyrazoline (Example 1) in 20 ml of dry pyridine [prepared as described in 109]. 2.30 g of the stirred mixture was cooled in a water bath and then 2.109 g of p-chlorobenzoyl chloride was added.

The mixture was left at room temperature for 16 hours and then poured with water to separate the solids. This solid was collected by filtration and dissolved in dichloromethane. This solution was passed through a short column of hydrated magnesium.

The eluent was refluxed and hexane was added until it became cloudy. The solution was cooled and filtered to collect raw material.

The product was recrystallized from the same solvent pair and had a melting point of 177-178.
The desired product 1B9 was obtained as yellow needles at °C.

Example 111 125 - Dissolve 102 of sodium metal in 100 of absolute ethanol, 200 of phenylhydrazine, then 24.0 of (mixed cis and trans) 4-methylcinnamonitrile.
Added in minutes. The reaction mixture was refluxed for 4 hours, then cooled. The precipitate was collected by one filtration, treated with activated carbon, and then recrystallized from acetone-X-mexane, melting point 165.
3-Amino-1 as pale orange needles at ~166 °C
-pheni)L/-5-p-)zyl-2-pyrazoline 14
．． I got 259.

The above product 5.09 and trifluoroacetic anhydride 25
- The mixture was left at room temperature for 5 hours. The mixture was filtered, the collected solid was dissolved in dichloromethane, and the solution was then evaporated to dryness. The residue was redissolved in dichloromethane, passed through hydrous magnesium silicate, and recrystallized as described in Example 110 to give the crystals as intertwined =126- pale yellow needles with a melting point of 206-207°C. Example product 15 was obtained.

Example 112 2.09% of sodium metal was added to 150tnl of absolute ethanol
40.0 d of phenylhydrazine and then 48.0 ml of cinnamonitrile were added over 5 minutes. The reaction mixture was refluxed for 6 hours, resulting in exothermic crystallization of the product. The product was collected by filtration and washed with water. This material was recrystallized from absolute ethanol and had a melting point of 195-197.
3-Amino-1,5-diphenyl-2- as a solid at °C
560 g of pyrazoline was obtained.

50 g of the above product and 25. trifluoroacetic anhydride.
The 0- mixture was left at room temperature for 16 hours.

The solvent was removed under vacuum and the residue was taken up in dichloromethane. The solution was passed through a short column of hydrous magnesium silicate and the product was recrystallized from the eluent as described in Example 110. The entire recrystallization process was repeated to give the desired product 3 as yellow needles with a melting point of 197-198°C.
．． I got 09.

Example 115 A) 2.09% sodium metal to 200% absolute ethanol
624 phenylhydrazine in 50 td ethanol, then 201 g crotononitrile
was added over 10 minutes. The reaction mixture was refluxed for 5 hours.

Most of the ethanol was removed under vacuum, water was added and the product was collected by filtration.

The solid was taken up in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The column eluent was then refluxed on a steam bath while hexane was gradually added to crystallize the product. The product was collected and recrystallized from acetone-hexane at 4 points 103.5-106"C.
Colorless prismatic crystals of 6-amino-5-methyl-1
26.9 units of -phenyl-2-pyrazoline were obtained.

B) Compound 5 above. The mixture of O(i) and trifluoroacetic anhydride 250- was allowed to stand at room temperature for 48 hours. Dichloromethane was added to dissolve the remaining sludge. The solution was evaporated to dryness under vacuum.

The residue was dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. Hexane was added to the syneresis solution to separate a green oily precipitate. The solvent was decanted and evaporated to give a solid. Redissolve this solid in dichloromethane and treat the column as above,
Recrystallized by addition of hexane. The product was collected by filtration and the above procedure was repeated to obtain 115 g of the product of this example as yellow entangled fC'fF crystals with a melting point of 189-1905°C.

Example 114 2.0 g of sodium doamide metal was dissolved in 200 g of absolute ethanol, and 37.4 g of phenylhydrazine and then 201 g of methacrylonitrile were added over 10 minutes.

The reaction mixture was refluxed for 4 hours and then evaporated to dryness on a JXX #1 top and bottom. Water was added to the residue and oil separated.

This oil crystallized upon standing. The solid was dissolved in dichloromethane and the solution was passed through a short column of hydrous silica magnenium. The column eluent was evaporated to give an oil. This oil was crystallized from acetone-hexane and then recrystallized from the same solvent pair as colorless crystals with a melting point of 83-84'C.
Methyl-1-phenyl-2-pyrazoline 20.88 (
I got l.

Compound 5.09 above and trifluoroacetic anhydride 25
, 0fnt was allowed to stand for 2 minutes. The separated solid was collected by filtration and washed with hexane.

This solid was dissolved in dichloromethane. The solution was passed through hydrous magnesium silicate and recrystallized as in Example 110 to give the desired product 1829 as needles with a melting point of 142-1435'C.

Example 115 6-amino-4-mecal-1-phenyl-2-pyrazoline (prepared as described in Practice Q114)
5. The mixture of OQ and trifluoroacetic anhydride 250- was left at room temperature for 24 hours. Dichloromethane was added to dissolve the resulting solid, then the solvent was evaporated. This solution was column-treated and recrystallized as described in Example 110,
5.2 g of the product of this example was obtained as pale yellow needles with a melting point of 203-204'C.

Practical Example 116 2.0 g of metallic sodium wafer was dissolved in 100 ml of absolute ethanol, and 92240,041 phenylhydrol and 26.04 g of acrylonitrile were added thereto. The reaction mixture was refluxed for 3 hours, resulting in exothermic crystallization of the product. The product was collected by filtration and washed with 95% ethanol. This material was recrystallized from dichloromethane-benzene, melting point 168
6-Amino-1-phenyl-2-pyrazoline 4369 was obtained as a solid at ~170.5'C.

15 g of the above product and 80 g of trifluoroacetic anhydride
The mixture was left at room temperature for 1 hour (exothermic anti-hG). The mixture was evaporated to dryness under vacuum, then dichloromethane was added. The solution was filtered twice and the f solution was evaporated to give the desired product as yellow needles with a melting point of 2285-2305°C.

Example 117 5.09 g of 3-amino-1,5-diphenyl-2-pyrazoline (prepared in Example 112) and 25.0 g of trifluoroacetic anhydride were heated until they went into solution. After standing for 2 minutes, the resulting precipitate was collected by filtration and washed with hexane.

1sx - This solid was dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. The eluent was refluxed and hexane was added to crystallize the product.

The product was recrystallized from hexane, melting point 151.5-15
0.95 ml of the desired product was obtained as needles at 3.5°C.

Example 118 Cetamide A) 1.09% sodium metal to 100% absolute ethanol
gLtK Solubility % l, , m-chlorophenylhydrazi 730, 759, then 12.0 g of acrylonitrile was added to 5
Added in minutes. The reaction mixture was refluxed for 5 hours, then cooled, filtered and filtered. The collected solids were dissolved in acetone, treated with activated carbon, filtered and filtered. The product was crystallized by adding hexane to the f solution, and the 154- product was collected as 6-amino-1-(m~chlorophenyl)-2- as off-white prismatic crystals with a melting point of 161-132°C. Pyrazoline 607 was obtained.

B) 5.02 of the above raw +iZ product was added to 25.0 - of trifluoroacetic anhydride, resulting in an exothermic reaction and formation of a precipitate. After standing for 5 minutes, the precipitate was collected by filtration. This solid was dissolved in dichloromethane and then passed through a short column of hydrous magnesium silicate. The eluent was refluxed and hegisan was added to prevent turbidity. The mixture was then cooled and filtered to give 47 g of the desired product 9 as yellow crystals with a melting point of 143-144°C.

Example 119 Sodium metal (2,89) was dissolved in absolute ethanol for 12 s
p-chlorophenylhydrazine hydrochloride 17
．． 99, then p-chlorozinecamonitrile 16.569
added. The reaction mixture was refluxed for 7 hours and then heated to room temperature for 1
It was left for 6 hours. The solvent was removed with pure F and water was added to separate the solids. The solid was collected by one sieve, dissolved in dichloromethane, columned as in Example 117, and crystallized. The product was recrystallized from acetone-hexitine, mp 150-15[L5'C 6-amino-
100 g of 1,5-bis(p-chlorophenyl)-2-pyrazoline was obtained.

5.00 of the above compound was mixed with 25.0 of trifluoroacetic anhydride at room temperature. This mixture was left for 16 hours,
Next, I got one. The solid was dissolved in dichloromethane. This solution was columned 9 times as described above and crystallized to give the desired product 4,529 as light yellow intertwined needles with a melting point of 1385-140°C.

Implementation Reli 120 Metallic sodium (2,89) was dissolved in absolute ethanol 125-
212 g of m-trifluoromethylphenylhydrazine hydrochloride and then 559 g of acrylonitrile were added. The reaction mixture was refluxed for 181 hours. The solvent was removed under vacuum and water was added to the residue resulting in a sticky solid. This solid was dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate and passed through a short column of hydrous magnesium silicate. The eluent was collected and concentrated to separate tan crystals. This rostrum was recrystallized from acetone to xane to give 3-amino-1-(α,α,α-trifluoro-m-tolyl)-2 as pale 137-yellow needle-like crystals with a melting point of 104-105°C. -Pyrazoline 14,89 was obtained.

2.7 of potassium carbonate in 100 of stirred chloroform
59 and 5.6 g of 3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline were added, and then 5.09 g of α-bromopropionyl chloride was added dropwise. After the addition was complete, the reaction mixture was refluxed on a steam bath for 4 hours. The solvent was then removed under vacuum and water was added to yield a gum. This gum was extracted with dichloromethane. The extracts were combined and dried over anhydrous magnesium sulfate. The solution was passed through a short column of hydrous magnesium butyrate and then evaporated to leave a gummy solid. This solid was triturated with ether to yield 1.139 of a yellow solid.

This solid was recrystallized from acetone-hexitine and had a melting point of 54.
The desired product 138- was obtained as yellow crystals at ~56 °C.

Actual m column 121 2-Bromo-N-(1-1α,α,α-trifluoro-m-tolyl)-2-pyrazolin-6-yl]propionamide (Example 120) 1.0 g was placed in a pressure bottle. It was dissolved in 50% of benzene, then sealed between the nails, and the crystals were separated. The mixture was heated on a steam bath for 6 hours and then cooled. The reaction mixture was partitioned between water and benzene. The benzene layer was dried over anhydrous magnesium sulfate and evaporated to give a dark colored rubber. This rubber was dissolved in hexane and passed through hydrous magnesium silicate for one hour. The first liquid was evaporated to obtain rubber (o, q9). 210η of this rubber was placed on a silica gel G plate with 2 parts of benzene and 1 part of acetone.
Thick 1-chromatography using the upper phase of a mixture of 1 part and 2 parts water gave 180 ml of the desired product as a light yellow gum.

Example 122 A) 2.89 d of sodium metal in 125 d of absolute ethanol
Ki%L, 21.359 of 3.4-dichlorophenylhydrazine hydrochloride, then 6.7 g of crotononitrile were added over 5 minutes. The reaction mixture was refluxed for 8 hours and then evaporated to dryness under vacuum. Water was added to separate the oil. This oil was crystallized, then dissolved in dichloromethane and passed through a short column of hydrous magnesium silicate. i@1 liquid,
Reflux while gradually adding hexane, melting point 103~1
Filter it as a colorless prismatic crystal at 04°C.
14.49 of 3,4-dichlorophenyl)-5-methyl-2-pyrazoline was isolated.

B) 2.5 g of the above compound and 1 of trifluoroacetic anhydride
The mixture was left at room temperature for 1 hour.

Passed through a short column of magnesium. The syneresis liquid was heated on a steam bath and hexane was added to crystallize the product. The product was collected and the entire crystallization procedure was then repeated to yield product 2 of this example as needles with a melting point of 150-152'C.
I got 509.

Example 123 2.8g of midometal sodium 9m was added to absolute ethanol 200-14
1 - One i@1ilL, 3.4-dichlorophenylhydrazine hydrochloride 21.359, then methacrylonitrile 67
was added at 60 minutes. The reaction mixture was refluxed for 5 hours and then evaporated to dryness in vacuo F. Water was added to separate the solids. The solid was collected and made up to 8M in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate,
Recrystallized as described in Example 110, melting point 161-13
3-Amino-1-(3
,4-dichlorophenyl)-4-methyl-2-bi7zo'
) was obtained.

3.0 g of the compound of above dC and a mixture of formic acid and acetic anhydride (Feiser and Felser, Re
agents for Organic 5yothes
is, m vol. 1, p. 4) 15 was poured onto ice and then filtered to collect the solids. Dissolve this solid in dichloromethane and perform l++1 ii.

142- to give the desired product 2729 as yellow prismatic crystals, melting point 150-152°C.

Example 124 3-amino-1-(3,4-dichlorophenyl)=2-
Pyrazoline (produced in Example 109) 50
g and a mixture of formic acid and acetic anhydride (Example I11!1 Example 123) 25- was allowed to stand at room temperature for 1 hour. The resulting solid was collected by filtration and washed with hexane. This solid was dissolved in dichloromethane, columned and recrystallized as described in Example 116, mp 151-1
Desired product 3859 as yellow prismatic crystals at 53 °C
I got it.

Actual 1/lj Example 125 -2-pyrazolin-3-yl) -2,2,2-tri4
- aminobiphenyl 5.09% in concentrated hydrochloric acid held at 5°C. Suspended in a stirred solution of Om and 2 ZO ml of water. Stirring was continued to maintain the temperature below 10'C while a solution of 809 ml of sodium nitrate in 160 ml of water was slowly added. The reaction mixture was stirred at 5°C for 15 minutes and then added slowly to a cooled solution of stannous chloride 5309 in concentrated hydrochloric acid 530°C (0-5°C). The resulting mixture was diluted with water and treated with a 40% solution of sodium hydroxide until completely alkali. The resulting solid was collected by filtration, dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and filtered. The f solution was passed through a short column of hydrous magnesium silicate.

The eluent was evaporated under vacuum to give a solid. This solid was dissolved in dichloromethane. This solution was heated to boiling, and hexane was added until it became cloudy.

The mixture was cooled and filtered, mp 135-168'C.
(decomposed) as orange crystals of 4-biphenylhydrazine 8
5g was obtained.

43 g of the above compound were added to a solution of metallic sodium 019 dissolved in 100 ml of absolute ethanol. Then 154 g of crotononitrile were added and the mixture was refluxed for 6 hours and poured into water to separate the dark solid. This solid was poured into dichloromethane, heated to reflux F, and recrystallized twice from hexane as above, leaving a solid with a melting point of 174-176°C, 3-amino-1-(4-biphenylyl)-5-
3.69 ml of methyl-2-pyrazoline was obtained.

0.5 g of the above compound was added to difluoroacetic anhydride 25-
and kept at room temperature for 2 hours. The solvent was removed under vacuum and water was added to separate the solids.

This solid was collected, dissolved in dichloromethane, and
- Column treatment in Example 110 for 3 times and recrystallization to give the product of this example as yellow crystals with a melting point of 192-193°C.

Example 126 3-Amino-1-phenyl-2-pyrazoline (Run 1
1007 (prepared in 16) and acetic anhydride 10,0- were mixed together and left at room temperature for 1 hour. The resulting solid was collected, dissolved in dichloromethane, and passed through a short column of hydrous siliceous magnesium. Heating the syneresis liquid,
Upon addition of hexane, the desired product 12 crystallized out as yellow prisms at 1 quart to 191°C.

Example 127 N-(1-(m-chlorophenyl)-2-pyrazoline-
3-yl]formamide 146- 3-amino-1-(m-chlorophenyl)-2-pyrazoline (prepared in Example 118) 2.09
and a mixture of formic acid and acetic anhydride (Example 126) 1
The 0- mixture was left at room temperature for 60 minutes. The solvent was then evaporated in vacuum F to give the desired product 132 as pale yellow needles, mp 146-145'C.

Example 128 Dissolve 1.729 g of sodium metal in 10-g of absolute ethanol and add 11.0 g of p-chlorophenylhydrazine hydrochloride.
Then 420 g of crotononitrile was added over 15 minutes.

The reaction mixture was allowed to flow at 18:01. The solvent was removed under vacuum and water was added to the residue to separate the gum. This gum was dissolved in dichloromethane and separated from the aqueous layer. organic 1-
was dried over anhydrous magnesium sulfate and passed through a short column of hydrous magnesium butyrate. Evaporation of the eluent gave a glass. A small amount of benzene and then hexane was added to the glass and it gradually solidified. The solid was collected, washed with hexane, dried and 6-amino-1-(p-chlorophenyl)-5-methy)v-2 (Example 123) 2s, o
- dissolved in The reaction mixture was left at room temperature for 3 hours, then ice water was added to separate the gum. The aqueous phase was decanted and the gum was dissolved in dichloromethane. The solution was dried over magnesium sulfate and passed through hydrous magnesium silicate. The eluent was evaporated leaving a gum.

This gum was dissolved in dichloromethane. The solution was heated and hexane was added until it became cloudy. Cool this mixture and
Filtration gave the desired raw Km3.6 as off-white crystals with a melting point of 112-113°C.

Example 129 8.09 g of 5-74/-1-(p-chlorophenyl)-5-methyl-2-pyrazoline (prepared as described in Example 128) was dissolved in dichloromethane 25 g with stirring.
．． Dissolved in 0 ml. While stirring this solution,
Add slowly to 250° C. of trifluoroacetic anhydride cooled. The reaction mixture was stirred at room temperature for 3 hours, then the solvent was removed under vacuum. Dissolve the residue in dichloromethane and
This solution was passed through a short column of hydrous magnesium silicate.

Concentrate the eluent while adding hexane until it becomes cloudy.
- It was. The solution was cooled and then passed once to a melting point of 170-17.
N-[1-(p-chlorophenyl)-5-methyl-2-pyrazolin-6-yl)-2 as a white solid at 2'C
, 85 g of 2,2-trifluoroacetamide were obtained.

Example 130 3-amino-1-phenyl-2-pyrazoline (Example 1
A mixture of 10.09 (prepared in Example 16) and a mixture of formic acid and acetic anhydride (Example 126) 500- was left at room temperature for 3 hours. Water was added and white crystals were collected by filtration. This solid was dissolved in dichloromethane. The solution was dried over magnesium sulfate and filtered through hydrous magnesium silicate. The P solution was evaporated under vacuum to obtain pink crystals. Crude product 500 1
50- was recrystallized from dichloromethane-hexane, melting point 140
Desired product 403r as a white solid at ~141'C
I got n9.

Example 131 1.29 m of sodium metal to 110 m of absolute ethanol
p-chlorophenylhydrazine hydrochloride 7.59,
Next, 2.99 g of methacrylonitrile was added. The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added to the residue to separate the gum. This gum was collected and dissolved in dichloroethane. The organic bath was washed with water, dried over anhydrous magnesium sulfate, and passed through a short column of hydrous magnesium silicate. Evaporation of the eluent left a gum that solidified when hexane was added. This solid was collected and recrystallized from ether-hexitine as white crystals with a melting point of 107-10B'C.
46 g of -(p-chlorophenyl)-4-methyl-2-pyrazoline was obtained.

22 g of the compound of Br2 above was dissolved in 10.0 - of a mixture of formic acid and n-acid anhydride (Example 123). This mixture was kept on power for 6 hours. Water was added and the yellow solid was collected by one filtration. The solid was dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate and passed through hydrous magnesium silicate for one hour. The f solution was concentrated while adding hexane until it became cloudy. The mixture was cooled and filtered to yield 2.1 g of the product of this example as a white solid with a melting point of 172-174°C.

Example 132 312 g of metallic sodium was added to anhydrous ether/-/l/200-
=jK dissolved m-chlorophenylhydrazine hydrochloride 2
0.9 q and then 76 g of methacrylonitrile were added.

The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added to separate the solids.

The solid was collected, dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and passed through hydrous magnesium silicate. The P solution was evaporated to obtain a solid. This solid was recrystallized twice from ether-hexane, mp 84-8.
16.29 of 3-amino-1-(m-chlorophenyl)-4-methyl-2-pyrazoline was obtained as white crystals at 5°C.

The above product 6.09 was combined with a mixture of formic acid and acetic anhydride (
Example 125) 10- to my! It was. The mixture was kept at room temperature for 3 hours and then poured into ice water to allow some of the gum and solids to separate. This material was collected, dissolved in dichloromethane, and filtered through a short column of hydrous magnesium silicate. Add hexane to the eluent! ka, melting point 140-142°C
Product 31 of this example was isolated as light yellow crystals.

Example 133 2.0 g of 3-amino-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 113), 5.0 g of acetic anhydride, and 10 g of 4-dimethylaminopyridine.
The mixture was left at room temperature for 3 hours. The mixture was filtered once to obtain a white solid. This solid was dissolved in dichloromethane, columned as in Example 122cB) and recrystallized to give 090 g of the desired product as colorless plates, melting point 1445-1465°C.

Example 134 154-Tyl-2-pyrazolin-3-yl]acetamide A) Sodium metal (2,89) in 200 t of absolute ethanol
1 m of p-fluorophenylhydrazine hydrochloride and then 677 g of crotononitrile were added over 10 minutes. The reaction mixture was refluxed for 1614 hours. The solvent was removed with a vacuum knife and water was added to the residue to separate the solids. This solid was dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium butyrate. The eluent was refluxed and hexane was added to give 3-amino-1-(p-fluorophenyl)-5-mecal-2-pyrazoline as prismatic crystals with a melting point of 163-135'C. C1 was crystallized.

B) A mixture of 60 g of the above compound and 7.5 g of acetic anhydride was kept at room temperature for 16 hours. The mixture was filtered to collect the solids. This solid was dissolved in dichloromethane. This solution was columned and recrystallized as in Example 122(B) to yield 16 g of the live proboscis of this example as colorless needles with a melting point of 1565-137.5'C.

155- 2.4.9 was obtained.

Example 135 1.41i of metallic sodium was added to 150ml of absolute ethanol
m-fluorophenylhydrazine salt mms, dissolved in
i, p, then 818 g of p-chlorocinnamonitrile 5
Added in minutes. The reaction mixture was heated under reflux for 6 hours, then filtered and cooled. Evaporate some of the solvent,
Water was added to separate the semi-solid, which was collected, dissolved in dichloromethane, columned as in Example 117, and recrystallized to form colorless needles with a melting point of 1355-136°C. cs-amino-5-(p-chlorophenyl)-1-(+η-fluorophenyl)-2-pyrazoli 1
56-Lui 6.35.9 was added over 5 minutes. The reaction mixture was left wet for 16 hours. Pour the resulting clear dark solution into 50 ml of water.
e, ethanol 50g and 5N sodium hydroxide 20m
1 mixture. The reaction mixture was refluxed on a steam bath for 30 minutes, then cooled 7 and filtered to collect the solids. This solid was dissolved in dichloromethane and Example 118(B)
Column treatment and recrystallization as follows, melting point 182
Desired product as yellow flakes at ~1835°C 1.82
Get N.

Example 136 2.8 Il of metallic sodium was added to 10 notes of absolute ethanol [4
1 6. 26, 9, then p-chlorocinnamonitri 157-. Water was added to separate the solids. This solid was dissolved in dichloromethane, columned as in Example 113(4), and recrystallized as a pale coral solid with a melting point of 182-183°C. )-1-(p-fluorophenyl)-2-pyrazoline s. 9 sli tt? I'c.

A mixture of 4.0 g of the above product and 15.0 WLl of acetic anhydride was left at room temperature for 16 hours. Then mix the mixture with 50-
Pour into a mixture of 50 td of 595% ethanol and 55 td of 5N aqueous sodium hydroxide solution. The reaction mixture was refluxed on a steam bath for 30 minutes, then cooled and filtered to collect the solids. This solid was dissolved in dichloromethane and Example 1
Column treatment as in 18 (B) and crystallization afforded the product of this Example 2.3, li+, as off-white needles with a melting point of 133-135°C.

Example 137 Metallic sodium (2,8,!7) in absolute ethanol 2
p-chlorophenylhydrazine hydrochloride 179,17. Next, acrylonitrile 5.5.9
was added over 25 minutes. The reaction mixture was refluxed for 6 hours and then filtered hot. The p-liquid was evaporated to dryness under vacuum, then water was added to separate the solids. This solid was collected by filtration and then dissolved in dichloromethane, Example 118 (B
) and crystallized with a melting point of 1.
6-amino-1 as colorless needles at 425-145°C
875 g of -(p-chlorophenyl)-2-pyrazoline was obtained.

A mixture of 0.517 μg of the above product and 125 μg of acetic anhydride was kept at room temperature for 16 hours. The mixture was cooled and filtered to give 222 pale yellow crystals. This material was recrystallized from dichloromethane-hexane, melting point 168-170°C.
The product of this example was obtained as a white solid.

Example 168 70 g of 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline (prepared as described in Example 131) were dissolved in 25.5 g of dichloromethane. Otuft
and cooled to 5°C. The solution was stirred and 140 ml of trifluoroacetic anhydride was added. Stir at room temperature for 6
This was continued for an hour and then the solvent was removed under vacuum. The residue was dissolved in dichloromethane and the solution was concentrated by addition of hexane until cloudy. The mixture was cooled and the solid collected to yield product 5.517. 10 g of this material was recrystallized from dichloromethane-hexane, melting point 181-186°C.
The desired product 75oTn9 was obtained as a white solid.

Example 139 3-Amino-1-(p-riprophenyl)-4-methyl-2-pyrazoline (prepared as described in Example 131) '9017 was dissolved in acetic anhydride 54, Ord. . The hot solution was left at room temperature for 16 hours, and some solids separated. This solid was collected by filtration and dissolved in methanol. Then 1N potassium hydroxide in methanol was added to make basic. After 15 minutes at room temperature, the solvent was removed under vacuum and water was added to separate the solids. This solid was collected and recrystallized from dichloromethane-hexane, with a melting point of 1.
Desired product-i as white crystals at 72-173°C
6 i- I got 6.5g.

Example 140 3-Amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline (prepared as described in Example 128) 90I, 4-dimethylaminopyridine 400
■ A mixture of 20.0 fnl of acetic anhydride was added at room temperature.
I left it for a while. The resulting solid was collected by filtration, washed with cold acetic anhydride, then hexane, and dried to give a white solid. This solid was recrystallized from dichloromethane-hexane.

66 g of the product of this example was obtained as a white solid with a melting point of 167-169°C.

Example 141 162-3-amino-4-methyl-1-phenyl-2-pyrazoline (prepared as described in Example 114) io
, og was dissolved in 50 yen of acid anhydride.

Then 5 oomys of 4-dimethylaminopyridine were added and the reaction mixture was left at room temperature for 18 hours. The mixture was poured into water to separate the solidifying gum, which was collected by filtration. This solid was added to 150 d of methanol containing sulfur and lithium io, oy hydroxide while stirring. After 30 minutes, the solvent was removed under vacuum and water was added to yield a gum which solidified. This solid was dissolved in dichloromethane, dried over anhydrous magnesium sulfate, and passed through a short column of hydrous magnesium silicate. The eluent was concentrated while adding hexane to form crystals. This material was collected and dried to give the desired product 3.3.9 as a white solid with a melting point of 149-150<0>C.

Example 142 N-(1-(p-)!J Fluoroacetylphenide N-(1-phenyl-2-pyrazolin-6-yl)acetamide (Example 126) 800 ~ and trifluoroacetic anhydride 5.0 The mixture of me was left at room temperature for 30 minutes. The mixture was evaporated to dryness under vacuum. The residue was dissolved in dichloromethane, columned as in Example 118(B), and recrystallized to give a melting point 85 m? of the desired product was obtained as yellow flakes at 243-244°C.

Example 142 A mixture of 800 ml+ of do-N-(1-phenyl-2-pyrazolin-6-yl)acetamide (Example 126) and 50-ml of trifluoroacetic anhydride was allowed to stand at room temperature for 30 minutes. The mixture was evaporated to dryness under vacuum. The residue was dissolved in dichloromethane, columned as in Example 118(B), and crystallized to give 85 ml of the desired product as yellow needles, mp 243-244°C.

Example 143 6-amino-1-phenyl-2-pyrazoline (Example 1
A mixture of 10, OIl, 501 nIV of propionic anhydride and 200 drops of 4-dimethylaminopyridine (prepared as described in Section 16) was kept room wet for 30 minutes.

The mixture was cooled and filtered to give yellow crystals. This solid was dissolved in dichloromethane, columned and crystallized as in Example 118 (B), mp 1705-1
4.55.9t of the product of this example was obtained as colorless -165- crystals at 71°C.

Example 144 2.8 g of sodium chloride was added to 200 ml of absolute ethanol, 1 lilML m-fluorophenylhydrazine hydrochloride
621/, then methacrylonitrile 1341 was added.

The reaction mixture was refluxed for 18 hours, then the solvent was evaporated under vacuum. Addition of water resulted in a gum. This rubber was dissolved in dichloromethane and the solution was passed through a column of hydrous magnesium silicate. The eluate was concentrated with hexane until cloudy. The solution was cooled, seeded with a pink solid, which was collected by filtration, dried, and 3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline. 42g-166- was obtained.

The above compound 4.29 was dissolved in 10.0 μm of acetic anhydride, then 100 μm of 4-methylaminopyridine was added and the reaction mixture was left at room temperature for 16 hours. The mixture was poured into water and the solidifying rubber was separated.

This solid was collected by p-filtration and washed with water.

This solid was mixed with 50% methanol. Dissolved in Onre and 1N hydroxide in methanol) IJum 10. Otnl
added.

The mixture was left at room temperature for 30 minutes, then the solvent was partially removed under vacuum. Water was added and a yellow solid separated. This solid was collected and dried to yield 4.1 g of the product of this example, melting point 171-172°C.

Example 145 2.8p of gold parent sodium was dissolved in 100% of absolute ethanol, 15.8ys of m-tolylhydrazine hydrochloride, and then β
-Ethoxypropioni) 'J Le9.9 E/t-
Added in 5 minutes. The reaction mixture was refluxed for 16 hours,
It was then evaporated to dryness under vacuum. Water was added to the residue to separate the solids. This solid was dissolved in dichloromethane, columned as described in Example 134(4), and crystallized as colorless crystals with a melting point of 119-120°C.
-amino-1-m-tolyl-2-pyrazoline 10.1.
I got p.

The above compound 3011, acetic anhydride 15.0m and 4-
The mixture of dimethylaminopyridine 1501n9 was left at room temperature for 16 hours. The mixture was filtered to collect a small amount of solid. This solid was washed with hexane. The p solution was allowed to stand for 16 hours and filtered to collect additional solids. This material was washed with hexane. The solids were combined and washed again with hexane to give the desired product 172y as off-white crystals with a melting point of 222-225°C.

Example 146 3-Amino-1-7enyl-2-hyrazoline (prepared as described in Example 116) 5,0.9,
(200 mL of dichloromethane) 5-ethylamine and 7.0 mL of trifluoroacetic anhydride (1) The mixture was kept at room temperature for 30 minutes. The mixture was evaporated to dryness under vacuum, then water was added to separate the semi-solid. This solid was dissolved in dichloromethane. Add this solution to sulfuric anhydride)
Dried over IJum, columned as in Example 122(B), and recrystallized to give 3.0 g of the desired product as yellow-orange prismatic crystals, mp 163-165°C.

Example 147 2,2,2-trifluoro-N-[4-methyl-116
9--(α,α,α-trifluoro-m-)lyl) 0.79 m of sodium metal was added to 350 mJ of absolute ethanol &, J[L
, 5.35 g of m-)lifluoromethylphenylhydrazine salt and then 1.3 g of methacrylonitrile were gradually added. The reaction mixture was refluxed for 18 hours. The solvent was removed under vacuum and water was added to separate the solids. This solid was collected and dissolved in dichloromethane. The solution was dried over anhydrous magnesium sulfate and then passed through a short column of hydrous magnesium silicate. Evaporation of the eluent gave a solid. This solid was recrystallized from ether-hexane as white crystals (to)-3-amino-4-methyl-1-
3.6 g of (α,α,α-trifluoro-m-tolyl)-2-pyrazoline was obtained.

7.9 g of the above compound (produced as above)
was dissolved in 250 mm of dichloromethane, then 15.81 nl of 170-trifluoroacetic anhydride was added, and the mixture was stirred at room temperature for 21 hours. Excess anhydride was removed under vacuum and the reaction was repeated using hexane as medium. The reaction mixture was again evaporated under vacuum and the resulting tan solid was dissolved in ether and filtered through 200 meshes of synthetic magnesium silicate adsorbent. The p solution was concentrated while adding hexane to precipitate white crystals. The mixture was cooled for 16 hours, filtered and mp 121~
84 g of the desired product were obtained at 122°C.

Example 148 3-Amino-1,5-diphenyl-2-pyrazoline (prepared as described in Example 112) 5.09
and a mixture of formic acid and acetic anhydride (Example 123) 2
The 5.0rnlV mixture was kept at room temperature for 30 minutes. Then hexane was added and the mixture was filtered. The resulting solid was dissolved in dichloromethane.

This solution was columned and recrystallized as described in Example 122(B), yielding 655 g of the product of this example as off-white needles with a melting point of 158-160°C.

Example 149 Gold maple sodium (2,8, P) was added to 1 liter of absolute ethanol
omeniWfW4 Ll)-fluorophenylhydrazine hydrochloride 16.26f1. Next, 5.5 g of acrylonitrile was added over 5 minutes. The reaction mixture was refluxed for 7 hours, then the solvent □ was evaporated to near dryness and water was added to separate the solids. This solid was dissolved in dichloromethane.

This solution was columned as in Example 113(A) and recrystallized to give 5-amino-1-(p-fluorophenyl) product 4.15 as colorless needles, mp 114-115°C. .!7, dichloromethane 100m
ε and trifluoroacetic anhydride 10.0 m/! The mixture was kept at room temperature for 30 minutes. The mixture was evaporated to dryness under vacuum. The resulting solid was washed with water and then dissolved in dichloromethane. This solution was columned as in Example 122(A) and the desired product was recrystallized, mp 1
Product 54 as a pale yellow prismatic group at 455-147 °C
5g was obtained.

Example 150 3-amino-1-m-)dyl-2-pyrazoline (prepared in Example 145) 40I and 173- and trifluoroacetic anhydride 20. The Onf mixture was stirred at room temperature resulting in an exothermic reaction resulting in a green solution.

The solution was cooled and a precipitate formed. The solvent was evaporated under vacuum to obtain a solid. This solid was dissolved in dichloromethane. This solution was columned as described in Example 134(4) and the desired product was recrystallized, melting point 171.
Product of this example 5. as yellow needles at 5-173°C.
9 lI was obtained.

Example 151 Sodium metal (2.8 Il) was mixed with 10 of absolute ethanol, 16.2 g of p-fluorophenylhydrazine hydrochloride, and then 129 g of cinnamonitrile.
g was added over 5 minutes. The reaction mixture was refluxed for tS hours.

The solvent was then evaporated under vacuum. Water was added to separate the solids. This solid was dissolved in dichloromethane, columned as described in Example 134(4), and re-crystallized six times, filtered as yellow-brown needles with a melting point of 160-161°C. Fluorophenyl phosphorus 6, 2, and 9 were obtained.

A mixture of 40 g of the above compound, 50 ml of dichloromethane and 10 - of trifluoroacetic anhydride was kept at room temperature for 60 minutes. The solvent was evaporated under vacuum.

The remaining solid was washed with water and dried. This solution was columned as described in Example 164(4) to recrystallize the desired product, yielding 4.36 g of the product as colorless intertwined needles with a melting point of 143-1435°C. Ta.

Example 152 -3-yl] 84 g of sodium acetamide metal was dissolved in 420 g of absolute ethanol, and p-fluorophenylhydrazine salt 4 was prepared. 8
, 9, then crotononitrile 2011 was added for 5 minutes. The reaction mixture was refluxed for 16 hours. The solvent was removed under vacuum and water was added to separate the solids. This solid is p
It was collected by filtration and dissolved in dichloromethane. This solution was treated with a column as in Example 134 (4), and the product was recrystallized as prismatic crystals with a melting point of 135-136°C.
255 g of -amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline was obtained.

A mixture of 10.0 me of the above product, 50 me of dichloromethane and 25 me of trifluoroacetic anhydride was kept at room temperature for 30 minutes. The solvent was removed under vacuum and water was added to separate the solids. The solid was collected and washed with saturated sodium chloride solution. This solid was dissolved in dichloromethane. This solution was columned as described in Example 134(A) and recrystallized twice to give the original product of Example ii. as yellow crystals with a melting point of 116-117°C. i5y was obtained.

Example 153 A mixture of 30 g of amide 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline (prepared in Example 152) and 50 ml of propionic anhydride was kept at room temperature for 2 hours. The reaction mixture was poured into water and the water was decanted.

This process was repeated. (precipitate with saturated bicarbonate)
It was treated with IJum solution and then filtered. The solid was dissolved in dichloromethane. This solution was columned as described in Example 134(A) to recrystallize the desired product 177-, yielding 277 g of the product as colorless plates with a melting point of 125-1265°C.

Example 154 2.8 g of sodium chloride was dissolved in 150 g of absolute ethanol, and 16.2 g of p-fluorophenylhydrazine hydrochloride was dissolved in 150 g of absolute ethanol.
6 fl, then methacrylonitrile 6. 7 17 was added over 5 minutes. The reaction mixture was refluxed for 8 hours, then the solvent was removed under vacuum. Water was added to the residue and the oil was separated.

This oil crystallized upon standing for 16 hours. This solid was dissolved in dichloromethane, columned as described in Example 134, and recrystallized twice as colorless prismatic crystals of 3-amino-1-(1)-fluorophenyl)-4.
-Methyl-2-pyrazoline 865y was obtained.

178 - 36 g of the above compound and a mixture of formic acid and vinegar anhydride (Example 123) 15. The OmJ mixture was kept at room temperature for 16 hours. Water was added and the mixture was filtered. The collected hedrons were recrystallized from acetone-hexane and had a melting point of 166-1.
Desired product 26 as pale yellow prismatic crystals at 685°C
5g was obtained.

Example 155 A mixture of 50 g of 3-amido-5-methyl-1-phenyl-2-pyrazoline (prepared in Example 116) and 250 g of propionic anhydride was kept at room temperature for 16 hours. The reaction mixture was poured into water and the oil that crystallized was separated. This solid was collected by filtration and dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate.

The eluent was heated under reflux and hexane was added. The first heavy precipitate (purple) was discarded. The solution was cooled and the subsequent precipitate was collected by filtration. The solid was redissolved in dichloromethane, columned and recrystallized from hexane, melting point 9.
Product 2.3 of this example as platelet crystals at 60-965°C
, li+ was obtained.

Example 156 50 g of mido-6-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline (prepared as described in Example 151) and a mixture of formic acid and acetic anhydride (Example 156) 123) 850- mixture was kept at room temperature for 2 hours. The solvent was evaporated under vacuum to give an oil. Water was added to separate the solids. This solid was dissolved in dichloromethane and columned as described in Example 134(4).
After recrystallization several times, 655 g of the desired product was obtained as colorless crystals with a melting point of 1585-1605°C.

Example 157 A) Sodium metal (1,41t) was dissolved in 150% of absolute ethanol. The solution was cooled in a cold water bath and m
-Fluorophenylhydrazine hydrochloride 81g 1st p-
Chlorcinnamonitrile 818I was added over 5 minutes. The reaction mixture was heated under reflux for 6 hours and then filtered. The p liquid was cooled and water was added. The resulting semisolid was collected by filtration, dissolved in dichloromethane, columned as described in Example 164, and recrystallized twice, giving a melting point of 165.
3-Amino-5-(
p-chlorophenyl)-1-(m-181-fluorophenyl)-2-pyrazoline 2.4.9 was obtained.

B) The above compound 2. A mixture of 10.0 - OII and a mixture of formic acid and acetic anhydride (Example 123) was kept at room temperature for 2 hours. The mixture was poured into water and the oil separated and became semi-solid. The material was decanted, then water was added and the solids were collected by filtration. This solid was dissolved in dichloromethane, columned and recrystallized as described in Example 134, melting point 12.
The desired product to2II was obtained as off-white needles at 85-130.5°C.

Example 158 500 g of absolute ethanol, 50 g of 50182-% choline in methanol, 32.4 g of phenylhydrazine. ? and p-chlorocinnamonitrile 4908.9.
It was refluxed for an hour and then left at room temperature for 16 hours. The solvent was evaporated under vacuum. The solid was dissolved in dichloromethane, the solution columned as described in Example 134(A), and recrystallized twice to give 3-7 minnows as colorless needles with a melting point of 1835-185.5°C. -(p-chlorophenyl)-1-phenyl-2-pyrazoline 12.0 g
Wo? i*.

A mixture of 100 g of the above product and 100 g of a mixture of formic acid and acetic anhydride (Example 123) was kept at room temperature for 25 hours. The mixture was poured into water and the semi-solid separated. Melting point 135-136°C according to the method of Example 157(B)
, 6.3 fl of the desired product was obtained as yellow prismatic crystals with a melting point of 149-150° C. upon reassimilation.

Example 159 Sodium N-(1-(p-chlorophenyl)-5-fetometal 5.52 ,!i' in anhydrous methanol 6
It was dissolved in 00ml. The solution was cooled in a cold water bath and p-
Chlorophenylhydrazine hydrochloride 55.8 C/, then cinnamonitrile 25.9! j was added over 5 minutes. After 2 hours, the mixture was cooled and a precipitate formed. Add water;
The mixture was extracted with dichloromethane. Dry the organic layer;
It was then column treated and recrystallized as described in Example 134(4) to yield 225 g of crude product. This substance s, o,! 7 was recrystallized as above, melting point 159~
Colorless needle crystals at 161℃ and 1, 3-7 minnows 1-(p
-chlorophenyl)-5-phenyl-2-pyrazoline 3
．． 351/ttfc.

150 g of the above crude product and a mixture of formic acid and acetic anhydride (Example 123) 85. The Ome mixture was kept at room temperature for 2 hours. The reaction mixture was poured into water and filtered to collect the solids. The solid was washed with saturated bicarbonate solution and then with water. This material was dried, dissolved in dichloromethane, then columned and recrystallized as above to give 120 g of the desired product as pale yellow crystals. This thing g5. Recrystallized as above to give 470 g of the desired product, melting point 164-166°C.

Example 160 5-Amino-1,5-diphenyl-2-pyrazoline (prepared in Example 112) In.

A mixture of G, gropionic anhydride 30 and 4-dimethylaminopyridine 5009 was heated on a steam bath for 6 hours. The mixture was poured into water and the oil was separated. The oil crystallized and the solid was collected by filtration. The solid was dissolved in dichloromethane.

This solution was dried over anhydrous sulfuric acid (IJ), then columned as in Example 134 (4), and recrystallized twice to give colorless plate-like crystals with a melting point of 148.0-148.5°C. 60 g of the product of this example was obtained.

Example 161 3-amino-1-(p-chlorophenyl)-5-phenyl-2-pyrazoline (prepared in Example 11h) 2.7579 and trifluoroacetic anhydride 10
．． The mixture of 01ILIV was kept wet for 16 hours. The solvent was evaporated under vacuum and the residue was dissolved in dichloromethane. This solution was columned and recrystallized as in Example 134(4) to yield 235 g of the desired product-is 6- as pale yellow crystals with a melting point of 176-178°C.

Example 162 6-amino-1-phenyl-5-p-tolyl-2-pyrazoline (prepared in Example 111) 4.51
! , 20.0 ml of propionic anhydride, and 4-dimethylaminopyridine 2009 was heated on a steam bath for 2 hours. The reaction mixture was cooled to room temperature 1 and water was added to separate the solids. This solid was collected and then dissolved in dichloromethane. This solution was passed through a short column of hydrous magnesium silicate. The eluate was heated under reflux and hexane was added until cloudy. The mixture was cooled and filtered to collect the solids. This solid was recrystallized again from 80% ethanol. This material was dissolved in 100 me of methanol, then 200 ml of potassium carbonate was added and the mixture was refluxed for 15 minutes. Water was added until it became cloudy. The mixture was cooled and filtered to collect the solids. This solid was dissolved in dichloromethane. This solution was columned and recrystallized as above to give the desired product 2.4.9 as colorless needles with a melting point of 1265-125°C.

Example 166 Dissolve 0.86N of sodium metal in 100% of absolute ethanol Lp-chlorophenylhydrazine hydrochloride 7. '0,
9. Next, 5.5 J of p-chlorocinnamonitrile was added over 60 minutes. The reaction mixture was refluxed for 16 hours and the solvent was removed under vacuum. Water was added to separate the solids. The solid was collected and dissolved in dichloromethane. This solution was passed through a column of hydrous magnesium silicate. The eluent was heated and hexane was added. The first oil appearing from the solution was removed by filtration. The F solution was cooled to produce a precipitate, which was collected and dissolved in acetone. The solution was treated with live charcoal and filtered.

Hexane was added to the P solution to crystallize the product. This material was recrystallized from acetone-hexane, mp 149-15
3-Amino-1,5-bis(
p-chlorophenyl)-2-hy.

Lazolin 1.48# was obtained.

6-amino-1,5-bis(p-chlorophenyl)-2
- Pyrazoline (prepared as above) tasy
and a mixture of formic acid and acetic anhydride (Example 123) 1
The 0.0- mixture was kept at room temperature for 2 hours, then water was added and the mixture was filtered to collect the semi-solid. The solid was dissolved in dichloromethane, the solution columned as in Example 164, and recrystallized twice, melting point 198-
Product i, i of this example as off-white crystals at 200°C
'o, I got p.

Example 164 Onamide A) 500 μm of sodium metal was added to 250 μm of absolute ethanol.
86 g of 2-hydrazinobenzothiazole was dissolved in the solution, followed by 4-methylcinnamonitrile, and then cooled. The resulting precipitate was collected by filtration and washed with ethanol and then water to yield the crude product 13,71I. This substance is 2
- recrystallized from methoxyethanol, filtered, washed with hexane and then with methanol, as a colorless prismatic group of 2-(3-amino-5-p-tolyl-2-pyrazoline-1 855 g of benzothia-yl)benzothia 190-sol were obtained.

B) A mixture of 150 μl of the above product 35.9.4-dimethylaminopyridine and 25 μl of propionic anhydride
Refluxed for an hour. The reaction mixture was then poured into water and the mixture was left at room temperature for 16 hours.

The separated solid was collected by filtration. The solid was dissolved in dichloromethane. The organic solution was passed through a short column of hydrous magnesium silicate. The eluate was concentrated with hexane until it became cloudy. The solution was cooled and then filtered to collect the solids. This solid was redissolved in dichloromethane, columned and recrystallized as above, mp 20
Desired product 2 as colorless prismatic crystals at 8-209°C
I got 459.

Example 165 460 ~ of midometal sodium is added to 150 parts of absolute ethanol
f[L,2-hydrazinobenzothiazole 165.9.
Cinnamonitrile 12.9J7 was then added. The reaction mixture was refluxed for 16 hours, then cooled. A portion of the solvent was removed under vacuum and the mixture was filtered. The precipitate was washed with hexane to give C2-(3-amino-5
-phenyl-2=pyrazolin-1-yl)benzothiazole 25,6711 was obtained.

A mixture of 200 Da of the above product 5.951.4-dimethylaminopyridine and 25 ml of acetic anhydride was refluxed for 2 hours. The solution was then cooled and the solvent was evaporated under vacuum to obtain a solid. This solid was recrystallized from acetone/hexane. The recrystallized product was dissolved in dichloromethane. This solution was columned and recrystallized as described in Example 164) to give 1.95 g of the product of this example as pale yellow prismatic crystals with a melting point of 220-222°C.

Examples 166-177 Following substantially the method set forth in Example 73, various hydrazino compounds were condensed with acrylonitrile to produce the following corresponding example compounds.

193- Example 178 0.3 Il of lysine metal sodium in 100 parts of absolute ethanol? lFL, 2-chloro-6-hydrazinopyridine (example zs) 72y, then 4-chlorocinnamonitrile 8
．． 2.9 was added. The reaction mixture was refluxed for 18 hours and then evaporated under vacuum to give a rubber. Water was added resulting in a solid. The solid was collected, dissolved in dichloromethane, dried over magnesium sulfate, and filtered. The p solution was concentrated while adding hexane, and when it was left to stand, yellow crystals were separated. The product was collected and washed with ether-hexane to give tan solid 106I. This solid was dissolved in dichloromethane, filtered through adsorbent magnesium silicate, and concentrated to 195-94 with addition of hexane to give the product of this example as white crystals with a melting point of 157-158°C.

Example 179 As in Example 73, from a mixture of 023 g of sodium metal, 50 g of absolute ethanol, 711.9 g of 2-chloro-6-hydracinoviridine and 6.5 g of cinnamonitrile, 7.35 g of the crude product is prepared. I got .9. This crude material was dissolved in dichloromethane, filtered through hydrous magnesium silicate and concentrated with the addition of hexane, mp 18
The desired product 5,90 Il was obtained as off-white crystals at 75-1885°C.

-19 (S- Example 180) A representative compound of the present invention was tested by carrageenin-induced edema in the rat paw test and was demonstrated to be active as an anti-inflammatory agent in vivo.

This test was conducted during Winter C,A,, at, a
l,, Proc.

Soc, Exp, Biol, andMed,
111 544.

(1962) method. The compounds found to be active in this test are: 2-(3-amino-2-pyrazolin-1-yl)benzothiazole 2-(3-amino-4-methyl-2-pyrazoline) -1-
yl)benzothiazole 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)benzothiazole 2-(3-amino-5-p-)sal-2-pyrazoline-
1-yl)benzothiazole 3-amino-1-(α,α,α-trifluorom-tolyl)-2-pyrazoline 3-amino-5-ethyl-1-(α,α,α-trifluorom -tolyl)-2-pyrazoline 3-amino-1-
Phenyl-2-pyrazoline hydrochloride 3-amino-5-methyl-1-phenyl-2-pyrazoline 3-amino-4-methyl-1-phenyl-2-pyrazoline 3-amino-1-phenyl-5-p-) Zyl-2-pyrazoline 3-amino-5-ethyl-1-phenyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-2=pyrazoline 3-amino-1-(3,4-dichlorophenyl) -4-
Methyl-2-pyrazoline 3-amino-1,5-bis(p-chlorophenyl)-2
-pyrazoline 3-amino-1-(2,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline 199- 3-amino-1-( m-fluorophenyl)-5-methyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Methyl-2-pyrazoline sulfate (2:1) 3-amino-
1-(p-fluorophenyl)-5-methyl-2-pyrazoline sulfate (2:1) 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline 3-amino-1-(p -chlorophenyl)-5-ethyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline 3-amino-1- (Poison-Chlorophenyl)-4-200
- Methyl-2-pyrazoline 3-amino-5-butyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-5-butyl-1-(p-chlorophenyl)
-2-pyrazoline 3-amino-4-butyl-1-(p-chlorophenyl)
-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-propyl-2-pyrazoline 3-amino-1-(3-chloro-p-)lyl)-5-methyl-2-pyrazoline 3-amino -1-(m-fluorophenyl)-5-ethyl-2-pyrazoline3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline3-amino-1ip-chlorophenyl)-5-phenyl- 2-Pyrazoline 1-(p-chlorophenyl)-5-methyl-3-methylamino-2-pyrazoline 1-(3,4-dichlorophenyl)-3-methylano 2-pyrazoline 1-(p-chlorophenyl)-4 -Methyl-3-methylamino-2-pyrazoline 1-(m-chlorophenyl)-4-methyl-3-methylamino-2-pyrazoline 1-(p-chlorophenyl)-5-methyl-3-(2,
2,2-trifluoromethylamine)-2-birazoline 1-(p-chlorophenyl)-4-methyl-3-((2
,2,2-1-lifluoroethyl)amine]-2-pyrazoline 1-(p-chlorophenyl)-3-ethylamino-4-
Nonal-2-pyrazoline 2,2,2-1-lifluoro-N-(4-methyl-
1-phenyl-2-pyrazolin-3-yl)acetamide #-[x-(a,4-dichlorophenyl)-3-pyrazolin-3-yl]formamide N-C1-<p-chlorophenyl)-5-methyl -2-pyrazolin-3-yl]acetamide N-(1-phenyl-2-pyrazoline-
3-il) Blow? onamide 2,2,2-1-lifluoro-N-(1-phenyl-2-pyrazolin'-yl)acetamide 2.2.2-
Trifluoro-N-(1-1p-fluorophenyl)-
2-Virazolin-3-yl]acetamidoN-C1-tp-fluorophenyl)-5-methyl-2
-pyrazolin-3-yl]propionamide A/-[1-(6-chloro-2-pyridyl)-2-20
3-Pyrazolin-3-yl]acetamide N-(1-(6-chloro-2-biritur)-2-pyrazolin-3-yl)formamide Example 181 Some of the compounds of this invention exhibit activity as analgesics. F-
j tamotsu. The method used to measure the in vivo activity of the compounds of the invention was described by Sgigmund, et.

at, Proc, Soa, Ezp, Biol
, and hhd.

↓5 729. (1957).

Representative compounds of the invention that are active when tested by the ``Writhing Syndrome'' test are: 2-(3-amino-2-pyrazolin-1-yl)benzothiazole 2-(3-amino- 5-methyl-2-pyrazoline-1-
yl)benzothiazole (±)-3-amino-5-phenyl-1-(α.

204- α, α-Trifluoro m-)lyl)-2-pyrazoline 3-amino-1-phenyl-2-pyrazoline 3-amino-1-71-tolyl-2-pyrazoline 3-amino-5-
(3,4-dichlorophenyl)-1-phenyl-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1=phenyl-2-pyrazoline 3-amino-1,4-tmethyl-1-phenyl-2- Virazolinium iodide 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(2,5-dichlorophenyl)=2-
Pyrazoline 3-amino-1-(p-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline hydrochloride 3-amino-5-(p-chlorophenyl)-1-(m-
Fluorophenyl)-2-pyrazoline 3-amino-1-
(3,4-dichlorophenyl)-5-p-tolyl-2-
Pyrazoline 3-amino-1,5-bis(3,4-dichlorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-propyl-2-pyrazoline 3-amino-1-(3-chloro -p-tolyl)-5-methyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-5-ethyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-5-phenyl- 2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-phenyl-2-pyrazoline 3-ethylami/-1-(m-fluorophenyl)-4
-Methyl-2-pyrazoline3-methyl7mi/-4-methyl-1-phenyl-
2-pyrazoline 2.2.2-trifluoro-N-[5-methyl-1-H
)-)Lifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide2.2.2-)Lifluoro-
N-(4-methyl-1-phenyl-2-pyrazoline-3
-yl)7cetamido N-(1,5-diphenyl-2-pyrazolin-3-yl)-2,2,2-trifluoroacetamide #-[1,5-bis(p-chlorophenyl)-2-pyrazoline- 3-yl]-2,2,2-trinoroacetamide N-(5-methyl-1-phenyl-2-pyrazoli207
- nor-3-yl)acetamide #-[1-(ff)-fluorophenyl)-5-methyl-2-pyrazoli/-3-yl]acetamide #-(1-
phenyl-2-pyrazolin-3-yl)propionamide #-(1-m-tolyl-2-pyrazolin-3-yl)acetamide 2.2.2-)lifluoro-N-[4-methyl-1-(
α,α,α-Trifluoro-m-tolyl)-2-pyrazolin-3-yl]acetamide 2.2.2-Trifluoro-#-[1-(p-fluorophenyl)-5-phenyl-2-hylaso IJ-3-yl]acetamide 2,2,2-trifluoro-#-(1-H)-fluorophenyl)-5-methyl-2-pyrazoline-3-
yl]acetamido N-[1-(p-fluorophenyl)-5-methy208
-2-pyrazolin-3-yl]propionamide #-(1-(p-fluorophenyl)-4-methyl-2
-pyrazolin-3-yl]formamide N-C5-<p
-chlorophenyl)-1-(m-fluorophenyl)-
2-Virazolin-3-yl]formamide #-(1-(6-chloro-2-bilitul)-2-pyrazolin-3-yl)acetamide Example 182 Other in vivo measurements of drug effects on painful conditions The method is a measurement of the effect on UV-induced erythema in guinea pigs [Windgr, C.V., et.al.

A 5tudy of Pharmacology
l Influenceson Ultraviole
tErytherntt 1ILGuinea Pi
gs.

Arch, Int, Pharmacodyn,
116, 261 (1958)). Representative compounds of the invention that are active when tested by the UV-induced erythema test are:

It is: 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline 3-7mi/-1-(m-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-2-virazoline 3-amino-1-(2,4- dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline 3-aino-1-(p-chlorophenyl) -5-ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline 3-aino 1-(m-chlorophenyl)-4-methyl-2-pyrazoline 3-amino-5-butyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-5-butyl-1-(p-chlorophenyl)
-2-pyrazoline 3-amino-4-butyl-1-(p-chlorophenyl)
-2-pyrazoline 3-amino-1-(7?!-fluorophenyl)-5-
Ethyl-2-pyrazoline 211-N-[1p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide was used to determine the total in vivo analgesic activity of the compounds of the present invention. This is a foot pain test. This test is based on U.S. Pat.
．． Randal, described in No. 863.010.
dal l ) and 5elitto [A
rch, Int, Pharmacodyn, 1
11, 409 (1957)). The following compounds were tested and found to be active by this test =3-amino-1-(m-fluorophenyl)-2-
Pyrazoline 3-Amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline Example 184 Representative compounds of the present invention exhibit antibacterial activity in vitro when tested by methods such as the Woodcutter semi-agar dilution method. Antibacterial agent and/or antifungal agent
It was proven to be active as t). Compounds 9 and 1 found to be active in these tests
It is: 2-(3-amino-2-pyrazolin-1-yl)benzothiazole 2-(3-amino-4-methyl-2-pyrazoline.-1
-yl)benzothiazole 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)benzothiazole 2-[3-amino-5-(p-chlorophenyl)-2-
Pyrazolin-1-yl]benzothiazole 2-(3-amino-2-pyrazolin-1-yl)pyridine 2-(3-amino-2-pyrazolin-1-yl)-6-
Chloropyridine 3-amino-1-(5-chloro-2-pyridyl)-2-
Pyrazoline 2-(3-amino-4-methyl-2-pyrazoline-1-
yl)-6-chloropyridine 2-(3-amino-4-methyl-2-pyrazoline-1-
yl)-5-chloropyridine 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)pyridine 2-(3-amino-5-methyl-2-birazolini/-1
-yl)-6-chloropyridine 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-5-chloropyridine 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-6-chloropyridine 2-(3-amino-5-ethyl-2-pyrazoline-1-
yl)-6-ri60pyrinone 2-[3-amino-5-(p-chlorophenyl)-2-
Pyrazolin-1-yl]-6-chlorovirinone 2-(3-amino-5-phenyl-2-pyrazolin'-
1-(L)-6-chloropyridine 3-amino-1-(
α,α,α-trifluoro'n'L-tolyl)-2-
Pyrazoline (±)-3-amino-4-methyl-1-(α,α.

α-trifluoro-m-)lyl)-2-pyrazoline (±)-3-amino-5-phenyl-1-(α.

α,α-trifluoro1n-tolyl)-2-t? Pyrazoline-aε-5-ethyl-1-(α,α,α-trifluororIt-l-lyl)-2-pyrazoline 3-7mi/
-1-phenyl-2-pyrazoline 3-amino-1-phenyl-2-pyrazoline hydrochloride 3-amino-5-methyl-1-phenyl-2-pyrazoline 215
- Lazoline 3-amino-4-methyl-1-phenyl-2-pyrazoline 3-amino-1,5-diphenyl-2-pyrazoline 3-amino-1-phenyl-5-p-tolyl-2-pyrazoline 3-amino -1-p-)Dyl-2-pyrazoline 3-amino-1-(4-biphenylyl)-5-methyl-2-pyrazoline 3-amino-1-phenyl-2-virazoline sulfate (2:1) 3-amino-5-(3,4-dichlorophenyl)-1-
Phenyl-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1-phenyl-2-pyrazoline 3-amino-1-(p-methoxyphenyl)-5216
- -Phenyl-2-pyrazoline 3-amino-5-ethyl-1-phenyl-2-pyrazoline 4/-(3-amino-4-methyl-2-pyrazoline-1
-yl)-2,2,2-)Lifluoroacetophenone 3-amino-1-(m-chlorophenyl)-5-phenyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline 3-7mi/-1-(m-fluorophenyl)-2-pyrazoline 3-amino-1-(TIL-fluorophenyl )-5-
Phenyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-4-
Methyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Phenyl-2-pyrazoline 3-amino-1-(3,5-dichlorophenyl)-2-
Pyrazoline 3-amino-1,5-bis<p-chlorophenyl)-2
-pyrazoline 3-amino-1-(2,5-dichlorophenyl)-per-
2-pyrazoline 3-amino-1-(p-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline hydrochloride 3-amino-1-(2,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2=pyrazoline 3-amino-1-(p-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-5-(p- Chlorophenyl)-1-(3,
4-dichlorophenyl)-2-pyrazoline 3-amino-
5-(p-chlorophenyl)-1-(m-fluorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-p-tolyl-2-pyrazoline 3-amino-1-( p-fluorophenyl)-5-methyl-2-pyrazoline 3-7mi/-1-(m-fluorophenyl)-5-methyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl) 219
- -5-Methyl-3-pyrazoline sulfate (2:1) 3-amino-1-(p-fluorophenyl)-5-methyl-2
-pyrazoline sulfate (2:1) 3-amino-1-(p-
chlorophenyl)-5-methyl-2-pyrazoline 3-amino-1,5-bis(3,4-dichlorophenyl)-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1-(p-
fluorophenyl)-2-virazol-3-amino-1
-(p-chlorophenyl)-5-ethyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-4-methyl-2-pyrazoline 220- 3-amino- 1-(m-chlorophenyl)-4-methyl-2-pyrazoline 3-amino-5-butyl-1-(p-chlorophenyl)
-2-pyrazoline 3-amino-1-(3-chloro-p-tolyl)-5-methyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-5-ethyl-2-pyrazoline 3-amino -1-(p-fluorophenyl)-5=phenyl-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-phenyl-2-pyrazoline (([1-(p-chlorophenyl)-2-pyrazoline −
3-yl]amino)methylene)malonic acid soethyl ester 1ip-chlorophenyl)-5-methyl-3-methylamino-2-pyrazoline 1-(3,4-dichlorophenyl)-3-methylamino-2-pyrazoline 1- (p-chlorophenyl)-4-methyl-3-methylamino-2-pyrazoline 1-(m-chlorophenyl)-4-methyl-3-methylamino-2-pyrazoline 1-(p-chlorophenyl)-5-methyl- 3-(2,
2,2-)Lifluoroethylamino)-2-pyrazoline #-(t-(a,4-dichlorophenyl)-2=pyrazolin-3-yl)-2,2,2-)lifluoroacetamide 2.2. 2-) Lifluoro-N-[5-methyl-1-(
p-trifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide 2.2.2-)refluoro-
N-[4-methyl-1-phenyl-2-pyrazoline-3
-yl)acetamide2.2.2-)lifluoro-N-[4-methyl-1-(
'II-)Lifluoroacetylphenyl)-2-pyrazolin-3-yl]acetamide N-(1,5-diphenyl-2-pyrazolin-3-yl)-2,2,2-)lifluoroacetamide #-( 1-(rn-chlorophenyl)-2-pyrazolin-3-yl)-2,2,2-)lifluoroacetamide 8l-[t,5-bis(p-chlorophenyl)-2-pyrazolin-3-yl) -2,2,2-trifluoroacetamide #-(1-(3,4-dichlorophenyl)-5-methyl-2-pyrazolin-3-yl)-2,2゜2-trifluoroacetamide #-(1- (3,4-dichlorophenyl)-4-223
- Methyl-2-pyrazolin-3-yl]formamide #-[x-(3,4-dichlorophenyl)-2-pyrazolin-3-yl]formamide N-(1-phenyl-2-pyrazolin-3-yl ) Acetamide N-(1-(rn-chlorophenyl)-2-pyrazolin-3-yl)formamide #-(t-(p-chlorophenyl)-5-methyl-2-
pyrazolin-3-yl]formide #-(1-(p-
Chlorophenyl)-5-methyl-2-pyrazoline-3-
yl)-2,2,2-)lifluoroacetamide N-(1-phenyl-2-pyrazolin-3-yl)formamide #-(1-(m-chlorophenyl)-4-methyl-2-
pyrazolin-3-yl]formamide 224-N-(5-methyl-1-phenyl-2-pyrazoline-3
-yl)acetamide #-1': 5-(p-chlorophenyl)-1-(m-fluorophenyl)-2-pyrazolin-3-yl]acetamide N-C5-<p-chlorophenyl)-1-(p- fluorophenyl)-2-pyrazolin-3-yl]acetamide N-C1-<p-chlorophenyl)-4-methyl-2-
pyrazolin-3-yl]acetamido N-(1-phenyl-2-pyrazolin-3-yl)globionamide N-(:1-(?7t-fluorophenyl)-4-methyl-2-pyrazolin-3-yl ] Acetamide #-(1
-m-)Clue2-pyrazolin-3-yl)acetamide2.2.2-)Refluoro-N-(1-phenyl-2-
pyrazolin-3-yl)amide #-(+,5-
-2-pyrazolin-3-ylformamide 2.2.2-) phosphorus N-[1-(p-fluorophenyl)-2-birazolin-3-yl]acetamide 2.2.2-) fluoro -#-(1-(4-iLifluoroacetyl-ryu-tolyl)-2-pyrazolin-3-yl]acetamide 2.2.2-)lifluoro-N-C1-tp-fluorophenyl)-5-phenyl -2-pyrazolin-3-yl]acetamide 2,2,2-trifluoro-#-[ip-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]acetamide N-C1-<p-fluorophenyl )-5-methyl-2
-pyrazolin-3-yl]propionamide #-[1-(
p-fluorophenyl)-4-ethyl-2-pyrazolin-3-yl]formamide N-Cx-<p-fluorophenyl)-5-phenyl-2-pyrazolin-3-yl]
Formamide #-[5-(p-chlorophenyl)-1-
(m-fluorophenyl)-2-pyrazolin-3-yl]formamide N-C3-(p-chlorophenyl)-1-phenyl-2
-pyrazolin-3-yl]formamide N-[1-(p
-chlorophenyl)-5-phenyl-2-pyrazoline-
3-yl]formamide N-(t,s-bis(p-chlorophenyl)-2-pyrazolin-3-yl)formamide #-(1-(6-chloro-2-pyrityl)-4-methyl-2-pyrazoline -3-yl]formamide 227- #-(1-(6-chloro-2-pyridyl)-4-methyl-2-pyrazolin-3-yl)acetamide #-(1-(6-chloro-2-pyridyl) -5-ethyl-2-pyrazolin-3-yl]acetamide #-(1-(6-chloro-2-pyrazolin-3-yl)-2-pyrazolin-3-yl)formamide N-(1-(2-benzothiazolyl)-5 -p-tolyl-2-pyrazolin-3-yl]zolopionamide #-(1-(2-benzothiazolyl)-5-phenyl-
2-pyrazolin-3-yl]acetamide implementation 111
85 Adjuvant arthritis
The test used to demonstrate activity against chronic inflammation in S. s) was the Newbold technique described in U.S. Pat. No. 3,863,010 [Newbold, B., et al.

” Chemotherapy of Arth
ritis InducedIn Rats by
A4ycobacterial Adjuvant”.

Brlt, J, Pharmacol, Chemo
ther,, 21.

127 (1963)). The nine representative compounds of this invention found to be active when tested in the adjuvant arthritis test are: 1=3-amino-1-(3
,4-dichlorophenyl)-2-pyrazoline 3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-2-pyrazoline 3-amino-1 -(p-chlorophenyl)-2-pyrazoline 3-amino-1-(2,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)=5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(p- fluorophenyl)-5-methyl-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1-(p-
Fluorophenyl)-2-pyrazoline 3-amino-1-
(p-chlorophenyl)-5-ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(m-fluorophenyl)-5-ethyl- 2-pyrazoline 3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline N2CI-(pilorophenyl)-5-methyl-2-pyrazolin-3-yl]-2,2,2 -) Lifluoroacetamide 2.2.2-) Lifluoro-#-[1-(p-fluorophenyl)-5-methyl-2-pyrazolin-3-yl]
Acetamide Example 186 Adjuvant-induced experimental polyarthritis 0 [, is a specific systemic disease in rats with interesting similarities to rheumatoid arthritis. For details, the histology of the two diseases is C, A/, P
garson et al., Am. J. Pat.
h.

42.73 (1963), a remarkable 231
- have similarities; E, A/, Glenn, Ayn
, J., Vet.

Rag, 27(116), 339 (1966).

Adjuvant-induced polyarthritis has been classified as an unpleasant permanent deformity resulting from the involvement of diffuse connective tissue around certain sensitive joints in rats.

Zahiri at at,, Can, Med,
Ass, J., 101.

269 (1969), fusiform swelling of the distal joints is associated with edema, retention and arthritis (including the formation of a /4'nus).
All of them have been shown to be associated with (preceding the ultimate destruction of bone and cartilage).

Furthermore, this literature shows that the destruction of cartilage in the joints.

It has been shown that it is due to an intrusive/Jnnus that originates from the sulcal membrane and extends across and erodes the articular surface. Nonsteroidal anti-inflammatory drugs, such as indomethacin, constituted an infiltration of inflammatory cells. When suppressing swelling of arthritic feet.

Their anti-inflammatory agents also prevent joint and bone deterioration232
- It was shown that (S, Wong at al,
J, Pharm.

& Ezp, Ther, 185, 127 (19
73) and G. R. Bobalick et at.
,, Agents and Actions 4, 3
64 (1974)]. The most relevant reference book showing the relationship between arthritis and joint deterioration is Blackham, who describes the X-ray analysis of adjuvant arthritis in rats.
et at,, Agents and Actions
7, 145 (1977).

Suppression of the progression of arthritis in the paws of rats treated with the following compounds of the invention in a similar manner will also reduce the associated deterioration: 3-amino-1-(3,4-dichlorophenyl)- 2-
Pyrazoline 3-amino-1-(m-fluorophenyl)-4=methyl-2-pyrazoline 3-amino-1-(971-fluorophenyl)-2-
Pyrazoline 3-amino-1-(p-chlorophenyl)-2-pyrazoline 3-amino-1-(2,4-dichlorophenyl)-2-
Pyrazoline 3-amino-1-(m-chlorophenyl)-2=Pyrazoline 3-amino-1-(3,4-dichlorophenyl)=5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(p- fluorophenyl)-5-methyl-2-pyrazoline 3-amino-1-(p-chlorophenyl)-5-methyl-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1-(p-
Fluorophenyl-2-pyrazoline 3-amino-1-
(p-chlorophenyl)-5-ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenylcin-2-pyrazoline 3-amino-1-(m-fluorophenyl)-5-ethyl- 2-pyrazoline' 3-amino-1-(p-fluorophenyl)-5=phenyl-2-pyrazoline #-El-(p-chlorophenyl)-5-methyl-2-
pyrazolin-3-yl)-2,2,2-trifluoroacetamide 2.2.2-trifluoro-#-(t-(p-fluorophenyl)-5-methyl-2-monosolin-3-yl)
Acetamide 3-amino-1-(α,α,α-trifluoro-tolyl)-2-pyrazoline 235- (±)-3-amino-4-methyl-1-(α,Jα-trifluoro-tolyl) -Tolyl-pyrazoline 3-amino-1-(α,α,α-trifluoro-m-tolyl)-2-pyrazoline(±)-3-amino-4-methyl-1-(α,α.

α-trifluoro-? 7L-)lyl)-2-pyrazoline (±)-3-amino-5-phenyl-1-(α.

α,α-trifluoro-tolyl)-2-pyrazoline #-[1-(6-chloro-2-pyridyl)-2-pyrazolin-3-yl]acetamide #-(1-(6-chloro-2- pyridyl)-2-pyrazolin-3-yl]formamide 1-(p-chlorophenyl)-5-methyl-3-methylamino-2-pyrazoline 236-1-(3,4-sochlorophenyl)-3-methylamino- 2-pyrazoline 1-(p-chlorophenyl)-4-methyl-3-methylamino-2-pyrazoline 1-(m-chlorophenyl)-4-methyl-3-methylamino-2-pyrazoline 1-(p-chlorophenyl) -5-methyl-3-(2,
2,2-)Lifluoroethylamino)-2-pyrazoline 3-amino-5-methyl-1-phenyl-2-pyrazoline 3-amino-4-methyl-1-phenyl-2-pyrazoline 2-(3-amino -2-pyrazolin-1-yl)-6-
Chlorogyricine 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-6-chlorobiricin Example 187 Tests to demonstrate that compounds of the invention prevent the onset of asthmatic symptoms and allergic disease in mammals include:
Mediators from immunologically stimulated human basophils (
Assess the ability of compounds to inhibit the release of histamine (histamine). r*1chtttnatein.

L, M, and 0alttr, A, G,, J,
Exp, Med.

120.507-530. (1964) l/(the procedure described.

Reagents 10X Concentrated Tris Buffer
) 140.3F sodium chloride, 7.452F potassium chloride and 74.5F Trizma-Tris Pre-8et
, reagent grade, pH 7, stored at 25°C (Sigma C
chemicalCo,) f, dissolved in enough water to make final volume f21.

Human albumin (Sigma Chemical Co.) (30my
/ml) Stock solutions of calcium and magnesium Calcium chloride dihydrate and magnesium chloride hexahydrate are used to make 0.075 mol and 0.5 mol, respectively.

Tris-A buffer 10 i.l. of 10x Tris buffer and Q ml
of human albumin is diluted 100-1 with water.

Dilute 10 ml portions of 10X Tris buffer, 1.01/ml of human albumin, Q, 3 ml of calcium stock and 0,2-magnesium stock to 100 m/iC with tube water.

Rabbit anti-human IQE diagnostics (generally 10 μf (D Tough J #ri/
The final concentration of Tnt is used. ) 239- Iehokorida, - (house dlLst 5ite
) Extract (Dermatophagoides Fa
rinae) Strength 1:100 (W:V) Allergen Extract (Hollister-8tier Labs,
). Generally, this is 1:1000~t:to,oo
(consider this vial the stock solution).

Iron solution or muscle self-preparation for desensitization of other allergens (Holli
ster-8etgr Labs). The final concentration used is of the order of IPNU/d.

Four 20
80 ml of blood is collected using an m/4 phosphorus tube. This 80 ml of blood'i is mixed with 29 ml of saline solution containing a total of 0.61 dextrose and 1.2 v dextran. Pour 240ml of this blood into two 50ml bottles. No, l? IJ car +1? The cells are allowed to settle in a Nate centrifuge tube at room temperature until a sharp interface between red blood cells and plasma appears (60-90 minutes). Remove the plasma (upper) layer from each tube with a pipette 1/
) Each 5Qml! Transfer to polycarbonate 7.

Plasma 'kl l OX? and centrifuge for 8 minutes at 4°C. Carefully pour off the supernatant as completely as possible, and pipette into 5 boxes of 1 button using a siliconized Pasteur pipette.
Pasteur Pipet) 2-3rn using f
Resuspend in 1 ml of Tris-A buffer. This resuspension is
This can be done quickly by placing the tip of the pipette below the liquid and gently moving it in and out of the pipette several times to obtain a homogeneous suspension of cells. Sufficient Tris-A buffer was then added to bring the volume inside the tube to 45 ml, and the tube was
Centrifuge at 0Xf for 8 minutes at 4°C. Pour off the supernatant and resuspend and centrifuge the cell buttons as described above. Pour out the supernatant and press the cell button 2~
Suspend in 3 ml of Tris ACM buffer and transfer to a siliconized or polycarbonate container with enough Tris-10M buffer to make the final volume sufficient for addition to the reaction tube.

Reactions containing anti-IQE or antigen alone or together with test compounds in a total volume of 0.2 ml.

Prepare and place in a 37°C bath. Warm the cells to 7ils-37°C and stir frequently to homogenize the suspension.

Meanwhile, add a 1.0 ml aliquot to each reaction tube.

The reaction tubes were then heated at 37°C for 60 minutes, and these tubes i
Gently vortex every 15 minutes to keep the cells evenly suspended. When the reaction is complete, cells are pelleted by centrifugation at 1500 rpm for 10 minutes at 4°C in one reaction tube. Transfer the supernatant to a 12 x 75 m polyethylene tube.

Then add 0.2 ml of 8% perchloric acid to each tube.

Include blanks and entires in each test. The blank is a cell,
Contains all reagents except antigen or anti-1gE. The whole contains 0.24 ml of 8% perchloric acid, 1 vJ of cells and 02% buffer. all trials v4
f then centrifugation to remove precipitated proteins.

Automated Fluorophotometric Determination of Released Histamine This automated method was developed by Siraganian, R.P.
Anal.

Biochem, 5U, 383 (1974) and J. Immunol, Methods, 283.
(1975) and Hortt, P.
, A., et al.

J, Pharmacol, Exp, Ther.
217, 182 (based on the manual method of 1959).

The automation system is first-order Technicon, Auto Analyzer (
Technicon Arbtoanatyzttr
) Consists of 11 components 243- Sampler ■, Dual-Speed Proportioning Pump ■, Narrow Passage Primary Filter 7-
60 and secondary filters 2-74 and i.
tgr), recorder, and desotal gri/tar. Manifold used lisiragαn1anυ
ide 5uprα, with the following modifications: the dialyzer is omitted, all pumping tubing is passed through a large volume single proportioning pump, and twice the sample volume is analyse.

The automated chemistry consists of the following steps: extraction from alkaline saline into butanol, back extraction into dilute hydrochloric acid with addition of heptane, reaction of histamine with theta-phthaldialdehyde (OPT) at high pH and Stable fluorophore-(f) of OPT adducts using phosphoric acid
luorophore) 244-. The already 5 reaction products are then passed through a fluorometer. The full scale response is adjusted to the histamine pace of f50nf, and the limiting sensitivity is approximately 0.5 n r.

Test the instrument blank (washing solution) for each sample's histamine nf.
Subtract from the number. Then, the histamine ny number of each sample was set to 3.
Divide by the average value of two whole cells (cells lysed with perchloric acid) to obtain the percentage release.

Control samples contain antigen but no test compound. Blank (spontaneous release) sample.

Contains no antigen and test compound. The mean value of the blank (three replicates) is subtracted from the percent release for control and test compound.

The mean values for the control group and the group of test compound are calculated, and the results for the test compound are calculated as % of the control by the following formula: -order regression using the values obtained at different concentrations of the test compound. (1inea
r regtttssion ) IC to EDso (
Calculate the concentration that inhibits histamine release by 50%, μmol).

The following representative compounds have been shown to prevent the onset of asthma symptoms and allergic disease in 51Ili mammals by this procedure: 2-(3-amino-5-phenyl-2-pyrazoline-1
-yl)-5-chloro-pyridine#'-(x-(s-chloro-2-pyridyl)-5-methyl-2-pyrazoline-
3-yl)-#,#-somethyl-formamison 2-(3-amino-4-methyl-2-pyrazoline-1-
yl)-6-methylpyrinone 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-5-chloro-pyridine 3-amino-1-(5-chloro-2-pyridyl)-2-
Pyrazoline N,N-tumethyl-N'-(1-p-tolyl-2-pyrazolin-3-yl)-acetaminone Example 188 The compound of the present invention is a lipoxidanase inhibitor
(Lipozygenase Inhibito)
Other studies to show that rScreening As5ay) prevents the onset of asthma symptoms in 009.

Human platelets are suspended in physiological buffer and incubated with 200 μmol arachidonic acid in the presence of vehicle or test compound for 20 minutes at 37°C. The culture is stopped by the addition of methanol. Measurement of 12-hydroxyeicosatetraenoic acid in the lipoxygenase product by high performance liquid chromatography is a measure of the activity of the lipoxygenase.

247- The most potent mediators of asthmatic bronchospasm are leukotrienes C,
D and E. These mediators are known for their role in arachidonic acid salt lipoxylation (l ipozygttnati
on). Therefore, suppressants derived from this measurement are expected to suppress bronchospasm and are useful in effective asthma treatment. Such compounds include the following: 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-pyridi/ 3-amino-5-methyl-1-phenyl-2-pyrazoline 3-amino-1-(2-naphthyl)-2-pyrazoline 3-amino-1-θ-chlorobenzyl-2-pyrazoline- 5-one 248- 3-amino-4=methyl-1-phenyl-2-pyrazoline 3-amino-1-(m-fluorophenyl)-4-methyl-2-pyrazoline 3-amino-1-(m-fluoro Phenyl-5-phenyl-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl) = 4-
Methyl-2-pyrazoline 3--amino-1-(3,4-dichlorophenyl)-5
-Phenyl-2-pyrazoline 3-amino-1-(3,6-dichlorophenyl)-2-
Pyrazoline 3-7mi/-1-(2,6-N chlorophenyl)-2-
Pyrazoline 3-amino-1-<p-chlorophenyl)-2-pyrazoline 3-amino-1-(3,4-dichlorophenyl)-2-
Pyrazoline hydrochloride 3-amino-1-(m-chlorophenyl)-2-birazoline 3-amino-1-(3,4-dichlorophenyl)-5-
Methyl-2-pyrazoline 3-amino-1-(p-fluorophenyl)-2-pyrazoline 3-amino-t-p-tolyl-2-pyrazoline 3-amino-5-(p-chlorophenyl)-1-(3 ,4-dichlorophenyl)-2-pyrazoline3-amino-1-(3
,4-dichlorophenyl)-5-p-)dyl-2-pyrazoline 3-amino-1-(α,α,α-trifluoro-trilutolylpyrazoline (±)-3-a,mi,・no 4-methyl-1-(α, α
.

α-Trifluoro-m-tolyl)-2-pyrazoline 3-amino-1-(p-fluorophenyl)-5-methyl-2-pyrazoline 1-(3,4-dichlorophenyl)-5-methyl-2-
Pyrazoline sulfate (2:1) 2-(3-amino-5-methyl-2-pyrazoline-1-
yl)-6-chloro-pyrazine 3-amino-1-<p-chlorophenyl)-6-methyl-2-pyrazoline 3-amino-5-ethyl-1-(α,α,α-trifluoro m-tolyl) -2-pyrazoline 3-amino-1-
(p-chlorophenyl)-5-ethyl-2-pyrazoline 3-amino-5-ethyl-1-(p-fluorophenyl)-2-pyrazoline 3-amino-1-(p-chlorophenyl)-4-methyl-2 -pyrazoline 3-amino-4-dityl-1-(p-chlorophene 251
- methyl)-2-pyrazoline 3-amino-1-(3-chloro-p-tolyl)-5-methyl-2-pyrazoline 3-amino-1,-(m,-fluorophenyl)-5-
Ethyl-2-pyrazolin-2-(3-amino-2-pyrazolin-1-yl)-6-
Chloro-pyridine 2-(3-amino-4-methyl-2-pyrazoline-1-
yl)-6-chloro-pyridine 2-(3-'7"/-5-jp-chlorophenylsin-
2-pyrazolin-1-ylcu-6-chloro-pyridine 1,4,5,6-titrahydro-2-(1-pyrazolyl)-pyridine hydrochloride 3-amino-1-(5-chloro-2-pyridyl)- 2-
Pyrazoline 3-amino-1-(p-fluorophenyl)-5252
- -Phenyl-2-pyrazoline 2-[3-aε)-5-<p-chlorophenyl)-2-
Pyrazolin-1-yl]-benzothiazole 2-[5-amino-3-(p-chlorophenyl)-1-
Pyrazolyl] -1.4,5.6-Titrahydrobyrimidine Patent Applicant American Zyanamide Cannoceni - 253 - Continued from page 1 4 [Int, C1,3 Identification code Office docket number C
07D 417104 7431
-4C・'・□(C07D 401104 31100 213100) (C07D 403104 31100 241100) (C07D 417104 31100 277100) Priority claim ■July 13, 1981 [Phase] United States (US
) [Yes] 282699 @ July 1981 13B + Oki United States (US) ■ 28270
0 @ July 13, 1981 [Yes] United States (US) [Yes] 28
2826 @July 13, 1981 ■United States (US) [Yes] 2828
27 ■ July 1981 13 Indo United States (US) ■ 282905 @ July 1981 138 (Oki United States (US) [Yes] 282
971 ■July 13, 1981 [Y] United States (US) [Y] 28
2972 Inventor Joseph Peter Joseph 14 Rutherford Place, Montvale, New Jersey 07645 Inventor Seymour Bernstein 26 Scott Drive, New York 10956 New York, United States

Claims (1)

[Claims] In the formula 1, when A is a group, R1 is ■; town is phenyl or p-
tolyl; and R1 is -CO-'R4, provided that R1 is C□~C, alkyl; or where A is a group, ■, and It6 are the same or different H,01
, F, O, ~C, Argyl, -OF. or 0OOF 8, then 1 (1 is H or OI~0.alkyl; 几 is Hlo, ~C4 argyl, phenyl or in the radical formula, R7 is helogen; and -000
F, l or 100R8, provided that R6 is C1 to C4
or in which A is a radical, l1Lll and R8° are the same or different and are H or halogen, provided that both cannot be H, then R1 is ■ or 01-0. is alkyl; R3 is C1-C, alkyl, phenyl or in the radical formula, R1 and J are the same or different, H, halogen or 01-G, alkyl, provided that both of these are not H; and R11 is ■; or A is a group, and R18 and R1 are H, C1 or F, then R3 and R2 are H, O, -04 alkyl And: and R3 ke 0□~0. Alekil, 01:
120F, or a group; or when A is a group; R, is H or 01-C4 alkyl; It is O, ~0. is alkyl or phenyl;
and R8 is H; or A is a radical, 2 is N or OH, and R1, is H1 halogen or 0. -04 alkyl, if 11. and R2 are the same or different,
H, 0, ~04 alkyl, phenyl or substituted phenyl; and R8 is H, provided that when both R□ and R8 are H, A further or (2) the group 5- or the above heterocycles can be a methyl-substituted pyridine; or where A is a group, R is H,0 ，〜
0. Alkyl, Ho, 0-1OH, 0-1-000F,
or phenyl, where R3 is H or 0□~C, alkyl; R1 is H, 0,~04 alkyl, phenyl or a group, where R17 and R88 are the same or different 6- , H1 halogen or 01-04 alkyl,
However, both of these cannot be H; and R3 is H; or if A is a radical, and X is halogen or 10F, then R1 and R7 are ■i or and R8 is 1000HR or 10HO, or a pharmacologically acceptable acid addition salt thereof. 2. A compound of the formula defined in claim 1, about 05
The development of inflammatory and/or arthritic disease in mammals by 8% of the progression of inflammatory and/or arthritic disease in mammals by containing a carrier capable of reducing the amount of weight per day and a carrier capable of reducing the amount of weight per day from m9 to about 1001 rui/day. Useful to improve asthma symptoms and allergies in milk or milk products; 11. A composition in dosage unit form useful for preventing the onset of disease or as an analgesic, antibacterial or bactericidal agent in a mammal. 3 Formula as a quaternary salt In the formula, R is 01-C1-arekyl; R8 and R
7 is hydrogen or o8~0. and X is halogen; the analgesic efficacy of the compound is pharmaceutically acceptable. A composition in dosage unit form containing 141 bottles.