JPH05239030A - Aminomethyltetrahydroisoquinoline derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new aminomethyltetrahydroisoquinoline derivative exhibiting antithrombotic action, vasoconstriction suppressing action and bronchoconstriction suppressing action and useful as an agent for the treatment of thrombic embolism and ischemic disease, an antiasthmatic agent and an antiallergic agent. CONSTITUTION:The compound of formula I [R1 is alkyl, aryl which may have substituent (halogen, alkyl, alkoxy, NO2 or CF3), aralkyl or heterocyclic group; R2 is H, acyl which may have substituent (halogen, NO2, methoxy or OH), alkyl, aralkyl, alkyloxycarbonyl or aralkyloxycarbonyl; R3 is OH, alkoxy, benzyloxy or NR4R5 (R4 and R5 are H, alkyl or aralkyl); (n) is 1-6], e.g. 1-[2- acetyl-benzenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6yl]ox yacetic acid. The compound can be produced by condensing a compound of formula II (Prot is amino-protecting group) with a compound of formula III (X is Cl, Br, etc.).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel aminomethyltetrahydroisoquinoline derivative useful as a pharmaceutical compound for improving symptoms caused by thromboxane A ₂ , a process for producing the same, and a process for producing an intermediate thereof.

[0002]

BACKGROUND OF THE INVENTION Thrombotic and atherosclerotic vascular changes are caused by the interaction of two substances in the arachidonic acid metabolic pathway, namely, thromboxane A ₂ (T
Regulation by XA ₂ ) and prostaglandin I ₂ (PGI ₂ ) has been revealed. These two kinds of substances have mutually opposing actions, and TXA ₂ has platelet aggregation, vasoconstriction and bronchoconstriction actions, while PGI ₂ has platelet aggregation inhibition, vasodilation and bronchodilation actions.

It is said that platelets are important for the onset and progression of atherosclerosis, and the administration of antithrombotic drugs, especially platelet aggregation inhibitors, is effective in treating atherosclerosis-related diseases. It is being recognized as effective. Moreover, in thrombosis and ischemic diseases, excessive aggregation of platelets or increase in platelet consumption is guided in the direction of TXA ₂ biosynthesis, thus disturbing the equilibrium of TXA ₂ and PGI ₂ . Therefore, in the treatment and prevention of thrombotic and ischemic diseases, those that inhibit the action of TXA ₂ and assist the action of PGI ₂ are desirable.

On the basis of these ideas, starting with the development of substances that act on PGI ₂ and focusing on TXA ₂ 's strong platelet aggregation and vasoconstriction activities, various TX
A ₂ synthase inhibitors and TXA ₂ receptor antagonists have been developed. As a TXA ₂ receptor antagonist, BM-13177 [Refer (L
efer AM), Drugs of Tod
ay) Volume 21, p. 283 (1985)], BM-13505 [West German Patent No. 3000377], SQ-29548 [Ogletre
e) et al., Journal of Pharmacology and
Experiential Tera-Beauty (J.Pharmaco
l.Exp.Ther.) Vol. 34, p. 435 (1985)].

[0005]

In patients with myocardial infarction, arteriosclerosis, thrombosis, diabetes, hyperlipidemia, etc., TXA ₂
It has been reported that the production of Lactobacillus spp. Is high and a physiological imbalance between TXA ₂ and PGI ₂ is occurring. So to suppress the physiological activities of TXA _2, the development of TXA ₂ synthetase inhibitor or TXA ₂ receptor antagonists have attracted attention. Inhibitors correct the pathophysiological imbalance of TXA ₂ / PGI ₂ , but their own physiological activities due to temporary accumulation of prostaglandin H ₂ (PGH ₂ ) (platelet aggregation and vascular smooth muscle contraction) There is a problem that you can not control. On the other hand, TXA ₂ receptor antagonists, TXA ₂ /
Since it directly antagonizes the PGH ₂ receptor, it has been proved that the inhibitory action is more effective than the inhibitor, and the development of the antagonist is particularly desired.

[0006]

The present inventors have completed the present invention by synthesizing an aminomethyltetrahydroisoquinoline derivative and found that this novel compound has a strong antagonistic action against thromboxane A ₂ . The present invention has the general formula (I)

[0007]

[Chemical 5]

(Wherein R ₁ represents an alkyl group, an aryl group, an aralkyl group or a heterocycle, which may be substituted with one or more of a halogen, an alkyl group, an alkoxy group, a nitro group and a trifluoromethyl group. R ₂ is hydrogen, or an acyl group which may be substituted with a halogen, a nitro group, a methoxy group, a hydroxy group, a linear or branched alkyl group, an aralkyl group, a linear or branched alkyloxycarbonyl group, an aralkyl Represents an oxycarbonyl group, R ₃ represents a hydroxy group, an alkoxy group, a benzyloxy group, or has the formula: —NR ₄ R ₅ (wherein R ₄ and R ₅ are the same or different, and are each hydrogen, Which represents an alkyl group or an aralkyl group), and n represents 1 to 6) or a pharmaceutically acceptable salt thereof. Is a Roisokinorin derivatives.

In the general formula (I), the alkyl group is generally a linear or branched hydrocarbon group having 1 to 12 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, tertiary. Butyl, pentyl,
Hexyl, isohexyl, heptyl, octyl, isooctyl and the like can be mentioned. As an aryl group,
It generally represents an aromatic group having 6 to 12 carbon atoms and includes phenyl, naphthyl and biphenyl. Aralkyl groups generally include aryl groups having 7 to 14 carbon atoms attached through an alkylene chain. Aralkyl groups of which the aliphatic part has 1 to 6 carbon atoms and the aromatic part has 6 to 12 carbon atoms are preferred. For example, benzyl, naphthylmethyl, phenethyl, phenylpropyl can be mentioned. Examples of the heterocycle include pyridine, isoquinoline, indole and pyrimidine. Examples of the alkoxy group generally include alkyl bonded via an oxygen atom, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy and the like.

Halogen includes fluorine, chlorine, bromine,
Iodine can be mentioned. As the acyl group, generally, an alkyl, an aryl, which is bonded via a carbonyl group,
It represents aralkyl, and examples thereof include formyl, asemyl, propionyl, malonyl, acryloyl, benzoyl, phthaloyl, naphthoyl and cinnamoyl. The alkyloxycarbonyl group generally represents a linear or branched alkoxy group bonded via a carbonyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, tertiary butoxycarbonyl, methylsulfonylethyloxycarbonyl, isobornyloxy. Carbonyl, 2,2,2-trichloroethyloxycarbonyl,
2- (trimethylsilyl) ethoxycarbonyl etc. can be mentioned. The aralkyloxycarbonyl group generally represents an aralkyl group bonded via a carbonyl group,
Examples thereof include benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzeneisopropyloxycarbonyl, tolueneisopropyloxycarbonyl and fluorenylmethyloxycarbonyl.

A more preferable specific example of the compound of the present invention is a compound represented by the following formula (Ia) and a pharmaceutically acceptable salt thereof.

[0012]

[Chemical 6]

(Wherein R ₁ represents halogen, an aryl group which may be substituted by one or more lower alkyl groups having 1 to 4 carbon atoms, and R ₂ represents hydrogen, an acyl group, a straight chain or A branched alkyl group, an aralkyl group, a linear or branched alkyloxycarbonyl group, an aralkyloxycarbonyl group, and n represents 1 to 6). Representative compounds in this group include 1- [2-acetyl-1-benzenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-acetyl-1- Toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-acetyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline -6-yl] oxyacetic acid 1- [1-benzenesulfonylaminomethyl-2-benzoyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-benzoyl-1-toluenesulfonylamino Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-benzoyl-1- (4-chlorobenzene) sulfonylamido Methyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1-benzenesulfonylaminomethyl-2-benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl] Oxyacetic acid 1- [2-benzyloxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-benzyloxycarbonyl-1- (4-chlorobenzene ) Sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1-benzenesulfonylaminomethyl-2-third
Butoxyoxycarbonyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-tert-butoxyoxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline- 6-yl] oxyacetic acid 1- [2-tert-butoxyoxycarbonyl-1- (4-
Chlorobenzene) sulfonylaminomethyl-1,2,3,4-
Tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1-benzenesulfonylaminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-benzyl-1-toluene Sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [2-benzyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline- 6-yl] oxyacetic acid 1- [1- (4-chlorobenzene) sulfonylaminomethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1-benzenesulfonylaminomethyl -1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1-toluenesulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid 1- [1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid 4- [2-benzyl-1- Third butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinoline-6-
Ethyl] oxybutyrate 4- [2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyrate 4- [2-benzoyl-1-toluenesulfonylaminomethyl Ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyrate 4- [2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyric acid Etc., and pharmaceutically acceptable salts thereof.

The novel aminomethyltetrahydroisoquinoline derivative of the present invention has a pair of diastereomers as an enantiomer, a mixture of a pair of enantiomers, or in the case where the compound has an asymmetric center in the substituent. It can exist as a mixture. When the compound (I) of the present invention is used as a medicine, it can be used in a free form or a pharmaceutically acceptable salt form. Examples of the pharmaceutically acceptable salt include sodium salt, potassium salt,
Alkali metal salts such as lithium salts, calcium salts,
Alkaline earth metal salts such as magnesium salts, ammonium salts, ethylamine salts, triethylamine salts, diethanolamine salts, triethanolamine salts, dicyclohexylamine salts, dimethylaminoethanol salts, arginine salts, ethylenediamine salts and the like amine salts. .. In addition, hydrochloride, hydrobromide, sulfate,
Examples thereof include inorganic acid salts such as phosphates, and organic acid salts such as oxalates, succinates, maleates, fumarates, and methanesulfonates. These salts can be formed by conventional means, for example in the free acid form in a solvent or medium in which the salt is insoluble, or in a solvent such as water which can be removed by vacuum drying or lyophilization. It can be produced by reacting a compound with one or more equivalents of a suitable base or by exchanging an ion of an existing salt with another ion in a suitable ion exchange resin.

According to the invention, the novel aminomethyltetrahydroisoquinoline derivatives of the general formula (I) have the general formula (II)

[0016]

[Chemical 7]

An amine represented by the general formula (III) R ₁ SO ₃ H (III) (wherein R ₂ , R ₃ and n have the same meaning as in the general formula (I)) R ₁ has the same meaning as in the general formula (I)) or an active derivative thereof, for example, an acid chloride or an active ester.

If the R _{3 of the} resulting compound (I) is not OH then the salt is prepared by subsequent hydrolysis to the free carboxylic acid and reaction with the corresponding base. The amines represented by the general formula (II) are novel, and the amines are represented by the general formula (IV)

[0019]

[Chemical 8]

(Wherein R ₂ has the same meaning as in formula (I), Prot represents a protecting group for an amino group, and is, for example, acetyl, benzyloxycarbonyl, tert-butoxycarbonyl, etc.) Is represented by the general formula (V) X (CH ₂ ) _n COR ₃ (V) (wherein R ₃ and n have the same meanings as in the general formula (I), and X
Is a leaving group, for example, a compound represented by salts, bromine, iodine, alkylsulfonyl or toluenesulfonyl) to give a protected form of the condensation product, and then removing the protecting group by a suitable method. Can be manufactured.

The compound of the general formula (IV) can be produced by the method shown below.

[0022]

[Chemical 9]

[0023]

[Chemical 10]

(In the formula, R ₂ and Prot have the same meanings as described above). Hereinafter, the above reaction will be described in detail. The final product (I) comprises an amine of the general formula (II), a sulfonic acid of the general formula (III) or an activated derivative thereof, such as a sulfonyl chloride, a sulfonic anhydride or a sulfonic acid ester, and a condensing agent such as a hydroxylation. Alkali metal or alkaline earth metal hydroxides such as sodium, potassium hydroxide and barium hydroxide, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate or triethylamine, pyridine, N-
It is obtained by reacting in the presence of an organic base such as ethylmorpholine. Depending on the type of sulfonic acid derivative used, inert solvents such as methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, ether, dimethylformamide, acetonitrile and / or protic solvents such as water, methanol or ethanol are used as solvents. The reaction temperature is preferably about -20 to 120 ° C, and is appropriately selected depending on the properties of the raw materials and products.

In the condensation reaction of the compounds (IV) and (V), the leaving group of the compound (V) is a halide such as chlorine, bromine or iodine, alkylsulfonyl such as methanesulfonyl or trifluoromethylsulfonyl or toluenesulfonyl. Is. The reaction can be carried out in a suitable solvent in the presence of a condensing agent. Examples of the condensing agent include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide and barium hydroxide, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, or triethylamine, pyridine or An organic base such as diazabicycloundecane can be preferably used, and examples of the solvent include acetone, butanone, dimethylformamide, dimethylsulfoxide, ethanol, and the like.
Dioxane or toluene or halogenated hydrocarbons such as methylene chloride or chloroform can be used. It is often advantageous to add alkali metal halides such as sodium iodide or potassium iodide. The reaction temperature is preferably about -20 to 150 ° C, and is appropriately selected depending on the properties of the raw materials and products.

Compound (VII) is the same as compound (VI) in a solvent such as water, dichloromethane-water, alcohol, dimethylsulfoxide, sodium cyanide, potassium cyanide,
It is obtained by reacting an inorganic cyanide such as calcium cyanide. The reaction temperature is preferably about −20 to 100 ° C., and is appropriately selected depending on the properties of raw materials and products. Compound (VIII) can be obtained by reducing the cyano group of compound (VII) in a suitable solvent. For the reduction of cyano group, in addition to Birch reduction for reducing metallic sodium, lithium, calcium, etc. in liquid ammonia, lithium aluminum hydride (preferably coexisting with concentrated sulfuric acid, aluminum chloride, etc.), methoxy aluminum hydride, hydrogen Sodium borohydride (aluminum chloride, boron trifluoride, Raney nickel, cobalt chloride, etc. coexist) is reduced in a solvent such as ether, tetrahydrofuran, alcohol, or Raney nickel (sodium acetate may coexist), Raney It can be obtained by a method of hydrogenating a catalyst such as cobalt in an alcohol containing ammonia, dioxane or acetic anhydride.

The compound (IX) can be obtained by cleaving the aryl ether from the compound (VIII). Cleavage of aryl ethers can be accomplished by hydrogen bromide, hydrogen iodide (red phosphorus may coexist), trifluoroacetic acid, pyridine salts, concentrated hydrochloric acid, magnesium iodide etherate,
It can be obtained by cleavage with an acid such as aluminum chloride, boron tribromide, boron trichloride or boron triiodide, or by cleavage with a base such as sodium-liquid ammonia, lithium-biphenyl, lithium iodide-collidine or sodium thiolate. can get. The solvent can be appropriately selected according to the nature of the raw material and the type of reaction reagent, acetic anhydride, benzene,
Methylene chloride, tetrahydrofuran, dimethylformamide (DMF), water and the like are used. Reaction temperature-80 ~
The temperature is preferably about 150 ° C and is appropriately selected depending on the properties of the raw materials and products.

Compound (IV) can be obtained from compound (IX) by protecting the amino group according to a conventional method. The condensate thus obtained is isolated and purified from the reaction mixture by using a usual separation and purification means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin layer chromatography. can do.
Condensates, if necessary, hydrochloric acid, trifluoroacetic acid,
Including acid treatment with formic acid, alkali saponification using aqueous solutions of sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., catalytic reduction using metal catalysts such as palladium black, palladium-carbon, platinum oxide, etc. The desired product can be obtained by performing deprotection by a known method.

The novel aminomethyltetrahydroisoquinoline derivative of the present invention or a salt thereof is used as an active compound in medicine. This compound is a platelet aggregation inhibitory action,
It shows a vasoconstriction inhibitory action and a vasoconstriction inhibitory action. The compound can preferably be used for the treatment of thrombosis, thromboembolism, ischemia, or as anti-asthma and anti-allergic agents. This novel active compound can be prepared in a conventional manner using an inert, non-toxic, pharmaceutically suitable excipient or solvent in a conventional manner such as tablets, capsules,
It can be a sugar coating, a pill, a fine granule, an aerosol, a syrup, an emulsion, a suspension and a liquid. The therapeutically effective compound is in each case about 0.5 based on the total combination.
To 90% by weight, ie an amount sufficient to achieve the above-mentioned treatment. Formulations are prepared, for example, by extending the active compound with solvents and / or excipients, if appropriate with emulsifiers and / or suspending agents. If water is used as the diluent, it is also possible, if appropriate, to use organic solvents as auxiliary solvents. Auxiliaries such as water, non-toxic organic solvents such as paraffin (eg petroleum fractions), vegetable oils (eg peanut oil, sesame oil) and alcohols (eg ethanol and glycerin), excipients, eg powdered natural minerals ( Eg clay, alumina, talc and chalk), powdered synthetic minerals (eg highly dispersible silica and silicates),
Sugars (eg sucrose, lactose and dextrose), emulsifiers (eg polyoxyethylene fatty acid esters and polyoxyethylene fatty alcohol ethers, alkyl sulfonates, aryl sulfonates), suspending agents (eg lignin sulfite waste liquor, methyl cellulose, Starch and polyvinylpyrrolidone) and lubricants such as magnesium stearate, talc, stearic acid and sodium lauryl sulphate.

Administration is carried out in the usual way, preferably orally or also parenterally. In that special case, it can also be done translingually or intravenously. Water is used in particular as injectable medium, which contains stabilizers, solubilizers and / or buffers which are customary for injectable solutions. Such additives include, for example, tartrate buffer, borate buffer, ethanol, dimethylsulfoxide, complexing agents (eg ethylenediaminetetraacetic acid), high molecular weight polymers for viscosity adjustment (eg liquid polyethylene oxide) or hydrogen. Is a polyethylene derivative of sorbitan chloride. For oral administration, especially in the case of aqueous suspensions, flavoring or coloring agents may be added to the active compound together with the auxiliaries mentioned above.

The dose depends on the route of administration, the age of the recipient,
It depends on the state of health and weight, the extent of the illness, at the same time, the type of other treatments that may be given, the frequency of treatment and the type of effect desired. Usually a daily dose of 0.01 to 1 active compound
00 mg / kg body weight. It is customary to obtain the desired results
0.05 to 50 and especially 0.1 to 30 mg / kg are effective after one or several use per day.

[0032]

The following will describe a particularly preferred embodiment of the present invention with reference to Examples, but the scope of the present invention is not limited thereto. [U-46619 Induced Vasoconstriction Inhibition Test] (U-46619: 9,11-dideoxy-9α, 11α-methanoepoxy prostaglandin F2α thromboxane A ₂ stable analogues) Each test substance was dissolved in distilled water. .. A substance insoluble in distilled water was dissolved in ethanol or dimethylsulfoxide, diluted with distilled water, and then subjected to the test.

Male Wistar-KY rats were killed by exsanguination, then thoracotomy was performed, and the thoracic aorta was extracted. 95% of the obtained blood vessel samples
O ₂ -5% CO ₂ gas aerated nutrient solution heated at 37 ° C (Kr
tissue chamber filled with ebs-Henselite solution)
(10 ml volume) Suspended inside. The application of U-46619 (prepared to be 3 × 10 ⁻⁸ M in the chamber) was applied to the specimen at 60-minute intervals, and the single-dose method (3 × 10 ⁻⁸ M) was used. Applying the test substance to the tissue chamber is U-
10 minutes before application of 46619. The results of U-46619-induced vasoconstriction inhibitory activity are shown in the table below.

[0034]

[Table 1]

[Preparation Example] Example 1 N-formyl-3-methoxyphenethylamine 3-methoxyphenethylamine (50.0 g) and p-toluenesulfonic acid (33 mg) in boiling ethyl formate (170 ml) was added to triethylamine (46.3 ml). Was added dropwise, and the mixture was heated under reflux for 20 hours. The reaction solution was cooled, the residue was filtered, and the filtrate was distilled to obtain N-formyl-3-methoxyphenethylamine (56.
3 g, 95%) was obtained as a colorless oil.

Bp _1.0 165 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.4 to 3.0 (2H, m, PhCH ₂ ), 3.4
~ 3.7 (2H, m, CH ₂ N), 3.8 (3H, s, MeO), 6.7 ~ 7.0 (3
H, m, Ph), 7.1-7.4 (2H, m, Ph), 8.1 (1H, s, CHO).

Example 2 6-methoxy-3,4-dihydroisoquinoline The oil (78.0 g) obtained in Example 1 in toluene (200 ml).
Phosphorus oxychloride (200 g) was added dropwise to the solution under ice cooling, and the mixture was stirred for 30 minutes. The obtained solution was further heated at 80 ° C. for 2 hours and then poured into ice water. After removing the toluene layer, the aqueous layer was made alkaline with sodium hydroxide and extracted with ether. The ether layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure.

The residue was distilled under reduced pressure to give 6-methoxy-3,4.
-Dihydroisoquinoline (51.7g, 74%) was obtained as a colorless oil. bp _1.0 : 105 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.5 to 3.0 (2H, m, PhCH ₂ ), 3.
5 to 3.8 (2H, m, CH ₂ N), 3.8 (3H, s, MeO), 6.6 to 6.9 (3
H, m, Ph), 7.1 ~ 7.3 (2H, m, Ph), 8.2 ~ 8.3 (1H, m, P)
hCH = N).

Example 3 2-Benzyl-1-cyano-6
-Methoxy-1,2,3,4-tetrahydroisoquinoline Ether (240 ml) of the oil (20.0 g) obtained in Example 2
Benzyl bromide (31.8 g) was added to the solution, and the mixture was stirred at room temperature for 16 hours. The formed precipitate was filtered, washed with ether, and dried. This precipitate was dissolved in water (240 ml) and potassium cyanide was added.
An aqueous solution (240 ml) of (10.0 g) was added. The reaction solution was extracted with ether, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from hexane to give 2-benzyl-1-cyano-6-methoxy-1,2,3,4-tetrahydroisoquinoline (28.4 g, 82%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.7 to 3.0 (4 H, m,
PhCH ₂ CH ₂ N), 3.75 (3H, s, MeO), 3.85 (2H, s, PhCH
₂ N), 4.6 (1H, s, CH), 6.6 to 7.2 (3H, m, Ph), 7.4 (5H,
s, Ph).

Example 4 1-Aminomethyl-2-benzyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide Ether of lithium aluminum hydride (12.0 g) (500 m
l) Concentrated sulfuric acid (8.6 ml) was added dropwise to the suspension at 0 ° C., and the mixture was stirred for 30 minutes. The crystals obtained in Example 3 (30.0
The ether solution of g) was added dropwise at room temperature and stirred for 3 hours.
The reaction solution was poured into ice water, made alkaline with potassium hydroxide, and extracted with ether. The ether layer was washed with water, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure (48.0 g, crude yield 96
%). The obtained oil (30.0 g) was added to 48% hydrobromic acid (530 m
l) was added and the mixture was heated with stirring for 3 hours. The reaction solution is concentrated under reduced pressure,
The obtained crude crystals were recrystallized from ethanol to give 1-aminomethyl-2-benzyl-6-hydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide (39.3 g, 86
%) As colorless crystals.

¹ H-NMR (D ₂ O) δ (ppm): 3.0 to 4.0 (7H, m, P
hCH ₂ CH ₂ N, CHCH ₂ N), 4.4 (2H, s, PhCH ₂ N), 6.8 to 7.3 (3
H, m, Ph), 7.5-7.6 (5H, m, Ph).

Example 5 2-Benzyl-1-tert-butoxycarbonylaminomethyl-6-hydroxy-1,2,3,4
-Tetrahydroisoquinoline The crystal obtained in Example 4 (38.8 g) and triethylamine (4
4.2 ml) water (90 ml), dimethylformamide (DMF, 90 ml)
DMF (180 ml) of tert-butyl-4,6-dimethylpyrimidin-2-ylthiocarbonate (23.8 g) was added to the mixed solution of
The solution was added and stirred at room temperature for 3 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The obtained crude crystals were recrystallized from ethyl acetate to give 2-benzyl-1-tertiary butoxycarbonylaminomethyl-6-hydroxy-1,2,3,
4-Tetrahydroisoquinoline (23.3 g, 70%) was obtained as colorless crystals.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.4 (9H, s, B
u ^t ), 2.7 to 3.4 (6H, m, PhCH ₂ CH ₂ N, CH ₂ N), 3.6 to
3.7 (1H, m, CH), 3.8 (2H, s, PhCH ₂ N), 6.5 ~ 7.1 (3H,
m, Ph), 7.3-7.5 (5H, m, Ph), 9.1 (1H, s, OH).

Example 6 1- [2-benzyl-1-third
Butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] ethyl oxyacetate The crystals (20.0 g) obtained in Example 5 were mixed with 2-butanone (250 m
l), the solution was added with anhydrous potassium carbonate (22.5 g) and heated under reflux for 30 minutes. Ethyl bromoacetate (10.0
g) was added dropwise, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5N aqueous sodium hydroxide solution and water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The oily substance obtained was purified by column chromatography to give 1- [2-benzyl-1.
Ethyl 3-butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (22.5 g, 92%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 1.5 (9H, s , Bu t), 2.7~3.8 (7H, m, PhCH 2 CH 2 N, CH
CH ₂ N), 3.9 (2H, s, PhCH ₂ N), 4.4 (2H, q, Et), 4.7 (2H, s, OCH ₂ CO), 5.0 to 5.3 (1H, m, NHCO), 6.7 to
7.3 (3H, m, Ph), 7.4 (5H, s, Ph)

Example 7 Ethyl 1- [2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate The oil obtained in Example 6 (6.8 g ) Was added with a 3N hydrochloric acid-dioxane solution (100 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain crude crystals. (5.7 g, 89%). The obtained crude crystals (5.7 g) were suspended in acetonitrile (55 ml),
Triethylamine (6.5 ml) was added. Toluenesulfonyl chloride (2.5 g) in acetonitrile (7 m
l) The solution was added dropwise and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
The ethyl acetate layer was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, 1-
Ethyl [2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (6.1 g, 91%) was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.5 (3H, s, PhCH ₃ ), 2.7 to 3.3 (6H, m, PhCH ₂ CH ₂ N,
CH ₂ N), 3.5 to 3.7 (1H, m, CH), 3.7 (2H, s, PhCH ₂ N),
4.3 (2H, q, Et), 4.6 (2H, s, OCH ₂ CO), 6.6 ~ 6.9 (3H,
m, Ph), 7.1-7.7 (9H, m, Ph).

Example 8 Ethyl 1- [1-benzenesulfonylaminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate Reaction and treatment were carried out in the same manner as in Example 7, 1- [1-benzenesulfonylaminomethyl-2-benzyl-1,2,3,4-
Ethyl tetrahydroisoquinolin-6-yl] oxyacetate (6.0 g, 91%) was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.7 to 3.3 (6H, m, PhCH ₂ CH ₂ N, CH ₂ N), 3.5 to 3.7
(1H, m, CH), 3.7 (2H, s, PhCH ₂ N), 4.4 (2H, q, Et),
4.7 (2H, s, OCH ₂ CO), 6.6 ~ 6.9 (3H, m, Ph), 7.3 ~ 7.9
(10H, m, Ph).

Example 9 1- [2-benzyl-1- (4
-Chlorobenzene) sulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] ethyl oxyacetate Reaction and treatment were carried out in the same manner as in Example 7 to give 1- [2-benzyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydro. Isoquinolin-6-yl]
Ethyl oxyacetate (6.7 g, 95%) was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.7 to 3.3 (6H, m, PhCH ₂ CH ₂ N, CH ₂ N), 3.5 to 3.7 (1H,
m, CH), 3.7 (2H, s, PhCH ₂ N), 4.4 (2H, q, Et), 4.7 (2
H, s, OCH ₂ CO), 6.6 to 6.9 (3H, m, Ph), 7.3 to 7.8 (9H,
m, Ph).

Example 10 Ethyl 1- [2-acetyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate Crystals obtained in Example 7 (1.2 g) Was dissolved in ethanol (25 ml), 3N hydrochloric acid-ethanol (0.8 ml) and palladium-
Black (200 mg) was added. The resulting mixture was stirred at room temperature under a hydrogen gas stream. After confirming deprotection, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude hydrochloride (1.0 g) was dissolved in dichloromethane (25 ml) and triethylamine (0.7 g) was added.
3 ml) was added. Acetyl chloride (0.2
A solution of g) in dichloromethane (3 ml) was added dropwise and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 1- [2-acetyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (0.89
g, 80%) as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.8 to 3.1 (2H, m,
PhCH ₂ ), 3.2 to 3.8 (5H, m, CH ₂ N, CHCH ₂ N), 4.4 (2H, q,
Et), 4.6 (2H, s, OCH ₂ CO), 5.5 to 5.8 (1H, m, NH), 6.6
~ 7.0 (3H, m, Ph), 7.2 ~ 7.4 (2H, m, Ph), 7.6 ~ 7.8 (2
H, m, Ph). Example 11 Ethyl 1- [2-acetyl-1-benzenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate

Reaction and treatment were carried out in the same manner as in Example 10,
Ethyl [2-acetyl-1-benzenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (0.83 g, 76%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.0 (3H, s, Ac), 2.6 ~ 3.0 (2H, m, PhCH ₂ ), 3.1 ~
3.7 (5H, m, CH ₂ N, CHCH ₂ N), 4.2 (2H, q, Et), 4.5 (2H, s, OCH ₂ CO), 5.5 ~ 5.8 (1H, m, NH), 6.5 ~ 6.
8 (3H, m, Ph), 7.3 ~ 7.9 (5H, m, Ph).

Example 12 1- [2-acetyl-1- (4
-Chlorobenzene) sulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] ethyl oxyacetate Reaction and treatment were carried out in the same manner as in Example 10 to give 1- [2-acetyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydro. Isoquinolin-6-yl]
Ethyl oxyacetate (0.75 g, 63%) was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.1 (3H, s, Ac), 2.8 ~ 3.1 (2H, m, PhCH ₂ ), 3.2 ~
3.8 (5H, m, CH ₂ N, CHCH ₂ N), 4.4 (2H, q, Et), 4.7 (2H, s, OCH ₂ CO), 5.5 ~ 5.8 (1H, m, NH), 6.7 ~ 7.
0 (3H, m, Ph), 7.3 to 8.0 (5H, m, Ph).

Example 13 Ethyl 1- [2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate Crystals obtained in Example 7 (1.2 g) Was dissolved in ethanol (25 ml), 3N hydrochloric acid-ethanol (0.8 ml) and palladium-
Black (200 mg) was added. The resulting mixture was stirred at room temperature under a hydrogen gas stream. After confirming deprotection, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained crude hydrochloride (1.0 g) was dissolved in dichloromethane (25 ml) and triethylamine (0.7 g) was added.
3 ml) was added. To the resulting solution, add benzoyl chloride
A solution of (0.4 g) in dichloromethane (3 ml) was added dropwise, and the mixture was stirred at room temperature for 3 hours. Dilute the reaction solution with dichloromethane,
After washing with water, it was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 1- [2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-
Ethyl tetrahydroisoquinolin-6-yl] oxyacetate (1.1 g, 86%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.5 (3H, s, PhCH ₃ ), 2.7 to 3.1 (2H, m, PhCH ₂ ), 3.
2 to 3.9 (5H, m, CH ₂ N, CHCH ₂ N), 4.3 (2H, q, Et), 4.7 (2H, s, OCH ₂ CO), 5.6 to 6.0 (1H, m, NH), 6.7 to 7.0
(3H, m, Ph), 7.5 (5H, s, Bz), 7.2-7.9 (4H, m, Ph).

Example 14 Ethyl 1- [1-benzenesulfonylaminomethyl-2-benzoyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 13, 1- [1-benzenesulfonylaminomethyl-2-benzoyl-1,2,3,4
Ethyl -tetrahydroisoquinolin-6-yl] oxyacetate (1.1 g, 88%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.7 to 3.1 (2H, m, PhCH ₂ ), 3.3 to 3.8 (5H, m, CH ₂ N,
CHCH ₂ N), 4.4 (2H, q, Et), 4.7 (2H, s, OCH ₂ CO), 5.7 ~
6.1 (1H, m, NH), 6.7 ~ 7.0 (3H, m, Ph), 7.5 (5H, s, B
z), 7.4-8.0 (5H, m, Ph).

Example 15 1- [2-benzoyl-1-
(4-chlorobenzene) sulfonylaminomethyl-1,2,
Ethyl 3,4-tetrahydroisoquinolin-6-yl] oxyacetate Reaction and treatment were carried out in the same manner as in Example 13 to give 1- [2-benzoyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3, Ethyl 4-tetrahydroisoquinolin-6-yl] oxyacetate (1.2 g, 89%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 2.7 to 3.1 (2H, m, PhCH ₂ ), 3.2 to 4.0 (5H, m, CH ₂ N,
CHCH ₂ N), 4.3 (2H, q, Et), 4.6 (2H, s, OCH ₂ CO), 5.6〜
6.0 (1H, m, NH), 6.7 ~ 7.0 (3H, m, Ph), 7.5 (5H, s, B
z), 7.3-7.9 (4H, m, Ph).

Example 16 1- [2-benzyloxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,
Ethyl 4-tetrahydroisoquinolin-6-yl] oxyacetate The crystals (1.2 g) obtained in Example 7 were treated with ethanol (25 ml).
It was dissolved in 3N hydrochloric acid-ethanol (0.8 ml) and palladium-black (200 mg) were added. The resulting mixture was stirred at room temperature under a hydrogen gas stream. After confirming deprotection, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Crude hydrochloride obtained (1.0 g)
Was dissolved in chloroform (25 ml), and triethylamine (0.73 ml) was added. A solution of benzyloxycarbonyl chloride (0.44 g) in chloroform (3 ml) was added dropwise to the resulting solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform, washed with water, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue is purified by silica gel column chromatography, 1-
Ethyl [2-benzyloxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyoxyacetate (1.1 g, 81%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 2.4 (3H, s, PhCH ₃ ), 2.5 to 2.9 (2H, m, PhCH ₂ ), 2.9
~ 3.4 (4H, m, CH ₂ N × 2), 3.5 ~ 3.9 (1H, m, CH), 4.3
(2H, q, Et), 4.5 (2H, s, OCH ₂ CO), 5.2 (2H, s, PhCH
₂ O), 6.6 to 7.0 (3H, m, Ph), 7.3 (5H, s, Z), 7.1 to 7.7
(4H, m, Ph).

Example 17 1- [1-benzenesulfonylaminomethyl-2-benzyloxycarbonyl-1,2,3,
Ethyl 4-tetrahydroisoquinolin-6-yl] oxyacetate Reaction and treatment were carried out in the same manner as in Example 16 to give 1- [1-benzenesulfonylaminomethyl-2-benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline. Ethyl-6-yl] oxyacetate (1.0 g, 77%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 2.5 to 3.0 (2H, m, PhCH ₂ ), 3.0 to 3.4 (4H, m, CH ₂ N
× 2), 3.6 to 3.9 (1H, m, CH), 4.3 (2H, q, Et), 4.5 (2
H, s, OCH ₂ CO), 5.2 (2H, s, PhCH ₂ O), 6.6 ~ 6.9 (3H, m,
Ph), 7.3 (5H, s, Z), 7.3 ~ 7.8 (5H, m, Ph).

Example 18 Ethyl 1- [2-benzyloxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate As in Example 16 After reaction and treatment, ethyl 1- [2-benzyloxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (1.1 g, 74% ) Was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 2.5 to 3.0 (2H, m, PhCH ₂ ), 3.0 to 3.5 (4H, m, CH ₂ N
× 2), 3.7 to 4.0 (1H, m, CH), 4.3 (2H, q, Et), 4.6 (2
H, s, OCH ₂ CO), 5.2 (2H, s, PhCH ₂ O), 6.6 ~ 7.0 (3H, m,
Ph), 7.4 (5H, s, Z), 7.3 to 7.8 (4H, m, Ph).

Example 19 1- [2-tert-butoxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4
Ethyl tetrahydroisoquinolin-6-yl] oxyacetate The crystals (1.2 g) obtained in Example 7 were dissolved in ethanol (25 ml), and 3N hydrochloric acid-ethanol (0.8 ml) and palladium-
Black (200 mg) was added. The resulting mixture was stirred at room temperature under a hydrogen gas stream. After confirming deprotection, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting crude hydrochloride salt (1.0 g),
Sodium hydrogen carbonate (0.60 g), ethyl acetate (25 ml), water (2
After stirring the mixture (5 ml) at room temperature for 30 minutes, a solution of di-tert-butyl carbonate (0.83 g) in ethyl acetate (5 ml) was added,
It was stirred for another 2 hours. The ethyl acetate layer was separated, and the aqueous layer was extracted with ethyl acetate. Combine the organic layers and wash with water, then add Na
Dried with ₂ SO ₄ . The residue obtained by concentration under reduced pressure was purified by column chromatography to give 1- [2-tertiary butoxycarbonyl-1.
-Toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] ethyl oxyacetate (1.1
g, 85%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 1.5 (9H, s , Bu t), 2.4 (3H, s, PhCH 3), 2.5~2.9
(2H, m, PhCH ₂ ), 2.9 to 3.3 (4H, m, CH ₂ N × 2), 3.5 to 3.
8 (1H, m, CH), 4.2 (2H, q, Et), 4.5 (2H, s, OCH ₂ CO),
5.0 ~ 5.3 (1H, m, NH), 6.6 ~ 7.0 (3H, m, Ph), 7.1 ~ 7.4
(2H, m, Ph), 7.6 to 7.8 (2H, m, Ph).

Example 20 1- [1-benzenesulfonylaminomethyl-2-tert-butoxycarbonyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] ethyl oxyacetate Reaction and treatment were carried out in the same manner as in Example 19 to give 1- [1-benzenesulfonylaminomethyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline. -6-yl]
Ethyl oxyacetate (1.0 g, 82%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 1.5 (9H, s , Bu t), 2.5~2.9 (2H, m, PhCH 2), 2.9
~ 3.4 (4H, m, CH ₂ N × 2), 3.6 ~ 3.9 (1H, m, CH), 4.2
(2H, q, Et), 4.5 (2H, s, OCH ₂ CO), 5.0 ~ 5.3 (1H, m, N
H), 6.5 to 7.0 (3H, m, Ph), 7.3 to 7.9 (5H, m, Ph).

Example 21 Ethyl 1- [2-tert-butoxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate Similar to Example 19. And treated to give ethyl 1- [2-tert-butoxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (1.2 g, 88%) as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 1.5 (9H, s , Bu t), 2.5~2.9 (2H, m, PhCH 2), 2.9~
3.4 (4H, m, CH ₂ N × 2), 3.6 to 3.9 (1H, m, CH), 4.2 (2
H, q, Et), 4.5 (2H, s, OCH ₂ CO), 5.0 to 5.2 (1H, m, N
H), 6.5 to 6.9 (3H, m, Ph), 7.3 to 7.7 (4H, m, Ph).

Example 22 1- [2-Acetyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid The oil obtained in Example 10 (0.79 g) Methanol (10 ml)
And add 1N potassium hydroxide aqueous solution (8.6 ml),
The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and the solution was made acidic with 6N hydrochloric acid. The obtained mixture was extracted with ethyl acetate, the ethyl acetate layer was washed with water, and dried over Na ₂ SO ₄ . The solvent was concentrated under reduced pressure and the obtained crude crystals were recrystallized from ethyl acetate-hexane to give 1- [2-acetyl-1-toluenesulfonylaminomethyl-1,2,3,4.
-Tetrahydroisoquinolin-6-yl] oxyacetic acid (0.73g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.1 (3H, s, A
c), 2.4 (3H, s, PhCH ₃ ), 2.7 to 3.1 (2H, m, PhCH ₂ ), 3.1
~ 3.5 (4H, m, CH ₂ N × 2), 3.5 ~ 3.9 (1H, m, CH), 4.6
(2H, s, OCH ₂ CO), 6.5 to 6.9 (3H, m, Ph), 7.0 to 8.0 (4H,
m, Ph). 1R (cm ^-1 ): 3300, 2900, 1730, 1660, 1500, 1430, 13
30, 1230, 1160, 1090.

Example 23 1- [2-Acetyl-1-benzenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1 -[2-Acetyl-1-benzenesulfonylaminomethyl-1,2,3,4-
Tetrahydroisoquinolin-6-yl] oxyacetic acid (0.
58 g, 85%) was obtained as colorless crystals.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.1 (3H, s, A
c), 2.7 to 3.0 (2H, m, PhCH ₂ ), 3.0 to 3.3 (4H, m, CH ₂ N
× 2), 3.9 to 4.2 (1H, m, CH), 4.7 (2H, s, OCH ₂ CO),
6.6 to 7.2 (3H, m, Ph), 7.4 to 7.9 (5H, m, Ph). 1R (cm ^-1 ): 3300, 2900, 1720, 1600, 1500, 1440, 13
30, 1250, 1220, 1170, 890.

Example 24 1- [2-acetyl-1- (4
-Chlorobenzene) sulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1- [2-acetyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline. -6-yl]
Oxyacetic acid (0.59 g, 96%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.2 (3H, s, A
c), 2.7 to 3.1 (2H, m, PhCH ₂ ), 3.1 to 3.9 (4H, m, CH ₂ N
× 2), 3.5 to 3.9 (1H, m, CH), 4.7 (2H, s, OCH ₂ CO),
6.5 to 7.1 (3H, m, Ph), 7.2 to 7.9 (4H, m, Ph). 1R (cm ^-1 ): 3250, 2900, 1740, 1610, 1500, 1430, 133
0, 1230, 1260, 1080, 890.

Example 25 1- [2-Benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1 -[2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid (0.90g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.4 (3H, s, PhC
H ₃ ), 2.6 to 3.1 (2H, m, PhCH ₂ ), 3.1 to 3.6 (4H, m, CH ₂ N
× 2), 3.6 to 4.0 (1H, m, CH), 4.6 (2H, s, OCH ₂ CO),
6.6 ~ 7.0 (3H, m, Ph), 7.5 (5H, s, Bz), 7.1 ~ 7.9 (4H,
m, Ph). 1R (cm ^-1 ): 3250, 2900, 1750, 1620, 1510, 1430, 13
20, 1240, 1150, 1100, 900, 820.

Example 26 1- [1-Benzenesulfonylaminomethyl-2-benzoyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1 -[1-benzenesulfonylaminomethyl-2-benzoyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid (0.83g, 97%) was obtained as colorless crystals.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 2.5-3.0 (2H,
m, PhCH ₂ ), 3.0 to 3.6 (4H, m, CH ₂ N × 2), 3.6 to 4.0 (1
H, m, CH), 4.6 (2H, s, OCH ₂ CO), 6.6 ~ 7.0 (3H, m, P
h), 7.4 (5H, m, Bz), 7.1-7.9 (5H, m, Ph). 1R (cm ^-1 ): 3250, 2900, 1740, 1610, 1500, 1450, 13
30, 1240, 1160, 1100, 1070, 900.

Example 27 1- [2-benzoyl-1-
(4-chlorobenzene) sulfonylaminomethyl-1,2,
3,4-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1- [2-benzoyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4. -Tetrahydroisoquinolin-6-yl] oxyacetic acid (0.92g, 99%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.6 to 3.0 (2H,
m, PhCH ₂ ), 3.0 to 3.6 (4H, m, CH ₂ N × 2), 3.6 to 3.9 (1H,
m, CH), 4.6 (2H, s, OCH ₂ CO), 6.6 to 7.1 (3H, m, Ph),
7.4 (5H, s, Bz), 7.2 ~ 7.9 (4H, m, Ph). 1R (cm ^-1 ): 3250, 2900, 1750, 1620, 1500, 1430, 13
40, 1240, 1160, 1080, 900, 830.

Example 28 1- [2-benzyloxycarbonyl-1-trienesulfonylaminomethyl-1,2,3,
4-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1- [2-benzyloxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline- 6-yl] oxyacetic acid (0.87 g, 99%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.4 (3H, s, PhC
H ₃ ), 2.5 to 2.9 (2H, m, PhCH ₂ ), 2.9 to 3.6 (4H, m, CH ₂ N
× 2), 3.6 to 4.0 (1H, m, CH), 4.5 (2H, s, OCH ₂ CO), 5.
6 (2H, s, PhCH ₂ O), 6.5 ~ 7.0 (3H, m, Ph), 7.4 (5H, s,
Z), 7.3-7.8 (4H, m, Ph). 1R (cm ^-1 ): 3250, 2900, 1750, 1680, 1600, 1500, 14
30, 1330, 1230, 1160, 1100, 1010, 820.

Example 29 1- [1-benzenesulfonylaminomethyl-2-benzyloxycarbonyl-1,2,3,
4-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1- [1-benzenesulfonylaminomethyl-2-benzyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline- 6-yl] oxyacetic acid (0.85 g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.4 to 3.0 (2H,
m, PhCH ₂ ), 3.0 to 3.6 (4H, m, CH ₂ N × 2), 3.6 to 4.0 (1
H, m, CH), 4.6 (2H, s, OCH ₂ CO), 5.1 (2H, s, PhCH
₂ O), 6.5 to 6.9 (3H, m, Ph), 7.3 (5H, s, Z), 7.0 to 7.8
(5H, m, Ph). 1R (cm ^-1 ); 3250, 2900, 1740, 1680, 1610, 1500, 143
0, 1330, 1290, 1230, 1160, 1100, 1010.

Example 30 1- [2-Benzyloxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction similar to Example 22 And treated with 1- [2-benzyloxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid (0.90 g, 99%). Obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.6 to 3.0 (2H,
m, PhCH ₂ ), 3.0 to 3.5 (4H, m, CH ₂ N × 2), 3.6 to 4.0 (1H,
m, CH), 4.6 (2H, s, OCH ₂ CO), 5.2 (2H, s, PhCH ₂ O),
6.6 to 6.9 (3H, m, Ph), 7.4 (5H, s, Z), 7.2 to 7.8 (4H,
m, Ph). 1R (cm ^-1 ): 3250, 2900, 1740, 1680, 1610, 1500, 14
30, 1340, 1230, 1160, 1100, 1010, 830.

Example 31 1- [2-tert-butoxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22, and 1- [2-tertiary butoxycarbonyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline- 6-yl]
Oxyacetic acid (0.85 g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.4 (3H, s, PhCH ₃ ), 2.6 to 2.9 (2H, m, PhCH ₂ ),
2.9 to 3.5 (4H, m, CH ₂ N × 2), 3.7 to 4.0 (1H, m, CH), 4.
6 (2H, s, OCH ₂ CO), 6.5 ~ 7.0 (3H, m, Ph), 7.2 ~ 7.8 (4
H, m, Ph). 1R (cm ^-1 ): 3250, 3000, 1750, 1670, 1610, 1500, 14
30, 1370, 1330, 1240, 1150, 1100, 820.

Example 32 1- [1-benzenesulfonylaminomethyl-2-tert-butoxycarbonyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid Reaction and treatment were carried out in the same manner as in Example 22 to give 1- [1-benzenesulfonylaminomethyl-2-tert-butoxycarbonyl-1,2,3,4-tetrahydroisoquinoline- 6-yl]
Oxyacetic acid (0.80 g, 96%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.5 to 2.9 (2H, m, PhCH ₂ ), 2.9 to 3.4 (4H, m, CH ₂ N
× 2), 3.6 to 3.9 (1H, m, CH), 4.6 (2H, s, OCH ₂ CO), 6.3
~ 7.0 (3H, m, Ph), 7.3 ~ 7.9 (5H, m, Ph). 1R (cm ^-1 ); 3250, 3000, 1750, 1670, 1610, 1500, 143
0, 1370, 1330, 1240, 1210, 1100, 850.

Example 33 1- [2-tert-Butoxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid As in Example 22 After reaction and treatment, ethyl 1- [2-tert-butoxycarbonyl-1- (4-chlorobenzene) sulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetate (0.95 g, 99 %) As colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.5 to 2.9 (2H, m, PhCH ₂ ), 2.9 to 3.4 (4H, m, CH ₂ N
× 2), 3.6 to 3.9 (1H, m, CH), 4.6 (2H, s, OCH ₂ CO), 6.
5 to 7.0 (3H, m, Ph), 7.3 to 7.9 (4H, m, Ph). 1R (cm ^-1 ): 3250, 3000, 1750, 1670, 1610, 1500, 14
80, 1430, 1360, 1340, 1240, 1160, 1100, 830.

Example 34 1- [2-benzyl-1-third
Butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester The reaction and treatment were conducted in the same manner as in Example 6 to give 1- [2-benzyl-1-tert-butoxy]. Carbonylaminomethyl-1,2,3,
4-Tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester (23.5 g, 85%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (9H, s, B
u ^t ), 1.5 (9H, s, Bu ^t ), 2.4 to 3.2 (7H, m, PhCH ₂ CH ₂ N, C
HCH ₂ N), 3.2 (2H, s, PhCH ₂ N), 4.5 (2H, s, OCH ₂ CO), 4.
9 ~ 5.2 (1H, m, NHCO), 6.6 ~ 7.0 (3H, m, Ph), 7.3 (5H,
s, Ph).

Example 35 1- [2-benzyl-1- (4
-Chlorobenzene) sulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester The oil obtained in Example 34 (21.4 g) was converted to ether (250 ml).
A solution of p-toluenesulfonic acid (16.9 g) in tetrahydrofuran (50 ml) was added dropwise at 0 ° C. The reaction solution was stirred at the same temperature for 3 hours and concentrated under reduced pressure. (32.8g, crude yield 97
%).

The resulting residue (8.8 g) was added to acetonitrile (75 m
It was dissolved in l) and triethylamine (5.7 ml) was added. The obtained solution was added with p-chlorobenzenesulfonyl chloride.
A solution of (2.4 g) in acetonitrile (13 ml) was added dropwise, and the mixture was stirred at room temperature for 3
Stir for hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and 1- [2-benzyl-1-
(4-chlorobenzene) sulfonylaminomethyl-1,2,
3,4-Tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester (5.3 g, 82%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.5 to 3.3 (6H, m, PhCH ₂ CH ₂ N, CH ₂ N), 3.4 to 3.6 (1
H, m, CH), 3.7 (2H, s, PhCH ₂ N), 4.5 (2H, s, OCH ₂ C
O), 6.5 to 6.8 (3H, m, Ph), 7.3 (5H, s, Ph), 7.3 to 7.7
(4H, m, Ph).

Example 36 1- [1-Benzenesulfonylaminomethyl-2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester Reaction and treatment as in Example 35. 1- [1-benzenesulfonylaminomethyl-2-benzyl-1,2,3,4-
Tetrahydroisoquinolin-6-yl] oxyacetic acid third
Butyl ester (5.2 g, 86%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.5 to 3.5 (7H, m, PhCH ₂ CH ₂ N, CHCH ₂ N), 3.6 (2H,
s, PhCH ₂ N), 4.6 (2H, s, OCH ₂ CO), 6.5 to 6.8 (3H, m, P
h), 7.3 (5H, s, Ph), 7.2-7.8 (3H, m, Ph).

Example 37 1- [2-Benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester Reaction and treatment as in Example 35. 1- [2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-
Tetrahydroisoquinolin-6-yl] oxyacetic acid third
Butyl ester (4.7 g, 75%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.4 (3H, s, PhCH ₃ ), 2.6 to 3.1 (7H, m, PhCH ₂ CH ₂ N,
CHCH ₂ N), 3.2 (2H, s, PhCH ₂ N), 4.5 (2H, s, OCH ₂ C
O), 6.5 to 6.8 (3H, m, Ph), 7.3 (5H, s, Ph), 7.1 to 7.4
(4H, m, Ph).

Example 38 2-Benzyl-1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride The crystal obtained in Example 35 (5.1 3 g hydrochloric acid-dioxane solution (46 ml) was added to g), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain 2-benzyl-1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride (4.7 g, 96%). It was

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 2.9
~ 3.9 (7H, m, PhCH ₂ CH ₂ N, CHCH ₂ N), 4.3 ~ 4.5 (2H, m, P
hCH ₂ N), 4.6 (2H, s, OCH ₂ CO), 6.7 to 7.1 (3H, m, Ph),
7.5 (5H, s, Ph), 7.3 ~ 7.8 (4H, m, Ph). 1R (cm ^-1 ): 3050, 2950, 1750, 1620, 1510, 1460, 14
40, 1340, 1210, 1160, 1080, 750.

Example 39 1-Benzenesulfonylaminomethyl-2-benzyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride The reaction and treatment were conducted in the same manner as in Example 38, and 1- Benzenesulfonylaminomethyl-2-benzyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride (4.3 g, 90%) was obtained.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 3.0
~ 3.7 (7H, m, PhCH ₂ CH ₂ N, CHCH ₂ N), 4.3 ~ 4.5 (2H, m, P
hCH ₂ N), 4.6 (2H, s, OCH ₂ CO), 6.7 to 7.1 (3H, m, Ph),
7.4 to 7.9 (10H, m, Ph). 1R (cm ^-1 ): 3050, 2900, 1730, 1620, 1510, 1460, 13
40, 1240, 1210, 1160, 1090, 870.

Example 40 2-Benzyl-6-hydroxycarbonylmethoxy-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline.hydrochloride The reaction and treatment were carried out in the same manner as in Example 38 to give 2- Benzyl-6
-Hydroxycarbonylmethoxy-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline.hydrochloride (4.4 g, 90%) was obtained.

¹ H-NMR (CDCl ₃ + CD ₃ OD) δ (ppm): 2.4
(3H, s, PhCH ₃ ), 2.9 to 3.6 (7H, m, PhCH ₂ CH ₂ N, CHCH
₂ N), 4.2 to 4.4 (2H, m, PhCH ₂ N), 4.6 (2H, s, OCH ₂ CO)
, 6.6 to 7.8 (12H, m, Ph). 1R (cm ^-1 ); 3050, 2850, 1750, 1620, 1510, 1460, 13
40, 1250, 1210, 1160, 1120, 1090, 870, 820.

Example 41 1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride The compound (3.0 g) obtained in Example 38 was converted into methanol. It was dissolved in (60 ml) and palladium-black (500 mg) was added. The resulting mixture was stirred under a hydrogen gas stream at room temperature for 3 hours. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure, and 1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline.hydrochloride (2.3 g, 96%). Got

¹ H-NMR (CD ₃ OD) δ (ppm): 2.9 to 3.9 (7H,
m, PhCH ₂ CH ₂ N, CHCH ₂ N), 4.7 (2H, s, OCH ₂ CO), 6.8 to 7.
2 (3H, m, Ph), 7.5 ~ 8.0 (4H, m, Ph), 1R (cm ^-1 ): 2950, 1750, 1660, 1640, 1510, 1440, 13
40, 1220, 1160, 1080, 830, 760.

Example 42 1-Benzenesulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4
-Tetrahydroisoquinoline-hydrochloride The reaction and treatment were carried out in the same manner as in Example 41, and 1-benzenesulfonylaminomethyl-6-hydroxycarbonylmethoxy-1,2,3,4-tetrahydroisoquinoline-hydrochloride (2.
2g, 89%) was obtained.

¹ H-NMR (CD ₃ OD) δ (ppm): 3.0 to 3.9 (7H,
m, PhCH ₂ CH ₂ N, CHCH ₂ N), 4.7 (2H, s, OCH ₂ CO), 6.8
~ 7.3 (3H, m, Ph), 7.5 ~ 8.0 (5H, m, Ph). 1R (cm ^-1 ); 3050, 2950, 1750, 1670, 1510, 1450, 133
0, 1220, 1160, 1090, 760.

Example 43 Hydroxycarbonylmethoxy-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline.hydrochloride The reaction and treatment were conducted in the same manner as in Example 41 to give 6-hydroxycarbonylmethoxy-1-. Toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.
2g, 90%) was obtained.

¹ H-NMR (DMSO-d ₆ + D ₂ O) δ (ppm): 2.4 (3
H, s, PhCH ₃ ), 2.8 to 3.9 (7H, m, PhCH ₂ CH ₂ N, CHCH ₂ N),
4.6 (2H, s, OCH ₂ CO), 6.7 ~ 7.1 (3H, m, Ph), 7.3 ~ 7.8
(4H, m, Ph). 1R (cm ^-1 ): 2950, 1730, 1620, 1510, 1440, 1330, 12
40, 1210, 1160, 1090, 820.

Example 44 6-Hydroxy-2-methyl-
3,4-Dihydrotetrahydroisoquinoline / iodine salt The oil (13.0 g) obtained in Example 2 in ethanol (80 ml)
Methyl iodide (7.5 ml) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The precipitate formed was filtered and then recrystallized from ethanol,
6-Hydroxy-2-methyl-3,4-dihydrotetrahydroisoquinoline.iodine salt (19.4 g, 79%) was obtained as pale yellow crystals.

¹ H-NMR (CD ₃ OD + DMSO−d ₆ ) δ (ppm): 3.0
~ 3.4 (2H, m, PhCH ₂ ), 3.7 (3H, s, Me), 3.9 (3H, s, Me
O), 3.8 to 4.2 (2H, m, CH ₂ N), 6.9 to 7.2 (2H, m, Ph), 7.
6 to 7.9 (1H, m, Ph), 9.0 (1H, s, CH = N).

Example 45 1-Cyano-6-methoxy-2
-Methyl-1,2,3,4-tetrahydroisoquinoline The crystal (18.6 g) obtained in Example 44 was dissolved in water (120 ml), and an aqueous solution (120 ml) of potassium cyanide (5.0 g) was added. The reaction solution was extracted with ether, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. The obtained residue is purified by column chromatography,
1-Cyano-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (7.8 g, 63%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 2.6 (3H, s, M
e), 2.7 to 3.0 (4H, m, PhCH ₂ CH ₂ N), 3.8 (3H, s, MeO),
4.7 (1H, s, CH), 6.6 ~ 7.3 (3H, m, Ph).

Example 46 1-Aminomethyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline dihydrobromide The reaction treatment was carried out in the same manner as in Example 4 to prepare 1-amino. Methyl-
6-Hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline dihydrobromide (7.6 g, 94%) was obtained as colorless crystals.

¹ H-NMR (D ₂ O) δ (ppm): 3.1 (3H, s, Me),
3.2 to 3.4 (2H, m, PhCH ₂ ), 3.4 to 3.9 (4H, m, CH ₂ N ×
2), 4.1 to 4.4 (1H, m, CH), 6.8 to 7.3 (3H, m, Ph).

Example 47 1-tert-Butoxycarbonylaminomethyl-6-hydroxy-2-methyl-1,2,3,4-
Tetrahydroisoquinoline Reaction and treatment were carried out in the same manner as in Example 5 to give 1-tertiary butoxycarbonylaminomethyl-6-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (5.8 g, 98%).
Was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (9H, s, B
u ^t ), 2.4 (3H, s, Me), 2.5 to 3.0 (4H, m, PhCH ₂ , CH ₂ N)
, 3.3 ~ 3.5 (3H, m, CH ₂ N, CH), 5.0 ~ 5.3 (1H, br, N
H), 6.5-7.0 (3H, m, Ph).

Example 48 1-tert-Butoxycarbonylaminomethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester The reaction and treatment were carried out as in Example 6. 1- [1-tert-butoxycarbonylaminomethyl-2-methyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester (2.2g, 27%) was obtained as an oil yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (9H, s, B
^{u t), 1.4 (9H,} s, Bu t), 2.4 (3H, s, Me), 2.5~2.9 (4
H, m, PhCH ₂ , CH ₂ N), 3.2 to 3.5 (3H, m, CH ₂ N, CH), 4.4
(2H, s, OCH ₂ CO), 4.7 to 5.1 (1H, m, NHCO), 6.4 to 7.0 (3
H, m, Ph).

Example 49 1- [1- (4-chlorobenzene) sulfonylaminomethyl-2-methyl-1,2,3,4-
Tetrahydroisoquinolin-6-yl] oxyacetic acid third
Butyl ester Reaction and treatment were carried out in the same manner as in Example 35, and 1- [1- (4-
Chlorobenzene) sulfonylaminomethyl-2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxyacetic acid tert-butyl ester (1.1 g, 53%) was obtained as a yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.5 (9H, s, B
u ^t ), 2.4 (3H, s, Me), 2.6 ~ 3.5 (7H, m, PhCH ₂ CH ₂ N, CH
CH ₂ N), 4.5 (2H, s, OCH ₂ C0), 6.5 to 7.0 (3H, m, Ph), 7.
2 to 7.8 (4H, m, Ph).

Example 50 1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.hydrochloride Reaction and treatment were carried out in the same manner as in Example 38. This was performed to obtain 1- (4-chlorobenzene) sulfonylaminomethyl-6-hydroxycarbonylmethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline.hydrochloride (0.90 g, 94%) as colorless crystals.

¹ H-NMR (CD ₃ OD) δ (ppm): 3.0 (3 H, s, M
e), 3.1 to 3.6 (4H, m, PhCH ₂ , CH ₂ N), 3.8 to 4.0 (3H, m,
CH ₂ N, CH), 4.6 (2H, s, OCH ₂ CO), 6.7 ~ 7.2 (3H, m, P
h), 7.4-7.9 (4H, m, Ph). 1R (cm ^-1 ): 3400, 3100, 1750, 1620, 1590, 1510, 14
30, 1340, 1160, 1080,1010, 870, 760.

Example 51 4- [2-benzyl-1-third
Ethyl butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyrate The reaction and treatment were conducted in the same manner as in Example 6, and the crystals (2.5 g) obtained in Example 5 and 4- From ethyl bromobutyrate (1.5g),
4- [2-benzyl-1-tert-butoxycarbonylaminomethyl-1,2,3,4-tetrahydroisoquinoline-6-
Ethyl] oxybutyrate (2.7 g, 82%) was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.3 (3H, t, E
t), 1.5 (9H, s , Bu t), 1.8~2.6 (4H, m, CH 2 CH 2 CO), 2.
7 to 3.8 (7H, m, PhCH ₂ CH ₂ N, CHCH ₂ N), 3.9 (2H, s, PhCH ₂
N), 4.0 to 4.6 (4H, m, OCH ₂ x 2), 5.0 to 5.3 (1H, m, NHC
O), 6.7 to 7.3 (3H, m, Ph), 7.4 (5H, s, Ph). Example 52 Ethyl 4- [2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyrate Reaction and treatment were carried out in the same manner as in Example 7, and 4- [ 2-benzyl-1-toluenesulfonylaminomethyl-1,2,3,4-
Ethyl tetrahydroisoquinolin-6-yl] oxybutyrate (2.2 g, 71%) was obtained as pale yellow crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 1.8 to 2.6 (4H, m, CH ₂ CH ₂ CO), 2.5 (3H, s, PhCH ₃ ),
2.7 to 3.3 (6H, m, PhCH ₂ CH ₂ N, CH ₂ N), 3.5 to 3.7 (1H, m,
CH), 3.7 (2H, s, PhCH ₂ N), 4.0 to 4.6 (4H, m, OCH ₂ ×
2), 6.6 to 6.9 (3H, m, Ph), 7.1 to 7.7 (9H, m, Ph).

Example 53 Ethyl 4- [2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyrate Reaction and treatment were carried out in the same manner as in Example 13, 4- [2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4
Ethyl tetrahydroisoquinolin-6-yl] oxybutyrate (1.5 g, 83%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.4 (3H, t, E
t), 1.8 to 2.6 (4H, m, CH ₂ CH ₂ CO), 2.5 (3H, s, PhCH ₃ ),
2.7 to 3.1 (2H, m, PhCH ₂ ), 3.2 to 3.9 (5H, m, CH ₂ N, CHCH
₂ N), 4.0 to 4.6 (4H, m, OCH ₂ × 2), 5.6 to 6.0 (1H, m, NHC
O), 6.7 to 7.0 (3H, m, Ph), 7.5 (5H, s, Bz), 7.2 to 7.9
(4H, m, Ph).

Example 54 4- [2-Benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4-tetrahydroisoquinolin-6-yl] oxybutyric acid The reaction and treatment were carried out as in Example 22 to give 4 -[2-benzoyl-1-toluenesulfonylaminomethyl-1,2,3,4
-Tetrahydroisoquinolin-6-yl] oxybutyric acid
(1.3 g, 98%) was obtained as colorless crystals.

¹ H-NMR (CDCl ₃ + DMSO-d ₆ ) δ (ppm): 2.4 (3
H, s, PhCH ₃ ), 1.8 to 2.6 (4H, m, CH ₂ CH ₂ CO), 2.6 to 3.1
(2H, m, PhCH ₂ ), 3.1 to 3.6 (4H, m, CH ₂ N × 2), 3.6 to 4.
0 (1H, m, CH), 4.2 to 4.6 (2H, m, OCH ₂ ) 6.6 to 7.0 (3H, m, Ph), 7.5 (5H, s, Bz), 7.2 to 7.9 (4H,
m, Ph).

Continuation of front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/47 ACF AED 7252-4C C07D 401/12 8829-4C

Claims (6)

[Claims] 1. A general formula (1): (Expressed in the formula, R ₁ represents an alkyl group, or a halogen, alkyl group, alkoxy group, nitro group, one or more optionally substituted aryl group a trifluoromethyl group, an aralkyl group, a heterocyclic ring, R ₂ Is hydrogen, or an acyl group which may be substituted with a halogen, a nitro group, a methoxy group, a hydroxy group, a linear or branched alkyl group, an aralkyl group, a linear or branched alkyloxycarbonyl group, an aralkyloxycarbonyl group. R ₃ represents a hydroxy group, an alkoxy group, a benzyloxy group or has the formula: —NR ₄ R ₅ where R ₄ and R ₅ are the same or different, and
An aminomethyltetrahydroisoquinoline derivative consisting of a compound represented by hydrogen, an alkyl group or an aralkyl group, and n represents 1 to 6) or a pharmaceutically acceptable salt thereof. 2. In the formula (I), R ₁ represents halogen, an aryl group which may be substituted with one or more lower alkyl groups having 1 to 4 carbon atoms, R ₂ represents hydrogen, or Represents an acyl group, a linear or branched alkyl group, an aralkyl group, a linear or branched alkyloxycarbonyl group, an aralkyloxycarbonyl group, R ₃ represents a hydroxy group, and n represents 1 to 3 The derivative according to claim 1, which is represented by 3. A pharmaceutical composition comprising as active substance a derivative according to claim 1 or 2 optionally together with one or more inert carriers and / or diluents. 4. The pharmaceutical composition according to claim 3, which is suitable for treating and preventing thromboembolic disorders and preventing arteriosclerosis. 5. A compound represented by the general formula (II): (Wherein R ₂ , R ₃ and n have the same meanings as defined in claim 1), an amine represented by the general formula (III) R ₁ SO ₃ H (III) (wherein R ₁ is A compound having the same meaning as that of claim 1) or an active derivative thereof,
General formula (I) (Wherein R ₁ , R ₂ , R ₃ and n are the same as above), R _{3 of the} compound is OH
If not, the method for producing a derivative according to claim 1 or 2, wherein hydrolysis is carried out to a free carboxylic acid if necessary. 6. A method for producing amines of the general formula (II) according to claim 5, which comprises the general formula (IV): (In the formula, R ₂ has the same meaning as in claim 5, and Pr 2
ot represents an amino-protecting group), and a compound represented by the general formula (V) X (CH ₂ ) _n COR ₃ (V) (in the formula, R ₃ has the same meaning as in claim 5) , X
Represents chlorine, bromine, iodine, alkylsulfonyl or toluenesulfonyl) and then removes the protecting group to produce an amine.