JPS60258134A - P-alkyl or cycloalkylphenoxyalkanol and alkanol ester and therapy for allergic condition - 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 [Technical Field] The present invention relates to the treatment or prevention of allergic reactions, and in particular to compounds effective in inhibiting the release of mediators of allergic symptoms.

[Background] A person is said to have an allergy when he or she exhibits hypersensitivity to a substance that is harmless to most people. This hypersensitivity manifests in various forms such as bronchial asthma, rhinitis, hives, and eczema. Substances in which individual alkylene groups exhibit hypersensitivity,
That is, allergens stimulate the production of specific antibodies. When an allergen comes into contact with its specific antibodies, several harmful substances are released from the cells, in particular kinins and prostaglandins such as histamine, slow reactant A, bradykinin, serotonin, leu=+4nin, kallikrein. The symptoms observed in all allergic diseases are due to the release of these toxic substances. In this field, Kalinen and Au5-ten have
Review of Pharmacolo' 1
A review article was published in 5°177-188 (1975).

Although various therapeutic agents have been prescribed for the treatment of allergies, no completely satisfactory treatment has been obtained.

Antihistamines reduce the sensitivity of some tissues to histamine, but bubbles are released during allergic reactions. , □□
13kao41. □、W □）□ has no effect. Antihistamines do not affect the release of histamine or other harmful substances released during allergic reactions.

Bronchodilators are used for symptomatic treatment of asthma, but
It does not have any particular anti-allergic effect.

Although large doses of corticosteroids suppress the inflammatory response, they are associated with serious side effects, which limit their therapeutic utility.

Several compounds are known that influence allergic reactions by inhibiting the release of mediators. However, none are known to have widespread effects, and some may have harmful side effects.

Cox, Nature, 218.1328 (191
(October 30, 1937) described the activity of a 4-H-1-benzopyrazo 2-carboxylic acid derivative (which he named cromolyn sodium or zincidium cromolygate). . However, this compound is only poorly absorbed in the gastrointestinal tract, so oral administration is ineffective and must be administered by inhalation. Furthermore, their activity is relatively low, making it impractical to administer effective amounts. Additionally, this drug must be used as a preventive drug; it is ineffective when administered as a therapeutic drug. For these reasons, although this drug has been known for a long time, it has not yet reached widespread use.
88B (H2SO), reported that chlorophenesin (ρ-chlorophenylglycerol ether) inhibits the release of histamine from human leukocytes. Before,
Berger and Bradley are The Br1tis
h Journal of Pharmacol.

, ↓, 265 (194B), describe that this compound has a muscle-binding effect with a sedative effect on central nervous system interneurons similar to that elicited by mephenesin. Furthermore, Berger
, Hubbard, Ludwig, Journal o
f Ap surplus work last Microbiolo, i, 14F
i (1953) describes the antifungal and bacterial effects of this compound.

Berger, 7: ukui, Goldenbaum
, DeAngelo and (:handlee, T
he Journal of Immunolo, 1
02 U. 1024 (+969), reported on the effects of this drug on the immune response. When chlorophenesin was given along with the antigen, antibody production was suppressed.

This drug can also help delay the onset of hypersensitivity reactions when administered when allergic symptoms are about to occur.

Chlorophenesin has also been shown to subside passive cutaneous anaphylaxis induced by penicillin.
ger, Fukui, Ludwig, and Mar
golin (+967).

Also, Malley and Baecher
l of Im-munology, bile 7. 588
(+971) report that chlorophenesin suppresses allergen-reagin-induced histamine as well as 5R3-A release from monkey lung tissue passively stimulated with human reagin.

Kimura, Inoue, Honda reported that chlorophenesin and cromolyn sodium are effective against IgE-anti-
They demonstrated that it suppressed the degranulation formation of rat mast cells mediated by the IgE response, and published their findings in 1Kunfukengi, 983 (1974).

S i raganian and Siragania
n, Journal of Im-munology
, Dan 2.211? (1974), chlorophenesin also. It also inhibits the release of histamine induced by concanahachilin A from basophilic leukocytes.

S 1tes, Brecher, Schmidt,
and Berger et al. showed that chlorophenesin inhibits B in mice and humans induced by phytohemagglutinin, lipopolysaccharide, or staphylococcal protein A.
reported that it suppresses the mitogenic response of cells and T cells. This compound also suppresses mixed lymphocyte reactions in inbred strains of mice and unrelated human companions (Immur+o-pharmacology, in press, 1978).

These results suggest that chlorophenesin has a wide range of effects in suppressing the release of various mediators, inducing antitoxicity and influencing the initiation of antigenicity in immune cells. 2'f
'＜Suggesting. However, chlorophenesin has low activity and is rapidly metabolized and degraded in the body, which has impaired its practicality. This interesting property of chlorophenesin has stimulated research into related compounds.

Inai, 0kazaki, Shimada, Kag
U.S. Pat. No. 3,846, by E.I. and Be5sho et al.
No. 480 (patent granted on November 5, 1974) describes chlorophenesine succinate and its alkali metal salts, and these compounds have been shown to be effective against chlorophenesine release suppressing effects in hypersensitivity. It has been reported that it has a much better effect than Shin. These compounds are not used clinically because of their insufficient medical and pharmacological effects.

Relsner, Ludwig, Fukui and Berger, U.S. Patent 3,879,544 (19
Patent granted on April 22, 1975) discloses a series of arylthioalkanols of the following formula.

Here, X represents halogen or lower alkyl, m represents an integer of 1 or 2, and n represents an integer of 2 to 6. Throughout this specification and claims, lower alkyl refers to
-8 carbon chain.

However, these compounds have serious side effects and high toxicity, making them too dangerous to use.

Prior to 1975, at the time of U.S. Pat. , was only evaluated for its ability to inhibit histamine release from stimulated cells. However, now allergy symptoms are caused by slow-reacting substance A (SR
3A), is understood to be caused by the release of a variety of substances, including serotonin, bradykinin, and a number of mediators of various prostaglanids.

Therefore, it is important to determine whether the compounds of this invention inhibit the release from cells and tissues not only of histamine but also of other mediators released during allergic responses or tissue stimulation. , a test designed to obtain the results was adopted. Compound 48/80 is one of the substances having such properties. This compound is Good+*
Pharmaco-1o by an Gilman
1cal Ba5is of Thera eutic
s, 3rd edition, p. 622, Macmillan Publishing, New York (19f15), now published by Lewis
Br1tish Journ by Whittle
al of Pharmacolo y, 61゜2
28 ('1977').

In studies other than allergic reactions, Berger and Fuku
In U.S. Pat. No. 3,549,766 (granted on December 22, 11170), in order to resist or alleviate hypersensitivity to penicillin, a specific phenoxydibrobanol or phenoxy compound having the structure of the following formula is used together with penicillin. It describes how to dispense propanediol.

wherein X is selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy groups. Also,
R and R1 are each selected from the group consisting of hydrogen and hydroxyl, and at least one is hydroxyl.

As used herein and in the claims, the terms "lower alkyl" and "lower alkoxy" refer to alkyl or alkoxy groups, respectively, having from 1 to about 6 carbon atoms.

This group of compounds includes chlorophenesin (where X is chlorine and R and R2 are each hydroxyl groups). The patent states that phenoxydibrobanol or phenoxypropanediol releases chemical mediators that are responsible for the symptoms of allergic diseases and many of the symptoms of irritation and inflammation caused by irritants and inflammatory substances. There is no suggestion of the possibility that by suppressing it, it has the effect of suppressing specific allergic hypersensitivity or abnormal tissue reactivity caused by specific irritants.

Berger and Fuku-i published a report at the same time,
rainbow nale dell' Arterioscler
osi V, No 5. In the September-October 1987 issue, we reported on the effects of phenoxypropanediol on the mitigation of penicillin-induced passive anaphylactic reactions, particularly chlorophenesin (3-p-chlorophenoxy-1,
2-propanediol). At the end of this report, the authors summarize as follows:

These observations are particularly interesting because the mode of action of these compounds is quite different from previously described inhibitors of anaphylactic reactions.
7-Noue Probanediol does not destroy penicillin or affect its action as an antibiotic. These compounds do not have antihistamine or anti-inflammatory properties, nor do they suppress general tissue reactivity. These seem to work by selectively protecting specific antibody sites, thereby preventing those antibodies from reacting with penicillin. This effect is of great interest, especially because of its specificity. Due to the effect of phenoxypropanediol on skin hypersensitivity,
New approaches to treating hypersensitivity and autoimmune diseases may become possible.

Berger, Fukui, Ludwig and
Margolin is 1.20 yen! ”! rainbow! 1st Bio Coffee LlIMedicine, 12%, 3
03-310 (198?), and reached the same conclusion on page 310.

A group of compounds synthesized according to this invention are analogs of chlorophenesin, but have a much stronger mediator inhibitory effect and are more resistant to inactivation by metabolic reactions in the body. Moreover, it has no toxicity or harmful side effects.

The efficacy of these compounds in inhibiting mediator release is virtually 4-20 times more effective by weight than chlorophenesin and 5-50 times more effective than cromolyn sodium. As a result, these compounds represent an important advance in the treatment of allergic conditions and allow for the first time a practical approach to inhibiting the release of all mediators.

SUMMARY OF THE INVENTION In one aspect, the present invention is directed to compounds of the following formula and pharmacologically acceptable esters of these compounds. Here, R is an alkyl group (having 1 to 6 carbon atoms) or a cycloalkyl group, which is optionally bonded to the 3rd and 4th positions of the benzene ring of the compound of formula 1, and Z is a heavy chain alkylene group (having 1 to 6 carbon atoms). 1
~15), optionally substituted with one or two lower alkyl groups (1 to 3 carbon atoms), and when the compound of formula I is not esterified, Z is unsubstituted propylene I can't. In one aspect, the present invention also relates to pharmaceutical formulations effective in preventing allergic reactions in humans, containing a compound of formula (1) as an active ingredient. However, such formulations also include those in which the compound of Formula 1 is not esterified and Z is unsubstituted propylene.

[Preferred embodiments] A, constant-1 ``alkyl group (having 1 to 6 carbon atoms)'' means having 1 carbon number
~6 linear or branched saturated hydrocarbons, examples of which include methyl, ethyl, orbutyl, and n-hexyl groups. It also includes cycloalkyl X such as cyclohexyl group and cyclopentyl group, and indanyl is a typical example of benzene with a cycloalkyl group bonded to it. )・1 ``Linear alkylene group (1 to 15 carbon atoms)'',! - is a residue represented by the formula -(CH2,)h-, where n is an integer from 1 to 15. Examples of such groups include hexylene, decyl, butylene, and the like. “°
Optionally substituted with 1 or 2 lower alkyl groups (1 to 3 carbon atoms) means that the alkylene residue is
This means that it may or may not be modified to have a methyl, ethyl, n-propyl, or i-propyl group as a side chain in place of one or two hydrogen atoms. That is, for example, when defining Z in the compound of formula 1, if alkylene is a butylene group, 2 is -(C)12)
4-+ -CHOHCHC; H-CH3, or CH containing -CH2-CH-CH-CH2-, etc.

I can do that.

``Pharmacologically acceptable esters'' are those in which the free 10H group of the compound of formula 1 is reacted with a pharmacologically acceptable acid or an active form thereof, i.e., a carboxylic acid or a carbamic acid, or a carbonic acid ester. It is an ester synthesized by

Suitable carboxylic acids include halogen- and nitrogen-containing acids, as well as alkyl and hydroxyalkyl carboxylic acids such as acetic acid, valeric acid, hexonic acid, and glycolic acid, as well as glyceric acid, erythronic acid, threonic acid, and gluconic acid. acids, galactonic acid, mannonic acid, gulonic acid,
Sugar acids such as idonic acid, atronic acid, and allonic acid, as well as cyclopropanoic acid, cyclobutanoic acid, cyclopenconic acid, cyclohexanoic acid, cycloheptanoic acid, cyclooctanoic acid, benzoic acid, salicylic acid, m-chlorobenzoic acid, p- Chlorobenzoic acid, m-hydroxybenzoic acid,
Protocatetic acid, gentisic acid, gallic acid, phenylacetic acid, toluic acid, xylenic acid, hydrocinnamic acid, naphthoic acid, α-picolinic acid, isonicotinic acid, nicotinic acid,
quinic acid, naldinic acid, zincronic acid, acridine monocarboxylic acid, phenanthridine 7/°carboxylic acid,
Pyrimidine monocarboxylic acid, pyrimidine monocarboxylic acid,
Examples include pyridazine monocarboxylic acid and triazine monocarboxylic acid. Furthermore, carbonic acid esters include alkyl esters such as methyl carbonate and ethyl carbonate.

81-1 Synthesis The compound of formula 1 can be synthesized, for example, as follows.

(B) Here, Z' is Z modified so that it does not have a hydroxyl group directly adjacent to the carbon, and R' is a protecting group, preferably an alkyl group, or a group that responds to nuclear attack on the adjacent carbon. is a suitable leaving group.

The nature of R' is not woody, and it may be any group as long as it is compatible with all reaction conditions, but intermediate B
Alkyl groups are preferred because the functionality of is simplified. X
Typical examples are halogen groups and sulfonic acid groups, but
All common leaving groups can be used.

In this series of reactions, the compound of formula A is, for example, a phenol having a suitable substituent R at the para position. This starting material can be combined with a suitable base such as an alkyl metal hydride, alkyl metal hydroxide, carbonate or alkoxide, or an organic base such as a quaternary amine, e.g. pyridine, or a quaternary base such as tetramethylammonium hydroxide. ammonium hydroxide in an inert polar aprotic solvent, such as dimethylformamide or THF, to form a phenoxide ion. Next, add compound 2B and heat from room temperature to about 25°C.
The reaction is carried out under appropriate heating conditions of -150°C. Then,
The condensation product C is either isolated by conventional methods or converted directly to the compound of formula I in step 2.

If there is no alkyl substituent on the carbon adjacent to the hydroxyl group of the compound of formula 1, step 2 is a simple reduction reaction using a metal hydride such as lithium aluminum hydride, diisobutyl aluminum hydride, or poran. This reaction is carried out in an inert solvent such as an ether such as THF or dioxane, or a hydrocarbon solvent such as toluene. If the alkyl group is attached to the linear alkylene group directly adjacent to the hydroxyl group in the compound of formula 1, the reduction in step 2 may be performed using a suitable reagent to compensate for the effects of the required alkyl substituent. Implemented. For example, in the compounds of the present invention, Z is -GHz, CH
In the case of 2(: (CH3) 2-), the compound 2 is treated with a suitable organic compound such as a methyl Grignard reagent, such as methyllithium, in the presence of a generally well-known inert solvent. In the compound of formula 1, Z is CH2C
In the case of H2CH (CH:s'), the chemical formula (CH3)
Reaction with a less reactive organometallic compound such as dimethyl cadmium 'z cd to give the corresponding methyl ketone is followed by the reduction method described above to give the corresponding alcohol.

A variation of the above-described method may also be used in which X is not used as a leaving group in response to attack by phenoxyto ions, but instead a suitable I-ene compound is used.

In other words, in this case, the compound 2B is 0H2=CH-Z''
- has the structure of GOOR'. Here, the π-bonded carbon is the terminal carbon of Z' and Z'' is its residue. The reaction conditions of this variant are as follows:
This is similar to case A above, which uses the structure of DOR'.

To convert the compound of formula ■ into a suitable pharmacologically acceptable ester, i.e., the following formula 9 compound (where Y represents the residue of a pharmacologically acceptable acid), it can be converted to boron trifluoride, ``Treatment'' with a suitable acid in the presence of a strong acid such as hydrogen chloride, sulfuric acid, p-1 luenesulfonic acid, etc. Since the alcohols of the present invention are mostly solid, this reaction is difficult because the free acid or alcohol reagent is soluble. carried out in an inert organic solvent, for example a hydrocarbon solvent such as hexane, decane, benzene, xylene, a halogenated hydrocarbon solvent such as methylene chloride, dichloroethane, chloroporm, or an ethereal solvent such as diethyl ether, tetrahydrofuran. This reaction is carried out at the reflux temperature of the reaction mixture from 0°C, but preferably at about 15-35°C using hydrogen chloride as a catalyst.

Alternatively, activated forms of acids such as acyl chlorides may be used.

The reaction product is isolated according to conventional methods. For example, after diluting the reaction mixture with water, the aqueous mixture is extracted with a water-insoluble organic solvent such as diethyl ether or benzene, the extracts are combined, washed with water until neutral, and then extracted under reduced pressure. The solvent is distilled off.

Alternatively, esters can also be obtained by transesterification according to well-known methods. Various esters of the present invention can be synthesized by changing the type of vinegar and the alcohol of the present invention.

C9-1 ratio.''8y These compounds were developed by Relsner et al.
It differs from the compound disclosed in No. 79,544 in that it is an oxyether rather than a thioether. moreover,
In the compound of the present invention, the para-substituent of the phenoxy group is an alkyl group or an alkylene group, and this alkyl group does not have to be branched, but it is a tertiary 7 jlz + Ay
The group is preferably 1 to 1.1. ,.

Relsner et al. do not disclose any branched alkyl group. Converting thioether to oxyether eliminates the toxic reaction, and Re1Sner
Although not mentioned in the patent, it is thought that this toxicity is associated with the thioether bond.

The compounds of the invention are chemical mediators of allergic symptoms, including allergic rhinitis, asthma, hypersensitivity of the skin and gastrointestinal system, and many other irritations and inflammations caused by irritants and inflammatory agents. By suppressing the release, it can be used to suppress specific allergic hypersensitivity or abnormal tissue reactivity due to specific irritants, and to suppress transplanted cells, organs,
In particular, it prevents rejection of Langerhans cells, which produce bone marrow insulin.

The compounds of the invention can also be used to reduce or alter graft-host and host-graft reactions to prevent rejection of transplanted tissues and organs. Examples of such applications include the transplantation of healthy bone marrow into leukemia patients, or the transplantation of insulin-producing Langerhans cells into diabetic patients.

When the compound of the present invention is administered together with substances that may cause allergic reactions to the skin, the development of hypersensitivity to these substances can be prevented.

The inhibitory effect of the compounds of the invention on all the above therapeutic effects can be summarized in the following sentences.

``By inhibiting the release of chemical mediators responsible for allergic diseases and the symptoms of irritation and inflammation caused by irritants and inflammatory substances, it is possible to prevent specific allergic hypersensitivity and tissue abnormalities caused by specific stimuli. Helps suppress reactions. '.

The compounds of the present invention can be administered orally, parenterally (intravenously,
They can be administered to animals by any route that allows administration, such as intraperitoneal administration, subcutaneous injection, intramuscular injection, etc.), or inhalation. By inhibiting the release of the chemical N4 that causes symptoms such as irritation and inflammation caused by allergic diseases and irritants and pro-inflammatory substances,
The amount should be sufficient to suppress specific allergic hypersensitivity and abnormal tissue reactions caused by specific stimuli. This amount depends on the species and weight of the animal. For example, when administered to humans, a dosage of about 2 mg/kg to 100 mg/kg per day of the alkanol or ester compound is sufficient. Treatment of lower test animals also shows therapeutic efficacy in a similar range of doses. The upper limit of the dosage is: determined by the adverse side effects, which can be determined by trial and error on the animals to be treated, including humans.

For ease of administration, the P-alkyl or cycloalkylphenoxyalkanol or ester compounds may be provided as a formulation, preferably in dosage unit form. Although the compound can be administered alone, it is usually administered with a pharmaceutically acceptable carrier that dilutes the compound for ease of handling. "Pharmacologically acceptable means that the carrier (as well as the resulting composition) is sterile and non-toxic.

The carrier, in other words, the diluent, may be solid, semi-solid, or liquid, and serves as an excipient, binder, or engraving agent for the p-alkyl or cycloalkylphenoxyalkanol or ester compound. accomplish Typical diluents and carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starch,
Gum arabic, calcium phosphate, mineral oil, cocoa powder, alginate, gum tragacanth, gelatin, syrup,
Examples include methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl and propyl hydroxybenzoic acid, talc or magnesium stearate. Other reagents that can be used to solubilize and disperse compounds of the invention include dimethyl sulfoxide (DM
SO), N,N-dimethylacetamide (DMAC),
Sorbitol or mannitol esterified with propylene glycol and hexitol fatty acid esters of polyoxyethylene ether, such as lauric acid, stearic acid, pal':・mitic acid, or oleic acid, is condensed with 10 to 30 moles of ethylene oxide. There are things like that. As a commercially available hexitol fatty acid ester of polyoxyethylene ether, Tween 80
．． Examples include polyoxyethylene sorbitol oleate, sorbitol oleate obtained by condensing 20 moles of ethylene oxide per mole of sorbitol, and the like.

For convenient handling, the P-alkyl or cycloalkylphenoxyalkanol, or ester compound, and carrier or diluent can be packaged or encapsulated in containers such as capsules, sachets, cachets, gelatin, paper, etc. . Dosage units can be in the form of tablets, capsules, suppositories, or cachets, for example.

The following examples are intended to illustrate various dosage unit forms of p-alkyl or cycloalkylphenoxyalkanol or ester compounds that can be prepared.

Actual JE usual p-alkyl or cycloalkylphenoxyalkanol or ester compound 15 Lactose 86 Cornstarch (dried) 45.5 Gelatin 2.5 Magnesium stearate 1. Powder the O p-alkyl or cycloalkylphenoxyalkanol or ester compound, pass through a mesh e-sieve and mix well with lactose and 3 (1 wg cornstarch) passed through the sieve, respectively.

The mixed powder is agglomerated with a medium temperature gelatin solution that is mixed with gelatin in water and heated to a 10% v/w solution.

The mass is granulated through a sieve and the wet particles are dried at 40°C.

Regranulate the dry particles through a sieve and add the remaining cornstarch and magnesium stearate and mix thoroughly.

The particles are compressed to produce tablets of +50II 1 g each.

p-Alkyl or cycloalkylphenoxy alkanol or ester compound 100 Lactose 38 Corn starch (dried) 80 Gelatin 4.0 Magnesium stearate 2.0 Hvag's M starch was used in the granulation process and 20 mg of starch was added during tabletting. The manufacturing method is the same as in Example A except for the use.

Capsules manufactured by Fusekikari S mg/capsule p-alkyl or cycloalkylphenoxy alkanol or ester compound '250 Lactose 150 p-alkyl or cycloalkylphenoxy alkanol or ester compound and lactose are passed through a sieve so that each capsule contains 400 mg of the mixture. Mix the powder well and fill into hard gelatin capsules of appropriate size.

Phantom 11 Locus J 1g/Suppository p-alkyl or cycloalkylphenoxyalkanol or ester compound 50 Cocoa butter 950 Powder the p-alkyl or cycloalkylphenoxyalkanol or ester compound, pass through a sieve,
Grind with melted cocoa butter at 45°C to form a smooth suspension.

The mixture is stirred well and poured into molds with a nominal capacity of 1 g to make suppositories.

Support ■1 (.

Cachet 11g/Cachet p-alkyl or cycloalkylphenoxyalkanol or ester compound 100 Lactose 400 p-alkyl or cycloalkylphenoxyalka/
The alcohol or ester compound is passed through the mensch loop, mixed with the rough lubricant previously passed through the jeep, and filled into suitably sized cachets containing 500+ig each.

Intramuscular Injection LL111111 Member Blue 5 p-Alkyl or cycloalkylphenoxyalkanol or ester compound 10 Sodium citrate 5.7 Sodium carboxymethyl cellulose (low viscosity grade) 2.0 Methyl paraoxybenzoate 1. 5 Propyl para-oxybenzoate 0.21.0 ml Injectable water seed J1 Intraperitoneal, intravenous or subcutaneous injection (aqueous carrier sterile milk 1 ml) p-Alkyl or cycloalkyl alkanol or ester compound 15 Citric acid Sodium 5.7 Sodium Carpoxymethyl cellulose (low viscosity grade) 2.0 Methyl para-oxybenzoate 1.5 Propyl para-Φoxybenzoate 0.21.0+al water for injection, Hikari Isao The following examples are It is for illustrative purposes only and is not intended to limit the scope of the invention.

10, Og (H, 7 mmol) of pt, butylphenol in anhydrous dimethylformamide → 5f) WIl solution in anhydrous dimethylformamide of 8.4 g of sodium hydride (as a 50% dispersion) → 500 II
into a mechanically stirred slurry consisting of L.

6.3 g (68.3 mmol) in this phenoxyto solution
Anhydrous dimethylformamide of monochloroacetic acid - 50m
1 solution was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 200 ml of diethyl ether and acidified with 3N hydrochloric acid. Remove the gummy residue from the aqueous phase. This was dried in vacuo to obtain 9.0 g (95%) of pt-butylphenoxyacetic acid.

Separation: NMR spectrum (CD(:I3)δ1-25(s,
9) 1゜7.03 (q, 4H, - (04M! ) -0
5.2 g (25 mmol) of 2-p-t-butylphenoxyacetic acid in anhydrous tetrahydrofuran cooled to 0 °C lomj1. 45 g (
A solution of 0.95 M poran (42 mmol) in tetrahydrofuran was added dropwise. After 10 minutes at 0°C, the solution was brought to room temperature.
Stir for 1 hour. Next, the reaction mixture was adjusted to pH with 3N hydrochloric acid.
Acidified to 2.5 hA, washed with 5 hA of water, and extracted with dichloromethane (2X 200 L). Combine the organic phase;
Dry and concentrate to give a yellow oil. This was distilled in vacuum (88°C 10,075+a+aHg) and 1! A clear colorless oil, 2-p-t-butylphenoxyethanol, was obtained.

Column: NMR spectrum (CDCl, ) 61.28 (s,
9H.

(CHyo)3G-), 4.00(m, 4H,-0(C
;H,CH2)-OH), 7.10(q,4H,-(
C,)+4)-).

Calculated value: CIZ Hllll O□: C,? 4.2
) I, 9.34 actual measurement value: C, 74,4; H,
9,5925 g (0,187 mol) of pt-butylphenol, 0.2 g of sodium hydride (as a 50% dispersion), 0.28 of N-phenyl-2-naphthylamine (basic polymerization inhibition) A solution consisting of 75.0 g (0,588 mol) of butyl acrylate of
Heated at 25°C for 4 hours. The temperature was then lowered to ioo'c and excess acrylate was distilled off under mild vacuum. The resulting oil was filtered through 900 g of silica gel (90-200 mesh) using chloroform as the eluent to yield 21.0 g of pure 3-(pt-butylphenoxy)-propione) (45%). Obtained.

21.0 g of the codiester were dissolved in 500+wI dry ether and cooled to -5°C in a water/acetone bath. To this cooled solution was carefully added 3.5 g of lithium aluminum hydride in 100% anhydrous ether. Bleed out the air for 1 hour and remove 200+wt of excess hydrogen lithium aluminum.
Disrupted by carefully adding ethyl acetate and then 50+wL water. Filter the solution and add the filtrate to 20ht ether/200f
It was distributed between fl trees. The organic phase is collected, dried and
It was then evaporated to give a yellow oil. This was vacuum distilled over potassium carbonate (116°C, 10.35 mHg),
10.1 g (I (4%)) of 3-p-t-butylphenoxyprop/'-ol were obtained as a clear colorless oil.

'tlJ: NMR spectrum (CDCl3) 61.31 (s,
9H.

(CH3)s-), 1-95(m, 2)1. -CH
z (CH2)G)! , OH), 3.88(t, 2
H, -CH, (CH2) (IH).

3.95 (t, 2H, -0(to H2) CH2(H
OH), 7.05(q, 4H, -(c', H4)
-).

Calculated value: C,,Hyu 02: C,75,0; )I,
, 9.68 Actual value: C, , 75,2; H, 9,7?
To a stirred slurry consisting of 1.8 g of anhydrous dimethylformamide (as a 50% dispersion) of sodium hydride was added pt-butylphenol (33 g.
, 3 mmol) of anhydrous dimethylformamide → 500
A solution consisting of a+L was added dropwise and the solution was stirred under nitrogen until the phenolate was completely formed. Add 5.0 g (33,3
A solution consisting of 50 ml of anhydrous dimethylformamide of Millimorun was added and the solution was stirred for 14 hours. The reaction mixture was partitioned between water/toluene. The organic phase was collected and washed with water then IN sodium bicarbonate. The organic phase was dried and decomposed to give 5.6 g of an orange oil.

This oil was chromatographed using 500 g, 90-200 mesh silica gel (eluent CH2'C1y) to give pure 4-(pt-butylphe/'xy)-butyl acetate.

Loss: NMR spectrum (CDCA3) δ1.3 (s,
9H.

(CH3) 3 G-), 2.00 (s, 3H,
CH3).

1 4.40(1,48,O-(CH2) CH2CH2C
H20G-) 7.03(q, trH,,-(C6L
)−).

Calculated value: Cre H24032C, 72Nia
; H, 9, 15 actual measurement value: C,? 3.0, H, 9
, 18 Gohiro' 1.1 g, 2.0 g into a stirred solution consisting of 14.0 mmol of acetyl chloride 50 mZ,
9.0 mmol of alcohol 4-p-t-butylphenoxy-1-butanol in anhydrous dichloromethane 25 m
/: The solution was dropped. The solution was stirred for 16 hours and 50I
It was quenched with IZ water. Collect the organic phase and dry it.
5O4) and concentrated to give a yellow oil. This was vacuum distilled with potassium carbonate-L (122℃/0.35m
mHg) L, te, clear colorless oil a-(pt
-butylphenoquine)-butyl acetate was obtained. N.M.
The R spectrum is the NM of the acetate obtained by method A.
It was consistent with the R spectrum.

This acetate ester (24,!3g) was heated under reflux for 1 hour.
25m1. Treated with IN methanolic potassium hydroxide. Then, methanol was evaporated and the residue was
Partitioned between ml dichloromethane and 300+ of water. Collect the dichloromethane solution and dry (Mg5O,)
, and evaporated to give a yellow oil.

This is vacuum distilled to produce a clear colorless oil, 4-pt-
Butylphenoxy-l-butanol 19.2g! □(
92%).

NMR spectrum (CDC: lA) δ1.27 (s,
9H.

(C)I:+) 3-), 3.85 (t, 2
H, -(OH2)OH).

3.95(t,2H,O(CH2)CH,-),
7.05 ((1,4H.

l　C6)+4　)-).

Calculated value: Cr 4 H2202: C,? 5. e ;
H, 9, 97 actual measurement value: C,? 5.8, )l,
10.0 Sodium hydride (as a 50% dispersion) 3.2 g of anhydrous dimethylformamide → 10.0 g (ee, e mmol) of pt-butylphenol in a stirred slurry of 10 hl of anhydrous dimethylformamide ÷100 mt solution was added dropwise, and the chlorine solution was stirred until phenol 1 was completely formed. 12.0 g of 5-bromo-1-pentene in the phenolate solution, Q
, 1lQ5 moles of anhydrous dimethylformamide ← 100
mA solution was added. Stir the reaction mixture and then
Partitioned between 500mf/500mL water. The ether was collected, dried (Mg5C14) and evaporated to give a yellow oil. This is vacuum evaporated (69°C/
0.03m+a) and clear colorless oil 5-
pt-butylphenoxy-1-pentene 10.5g
(72.2%) was obtained.

Nine prayers: NMR spectrum (CrJC13) 81.27 (s,
f3H.

(GHj) :+ C-), 3.92 (t, 2H
, -0 (CH7).

5.87 (m, IH, -(' CH,) = CH7)
,? , oa(q, 4H.

-GeH4)-.

5-(p-t-butylphenoxy)-1-pentene (1
0.5g) to 0.5M 9-borabicyclononane 11
It was treated with 5 m/ml of tetrahydrofuran solution and the reaction mixture was stirred under reflux for 1 hour. Cool the solution to room temperature, 3
2511 parts N sodium hydroxide, then 1 part 30% hydrogen peroxide
It was treated with 0ml. After the bubbling stopped, the reaction mixture was partitioned between 150st/150mf water. The ether phase was collected, dried (Mg5o, ) and evaporated to give a yellow oil. 300g.

Silica gel of 80 to 200 mesh (eluent 2% Me
This oil was chromatographically separated using OH/+1; H2R7) to give a yellow oil. This was vacuum distilled (126° C./Q, 75+i layer) to obtain 1.7 g of a clear colorless oil, 5-pt-butylphenoxy-1-pentanol.

Separation: NMR spectrum (CIICA3) δ1.27 (s,
9H.

(CH3) 3'(: -), 3.83 (t, 2
H, -(CH2).

OH), 3.93(t, 2H, -(OH7) OA
n), 7.08 (q.

4)1. -(0684)-).

Calculated value: C+s H2402: C, 7B, 2;
H,10,2 actual measurement value: C,7B,2; H,10
, 3 branch lamps Sodium hydride (as a 50% dispersion) 0.8
To a stirred solution of 4 g of anhydrous dimethylformamide was added 2.0 g of pt-butylphenol (13.3
A solution of 1 mmol) in anhydrous dimethylformamide was added dropwise. After complete formation of phenolate, 6-chloro-1
A solution of 1.3 g (13.1 mmol) of -hexanol in 10 ml of anhydrous dimethyl formaldehyde was added and the mixture was stirred for 48 hours. The reaction mixture was partitioned between 10hi ether 7 100+wf water. The ether phase was then collected, dried (MgSO4) and evaporated to give an orange oil. 200g, 90
~200 meshes of silica gel (2% eluent) IeOH
This oil was chromatographically separated using 20% chloride/CH2Cl,) to give a yellow oil. This was vacuum distilled (136°C 10.25111!l) and 0.88
g of fi-pt-butylphenoxy-l-hexanol was obtained.

External: NMR spectrum (CDCLx) δ1.30 (s,
9H.

(OH3) 3 G-), 3.58 (t,
2H. -(c)12)OH), 3.91(5, 2
H, − 0 ((Jl, ) − CH2−)
.

7, 05 (+1, 4H, - (s H4 -).

Calculated value: C+ 6 H26 02 2 G, 7B.
8 i H, 10.5 town 1.

Actual measurement: C, 7B. 8, H, 10.4 Shugon h
Methyl-8-bromooctanoate was prepared by treating 8-bromocaprylic acid with excess thionyl chloride under reflux in l-octanoate for 8 hours. Evaporate excess thionyl chloride,
Treatment of the acid chloride with excess methanol then yielded methyl-8-bromooctanoate as a yellow oil. Sodium hydride (as a 50% dispersion) 0. f14g anhydrous dimethylformamide 10mL
2.0 g of p-t-butylphenol to a stirred solution of.

13, 1 mmol of anhydrous dimethylformamide → 1
0+sL solution was added dropwise. After complete formation of the phenolate, 3.2 g of methyl 8-bromooctanony) (
13.3 mmol) of anhydrous dimethyl formaldehyde 1
0ml solution was added. The reaction mixture was stirred at room temperature for 16 hours and then partitioned between 100+wi hexane/100 μL water. The organic phase was collected and dried (MgSO.
) I, and concentrated to give a yellow oil methyl 8-
3 Jg of p-t-butylphenoxytanoate was obtained.

External station: NMR spectrum (CD (4h) δ2.2so,
2H.

- (, CH2) - 000 CH3), 3.6
3. (s, 3H.

1-C-0 (CH3), ), 3.90 (
t, 2H, 0-(C)12)-GH? ' −
), 7.05 (q. 4H, -( Ce H4)
- ).

Ester methyl 8-pt-butylphenoxyoctanoate-1 3. fig anhydrous diethyl ether 100+1
0.4 g of lithium aluminum hydride was added dropwise to a stirred solution of 200 mL of anhydrous diethyl ether. The mixture was filtered through Celite. The organic phase was collected from the filtrate and dried (MgSO4).
It is then concentrated to give a yellow oil, methyl (8-p-t-butylphenoxyothanoate).
3.8g was obtained.

External station: NMR spectrum (CDIJ:+) δ2.2B (
t, 2H.

- (CH2) -Coo ()h), 3.
f(3 (s, 3H.

-''C-0(CH3)), 3.90 ct, 2
H, Ch(CH2)-CH7-, 7,05(I?, 4)
1. -(06H4)-ester methyl e-p-t-butylphenoxyoctanony) was dissolved in 100 ml of anhydrous diethyl ether and added dropwise to the stirred solution consisting of 0.4 lithium aluminum hydride and 200+ wf of anhydrous diethyl ether. did. After 2 hours, the methylamluminium hydride was quenched with 100 μL of distilled water.

The mixture was filtered through Celite. The organic phase was collected from the filtrate, dried (Mg5On), and concentrated to give 0.8 g of a yellow oil. This oil is vacuum distilled (1
55℃ 10.2 ■ Intestine) Clear colorless oil 8-p
0.7 g of -t-butylphenoxy-1-octatool was obtained.

External station: NMR spectrum (CDGA3') δ3.57 (t,
2H.

-(GHp) -OH), 3.91(t, 2H,
-0-(CHt)'CH2), 7.05(q, 4
)1. -(Os H4)-)-Calculated value: G, eH3
oO,: (:, ?7.7, H,10,9 found: c, 77.5;) I, io, 8 12.0 g, 48.2 mmol of 11 with excess thionyl chloride for 2 hours under reflux - Treated with bromoundecanoic acid. Excess thionyl chloride was distilled off. The resulting residue was dissolved in dichloromethane and treated with excess methanol. Evaporation gave 12.1 g of methyl 11-promodecanoate as an orange oil. Sodium hydride (as a 50% dispersion) 2.0 g (13.3 mmol) of pt-butylphenoxy in 10 L of anhydrous dimethyl formaldehyde are added to a stirred solution of 4 g of anhydrous dimethyl formaldehyde. 10 IIL solution was added dropwise. After the phenolate was completely formed, 3.7 g (13,3□, engineering 1.) of methyl!1-bromoundeca/x-) was added dropwise.
,) O, 7, 1) □ A 10-red solution of shimaldehyde was added, and the solution was allowed to stand for 14 hours at room temperature under nitrogen. The reaction mixture was partitioned between IQOmL-xane/100ml water. The first phase was collected and dried (gso
, ) L, and concentrated to a yellow oil, methyl 11
-p-t-butylphenoxyundeca7'ate 3
．． 7g was obtained.

3.7 g, 10.8 mmol of methyl 11-(p-tj thylphenoxy)-undecanoate are dissolved in 100 mL of anhydrous diethyl ether and added to a stirred solution of 0.5 g of lithium aluminum hydride in 100 mL of anhydrous diethyl ether. dripped. After 1 hour, the reaction mixture was filtered through Celite, and the filtrate was poured into 100 L of INN hydrochloric acid.
Processed. The organic phase was collected, dried (Mg504) and concentrated to give 2.7 g of a yellow oil. 80-20
0 mesh silica gel (eluent 2% MeO) 1/C4
12c, L2) This oil was chromatographed using 200 g to give a white waxy solid. The solid was recrystallized using a medium-temperature penkun to obtain 1.1 g of pure 11-(P-t-butylquenoxy)-undecanol, mp 38-40'C.

NMR spectrum (CDCl!, 3) 63.75 (
t, 2) 1°-(0H2) OH), 3. '89.
(t, 2H, -0-(CH,)-CH2-), 7.
05((1,4H,-((6H4)-1 Calculated value: C2
+ H3,102: C,78,7; H,11,3 Actual value: C,78,8, H,11,3 Methyl 4-crotonyltriphenylphosphonium bromide L2 g (20,
9 mmol) was dissolved in 50 hL of ice water and carefully neutralized with 2% thorium hydroxide. The precipitate formed was filtered and dried in vacuo to yield 8.8 g of phosphorane. 6.8 g (18.8 mmol) of this phosphorane was suspended in 100 g of methanol, to which 3.0 g (18.9 mmol) of pt-butylbenzaldehyde was added, and the mixture was stirred at room temperature for 1 hour. Next, the mixture was stirred at 0°C for 16 hours. The product was collected by filtration and yielded 1.4 g of methyl! 1-pt-butylphenyl-2,4-pentagenoate was obtained.

4 Kusu Hill.

NMR spectrum (CDCl3) δ1.33 (s,
9H.

0 +1 (CH3) 3 C-), 3.72 (s, 3H, -C
-0GH3).

Olefin, methyl 5-pt-butylphenyl-2,
1.4 g of 4-pen tagenoate in 50 m of methanol
f and hydrogenated at 1 atm using 5% rhodium mixed with alumina. Filter the reaction mixture through Celite,
The filtrate was evaporated to a yellow oil, methyl 5-pt-
1.4 g of butylphenylpentanoate was obtained.

Separation: NMR spectrum (CDCA3) 61.30 (s,
9H.

(f; H3) 3G), 2.45 (+*, 4) 1.
-06 84((:lb) 2Rv-”(CH2)
C'OCH3,3,81(s, 3H.

-C'-OCH3), 7.18(q, 4H, -Os
H4-).

The ester, 1.1.4 g of methyl 5-p-t-butylphenylpentanony, was dissolved in 50 ml of anhydrous ether and added dropwise to a water-cooled slurry consisting of 200 sg of lithium aluminum hydride and 50 sg of ether.

After 1 hour, the solution was filtered through Celite and the filtrate was
Washed with 200 mZ of hydrochloric acid. The organic phase was collected and dried (M
gS04) and concentrated to give a yellow oil. This was vacuum distilled (134° C./0.75 mm) to obtain 0.34 g of clear colorless oil 5-p-t-butylphenylpentanol.

Pi-death: NMR spectrum (CDCl-3) 61.32 (s,
9H.

(CHa) 3C: -), 2.58 (t, 2)
1. -C6H4-(C)+2)-), 3.59.
(t, 28.-(CH2)OH).

7.18 ((1,4H,-Cr,)+4-).

Calculated value: C+s H740: C,81,8; H
, 11,0 actual value: C, 81,0, H, 10,8 power 32 upper momme 11 alcohol, 4-pt-butylphenoquine-1-butanol 2.0 g (9.0 mmol) and pyridine 1.2
1.8 g (13.4 mmol) of benzene 3 (1 mi) in a well-stirred solution of 5+aL of benzene 3 (1 mi)
Add a 30mf solution of benzene of
Stir for hours. The reaction mixture was then filtered and the filtrate was washed with 50% of IN hydrochloric acid. The organic phase was collected, dried (MgSO4) and evaporated to give a yellow oil. This oil was distilled under vacuum (188℃10.4mm)
) to obtain 1.6 g of a clear colorless oil, 4-p-t-butylphenoxy-1-butylbenzony).

External station: NMR spectrum (CDCl3) δ1.28 (s,
9H.

(CH3) 3 G −), 1.95 (If, 4H,
OCH2(GH2CH7) CH20).

1 4.00 (t, 2H, -COCH2-), 4.40 (
t, 2H.

-CRH40(CH2)-), 7.05(Q, 4H
.

-C: 6 H4-L 7.53 (11,3H, benzoyl 3,4°5-H's) 8.08 (m, 2H, benzoyl 2.6--H's).

Alcohol, 4-pt-butylphenoxy-1-butanol', Qg, 9.0 mmol and pyridine 0.
To a well-stirred solution of 8wi of dichloromethane 25 + sji was added 1-1.8 g of methylchloroforme-1 (1
6,8 mmol) of dichloromethane 25+ij! , solution was added and the solution was stirred for 48 hours. The reaction mixture was then evaporated and the residue was chromatographed using 200 g of 90-200 mesh silica gel (eluent chloroform) to give a pale yellow oil. Vacuum distillation (131'0/0.25+o+w) yields a clear colorless oil, methyl-p(-butylphenoxy-
1.5 g of 1-butylcarpone) was obtained.

Branch Knee-+-+--11+-1/L'NnL'A) RIsuQ
/, QLI(CH3)i C-), 1.82(1,4H
,0CH2(CH2CH2) CH20), 3.73
(S, 3H.

1 CO(CH3)), 8.93(t,2)1. −
(C)I2)QC-).

4.18 (t, 2H, -Cs H40(Glh)-)
.

7.05 (q, 4H, -G, H4-).

Calculation @: C,6H240,: C,68,5,H,
8,83 Actual value: C96θ, 3;)l, 8.73
Nicotinic acid I in 280 mL of thionyl chloride for 2 hours under reflux.
Nicotinoyl chloride was prepared by treating QOg (0.81 mol). Excess thionyl chloride was removed in vacuo and the crystalline acid chloride hydrochloride was suspended in dichloromethane 500 mA. Add 40% dichloromethane to the stirred mixture.
4-pt-butylphenoxy-1 dissolved in 0 mJ
-88 g ('0.3 o mol) of butanol were added. 4
After 8 hours, the mixture was washed with IL saturated sodium bicarbonate. Dry the dichloromethane solution over magnesium sulfate;
It was then evaporated to obtain a syrupy residue. 1k while dissolving in dichloromethane/methanol (96:4)
This material was chromatographically resolved using 1 g of silica gel to yield 43.8 g (45%) of nicotinic acid ester as an oil. 4.5NJj hydrogen hydride 30m
, 43.8 in 800 m of ethyl acetate with an ether solution of 6
The hydrobromide salt was prepared by treating a solution of g. The precipitate was collected, washed with pentane, and dried. Melting point 132~
133℃.

Minute wheel: 15 NMR spectrum (dSnMscl) δ1.3
0 (s, 9H.

(fJ3)3G-), 1.36(yr, 4
H, OCH7(CH2CH2) CH20), 4.0
5 (t, 2H.

1 -CCH2) QC-), 4.49(t, 2H,O
(GH2) -CH,~) +7-0!3(L4L-C
[i H4-)l i8.14(q, IH, Pyr
-5H), 111.01(q, 2)1. Pyr-
4,6-H's), 9.34(q, 2H, Pyr
-4,6'-)1's), 9.34(s, IH,
Pyr-28).

Calculation I @: C2+) H/ 5 NOj @) I
BT: C, 58,5; i, 6.42, N, 3.4
3 Actual measurement value: C, 59,0; H, 8,43; N, 3
．． To a stirred solution of 3.0 g, 14.4 mmol of 33 alcohol, 3-p-t-butylphenoxypropanol and 2.5 g of potassium cyanate in 50+ sL of benzene was added 3.4 g of trifluoroacetic acid and the solution was The mixture was stirred under water for 2 hours. Next, mix the mixture with 5 liters of water.
It was treated with 0 mL. The organic phase was collected and dried (Mg5o4
) L and concentrated to give an orange oil. This oil was dissolved in 25 volumes of pentane and stored at 0°C. The crystals were filtered and dried in vacuo to give a urethane, melting point 84-85°C 0.8.

Perversion: (OH3) 3 G-), 2.08 (II, 2H,
O-CH2(CH2)CH20,-), 4.02(t,
2H, (Ill:H2)1 QC: -), 4.24 (t, 2H, -0(CH
2) CH2-).

? , '05 (CI, 4H, -as H4~).

Calculated value: G, , H2, No3:, C, ee, s;
H, 8,42; N, 5.57 Actual value: C;, 6B, 9, )l, 8.20
; N, 5.51 (t#, from 144 g, 1.01 mol of methyl iodide and 54 g, 2.25 mol of magnesium in water diethyl ether 700) to a solution of freshly prepared methylmagnesium iodide to the ester butyl 3- p
-t-butylphenoxypropionate 10.0g (
38,0 mmol) of diethyl ether 200rr+1
solution was added.

After 1 hour, the reaction mixture was poured onto ice/20% H2304. The yellow organic phase was dried and evaporated. 30-20 (l mesh silica gel (eluent dichloromethane) 500g
The dark oil produced was chromatographically resolved to give a yellow viscous oil. This was cooled and solidified to produce 2-methyl-4-p-t-butylphenoxy-2-
3.1 g of butanol was obtained.

Branch: NMR spectrum (CDCL3) 81.27 (s,
15H.

(CH3)3c, -, -C(CH3)zO)l).

01) I. (t, 2) 1. -〇-(CH2)-), 7.05(q
, 4H.

-CiL-).

Calculated value: C+s 87402:C,75,0;
H,10,0 Actual value: G, 75.1; H,10
, 1゜Seed 1μ 3--t-Butylphenoxyprobyl Nicotine Hydrochloride Treated with cyclized thionyl 10.0+*i with 3.0 g, 8.3 mmol of nicotinic acid under reflux for 2 hours. Nicotinyl chloride was prepared. Excess thionyl chloride was distilled off, and the crystalline acid chloride was suspended in 25 L of dichloromethane. Add alcohol 3-p-t-butylphenoxypropanol 1. to the stirred slurry. A solution of 25 μg (4.5 mmol) of dichloromethane was added dropwise.

After 30 minutes, excess acid chloride was carefully quenched with water.

The organic phase was collected, dried (MgSO4) and concentrated to give an orange gum. Dissolve this in 25IIL of methanol and add 3% methanol-based hydrogen chloride to 10+st.
Processed with. The methanol was evaporated and the white solid produced was recrystallized from hot ethyl acetate.
White crystalline product 3-pt-butyl fair'xypropyl nicotinate hydrochloride 0.4 g, melting point 134
~1311°C was obtained.

1',! j Calculated value: C+ 9)123NO3・HCL: C,
B5.2, H.

fl, 92; N, 4.00 Actual value: G, 65.5, H, 6,89, N,
4.29 Sodium hydride (as a 50% dispersion) 3.8
5. g of p-n-propylphenol to a well-stirred solution of 300 mt of anhydrous dimethylformamide. Q
g (38,7 mmol) of anhydrous dimethylbormamide
125 [The solution was added dropwise. After complete formation of the phenolate, a solution of 3.5 g of monochloroacetic acid, 3B, 8 mmol in anhydrous dimethylformamide in 50+aL is added,
The solution was heated to eo'c for 1.5 hours. Mixture then 2
00 mL) toluene and 30 hL 3N hydrochloric acid. The organic phase was collected, washed with water (3×200 mL), dried (MgSO4), and concentrated to give a pale yellow crystalline product. This crystalline product was dissolved in 25 WaL of water-cooled anhydrous tetrahydrofuran. Add 33m of poran to this cold solution.
L, 0.94 mol of tetrahydrofuran solution was added dropwise. After 2 hours, remove excess poran and carefully acidify the water.
Diluted with 250 f of water and extracted with 2 Q OmA of dichloromethane. The organic phase was collected and dried (MgS
O4) L and evaporated to give a yellow oil. This oil was vacuum distilled (105℃70.35m++),
1.0 g of clear colorless oil 3-p-n-propylphenoxyethanol was obtained.

Layer separation: NMR spectrum (CD(43) δ0.93 (t,
3) 1゜(CH:l) -CHz -), 1.5(
i+, 2H, CH3(CH2)CH2-), 2.5
2(t, 2H, -CHz -(CHz) -Cs
H4-), 3.90(a+, 4FI, -Q-(C:H2
-CHz )OH), 6.93 ((T, 4H, -
C6H4-).

Calculated value: C+ + H + s02: C, 73, 3; H
,8,95 Actual reconnaissance: C,? 2.9, H,9,18
Sodium hydride (as a 50% dispersion) 260
g of anhydrous dimethylformamide 5h/:consisting of/
Naka 7 pattern -- zu 2 11 - ge --------
5.0 g (36.8 mmol)
of anhydrous dimethylformamide 50 n=L! Solution B was added dropwise. After complete formation of the phenolate, a solution of 5.5 g (3e, a mmol) of 4-chlorobutyl acetate in anhydrous dimethylformamide 50111A was added and the solution was heated at 55° C. for 16 hours.

The mixture was then diluted with IL of water and extracted with 3 GOIIL of toluene. The l.luene was collected, dried and evaporated to give a yellow oil. This oil was treated with 75 mL of iced methanolic lithium hydroxide IN for 1 hour under reflux. The methanol was then distilled off and the residue was partitioned between water/diethyl ether. The ether was separated and dried (Mg
SO4)j and concentrated to give a yellow oil. This oil is vacuum distilled (110”C/0.10ts+H
g) 1.7 g of 4-p-n-propylphenoxybutanol was obtained as a clear colorless oil.

External station NMR spectrum (CDCA3) δ0.93 (t,
3) 1°(CH3)-CH2-), 1.68(■, 8
8. OH2(0H2G)+2)COH+CH2(C
H2)CH2-), 2.50(t, 2M.

-(CH2) -1,s H4-), 3. ft4(m,
2H,C)12-(CH2)OH), 3.96(t,
2)1. -c6H4-0(CHt)-), 6.1
34 (q, 4H, -0IiHr-).

Calculated value: C+ 3 H2oO7:C, '75', 0
;H, 9, 88 Actual measurement value: C,? 5.2, H,9,
72° 1 equivalent of substituted phenol, 1 equivalent of sodium hydride, 2.5 equivalents of acrylic ester and N-phenyl-2-naphthylamine (0.01 mol/1 mol phenol) - acts as main polymerization inhibitor - solution under nitrogen 3
The mixture was heated to 115°C for an hour. Next, lower the temperature to 85℃,
Excess acrylic ester was removed under vacuum. 90-2
The residue was chromatographically separated using 00 mesh silica gel to obtain pure 3-phenoxypropionic acid ester. 0 was dissolved in anhydrous 3-phenoxypropionate and hydrogen (lithium aluminum chloride) Carefully added to a stirred slurry of anhydrous ether. After 1 hour, excess hydride was quenched with sodium sulfate + hydrate. The residue was partitioned between water/ethyl acetate. The organic phase was It was collected, dried (MgSO4), and concentrated to give an oil, which was vacuum distilled to give the desired 3-(aryloxy)bripanol.

The following 3-(aryloxy)propertools were prepared by this method.

Preparation of β-methoxyethoxy glycolate ester of p-t-butylphenoxy-l-butanol Methyl glycolate9. To a 150 mJ solution of Og (0.1 mol) in acetonitrile was added 24.7 g (0.11
mol) is added and the mixture is stirred under reflux for 1 hour. The solvent is removed in vacuo and the residue is treated with 200 mL of toluene. Insoluble salts were removed by filtration, and the filtrate was added to 4-p
-t-butylphenoxy-1-butanol 22.0g
(0.1 mol) is added. After adding 0.24 g (0.005 mol) of sodium hydride as a 50% dispersion, the mixture is heated to boiling and the methanol is fractionated until the transesterification is complete. The solvent is removed in vacuo and the product is purified by chromatography on silica gel.

Lewis and Whittle, the effects of compounds according to the invention on inhibiting the release of mediators from oak and beech nuts induced by administration of compound 48780.

Br1tish Journal of Pharma
Colo 81 229 (1977) was applied for evaluation.

Seventeen compounds of the present invention having the structures shown in Table 1 were evaluated in comparison with four test compounds including chlorphenesin and cromolyn sodium as well as two other structurally related compounds. .

In addition to chlorphenesin and cromolyn sodium,
3-(4-chlorophe,noxy)lactic acid and 3(3-bromophenoxy)propanol were used as controls.

None showed activity.

The results are shown in Table 1.

匪　pu 禦 p drunkenness The following esters were also tested as described below.

Once the release of Z ester is suppressed by more than 30%, t-Bu-(CH2)3 carbamate 1゜t-
Bu 1CH2) 3 = cochinate 1°t-Bu
-(CH2) 4 Acetate 10t-Bu -(CH
2) 4 Methyl carbonate 15t-Bu, 1GH
z ) 4 Nicotinate 5t-Bu -(CH2)
4 Benzoate 5° IQ People Frank Fist M Berger Joseph I. Dogrow, Jr. Howard L. Johnson Agent Patent Attorney Kato Asami crocin cromolyenecin 5. August 1959 2'i!8 Patent Office Commissioner Shiga Manabu 1, Indication of the case 1982 Patent Application No. 106696 (JF1 issued on May 28, 1980) 2. Name of the invention P-alkyl or cycloalkyl Phenoxyalkanols and Alka/'-Lue Esters and Treatment of Allergic Conditions 3, Relation to the Case of the Person Who Makes the Amendment Frank M. Purger Joseph Kenai Middle School Dogrow, Jr. Howard L. Johnson 5, date of amendment order spontaneous 6, number of inventions increased from 1 amendment 7, subject of amendment 1) Engraving of specification (no change in content) -.

Claims (1)

[Claims] 1) Compounds consisting of the following formulas and pharmacologically valid esters of these compounds: where R is an alkyl group (carbon number 1 to 6) or a cycloalkyl group (carbon number 1 to 6); , is optionally bonded to the 3rd and 4th positions of the benzene ring of the compound of formula l, Z is a linear alkylene group (having 1 to 15 carbon atoms), and 1 or 2 lower alkyl groups (having 1 to 15 carbon atoms) ~3), and when the compound of formula 1 is not esterified,
Z cannot be unsubstituted propylene. 2) Claim 1, which is a pharmacologically valid ester
Compounds described in Section. 3) The ester is an acetate ester, a benzoate ester,
3. The compound according to claim 2, which is selected from the group consisting of nicotinic acid esters, carbamic acid esters, and alkyl carbonic acid esters. 4) The compound according to claim 1, wherein Z is an optionally substituted alkylene group having 2 to 8 carbon atoms. 5) A drug formulation effective to prevent the key reaction of a compound of the following formula as an active ingredient: where R
is an alkyl group (1 to 6 carbon atoms) or a cycloalkyl group (1 to B carbon atoms), which is optionally bonded to the 3rd and 4th positions of the benzene ring of the compound of formula 1, and Z is a linear is an alkylene group (having 1 to 15 carbon atoms), l or 2
Optionally substituted with lower alkyl groups (1 to 3 carbon atoms). 8. A formulation according to claim 5, wherein the compound of formula 1 is a pharmacologically relevant ester. 7) The ester is an acetate ester, a benzoate ester,
7. A formulation according to claim 6, which is selected from the group consisting of nicotinic acid esters, carbamic acid esters, and alkyl carbonic acid esters. 8) The formulation according to claim 5, wherein Z is an optionally substituted alkylene group having 2 to 8 carbon atoms.