JPH01199976A - Oxazoloisoquinoline compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R<1> and R<2> are OH, alkoxy or R<1> and R<2> are bonded to form alkylenedioxy; X, Y and Z are OH or alkoxy). EXAMPLE:cis-1,3,4,5,10,10a-Hexahydro-5-(3,4,5-trimethoxyphenyl)-7,8-methy lenedioxyoxazolo[3,4-6]isoquinolin-3-one. USE:A drug showing antitumor activity and low toxicity. PREPARATION:For example, a DL-DOPA shown by formula II is condensed with an aromatic aldehyde shown by formula III by Pictet-Spengler reaction to form a compound shown by formula VI, which is reacted with an alkyl chlorocarbonate to give a compound shown by formula V. Then this compound is reacted with a methyl halide in the presence of a deoxidizer to form a com pound shown by formula VI (R<1>' and R<2>' are H, alkyl, etc.), which is reacted with a base and further with a reducing agent to give an optically active com pound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to novel oxazoloisoquinoline compounds exhibiting anti-11i tumor activity.

[Problems to be solved by conventional technology and invention] Conventionally,
Aryltetrahydronutthalide-type gnanes contained in plants of the barberry family, such as Podophyllu
Podophyllotoxin contained in M. peltatum is known to have antitumor and microtubule polymerization inhibitory effects (J, M, Ca5sady eL
al.

Anticancer Agents Ba5ed o
n Natural Product Models'
Academic Press, New York
However, these are highly toxic and are said to be extremely difficult to use clinically.

[Means for solving problems]

The present inventors conducted intensive research with the aim of searching for a compound that has reduced toxicity, has strong antitumor activity, and is useful as a pharmaceutical, and found that oxazoloisoquinoline, which can also be called azapodophyllotoxin, The present invention was completed by discovering that the compound satisfies the intended purpose. That is, the present invention is based on the general formula % (wherein R1 and R2 represent a hydroxyl group, an alkoxy group,
Alternatively, R1 and R2 combine to form an alkylenedioxy group, and X, Y, and Z are the same or different and represent a hydroxyl group or an alkoxy group. ) is related to an oxazoloisoquinoline compound represented by

In the above definition, alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,
Examples include tertiary butoxy, pentyloxy, hexyloxy, octyloxy, etc., and alkylenedioxy includes methylenedioxy, ethylenedioxy, trimethylenedioxy, propylidenedioxy, isopropylidenedioxy, etc.

The compound (r) of the present invention has stereoisomers and optical isomers, and the present invention includes all of them. Each of these isomers can be produced from optically active starting materials, or can be optically resolved or separated by methods known per se. Moreover, each isomer can also be converted into each other by racemization or ebimerization as appropriate.

Compound (I) of the present invention can be produced, for example, by the method shown in the scheme below.

[Margin below]

Child, deceased ≦ Gi soil [mouth CB), (G) Known compounds DL-dopa (■) and aromatic aldehydes (
III) by a Pictet-5pengler reaction to produce cystetrahydroisoquinoline (TV). This reaction is preferably carried out in a suitable reaction solvent, and examples of the reaction solvent include water, methanol, ethanol, pyridine, acetic acid, tetrahydrofuran, and mixtures thereof. This reaction may also be carried out in the presence of a suitable catalyst, such as acetic acid,
Acids such as hydrochloric acid and sulfuric acid, pyridine, triethylamine,
Bases such as morpholine, piperidine, and pyrrolidine are used.

In this reaction, depending on the aromatic aldehyde used, trans-tetrahydroisoquinoline (rV) can also be obtained at the same time, but by methods such as column chromatography and recrystallization, (rV) and trans-tetrahydroisoquinoline (■) can be obtained.
can be separated. The following reaction is (IV)
, (IV)' as a starting material, the case where the reaction starts from the cis isomer (IV) will be described in detail below as a representative example.

That is, the cis N-carbalkoxy compound (V) can be produced by reacting (IV) with an alkyl chlorocarbonate in the presence of an appropriate base. Examples of the base used in the reaction include alkali carbonate and alkali hydrogencarbonate. , alkali hydroxide, etc. are preferred, and the alkyl chlorocarbonate is preferably methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isobutyl chlorocarbonate, Hensyl chlorocarbonate, etc. The reaction is preferably carried out in a suitable reaction solvent. The reaction solvent is preferably a solvent that does not participate in the reaction, such as water, methanol, ethanol, or a mixture thereof. (V) can be optically resolved by using a suitable optically active base.

The cis N-carbalkoxymethyl ester (■) is (
It can be produced by esterifying V) with dimethyl sulfate in the presence of a suitable deoxidizing agent, and preferred examples of the deoxidizing agent include alkali carbonate and alkali hydrogen carbonate.

This reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent may be any solvent that does not participate in the reaction, such as acetone, methanol, tetrahydrofuran, dioxane, and mixtures thereof.

The cis N-carbalkoxymethyl ester (■) can also be produced by reacting the cystetrahydroisoquinoline methyl ester (■) with an alkyl chlorocarbonate in the presence of an appropriate deoxidizer. Preferred examples include alkali carbonate, alkali hydrogencarbonate, and alkali hydroxide. Preferred examples of alkyl chlorocarbonate include methyl chlorocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isobutyl chlorocarbonate, and benzyl chlorocarbonate. This reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent is preferably a solvent that does not participate in the reaction, such as water, methanol, ethanol, chloroform, ethyl acetate, toluene, or a mixture thereof.

Cystetrahydroisoquinoline methyl ester (■)
is the known compound DL-dopa methyl ester hydrochloride (■)
and aromatic aldehyde (III) in Pictet-5p.
It can be produced by condensation by Engler reaction. This reaction is preferably carried out in a suitable reaction solvent,
Examples of the reaction solvent include water, methanol, ethanol, pyridine, acetic acid, tetrahydrofuran, and mixtures thereof.

The cis-0-alkyl compound (IX) can be produced by reacting (Vl) with methyl halide, dimethyl sulfate, methylene halide, etc. in the presence of an appropriate deoxidizing agent, and the deoxidizing agent may include alkali carbonate, Alkali fluoride and the like are preferred. This reaction is preferably carried out in a suitable reaction solvent,
The reaction solvent may be any solvent that does not participate in the reaction, such as acetone, dimethylformamide, dioxane, dimethoxyethane, and mixtures thereof.

Cis-0-alkyl derivatives (IX) in which R+'' and R2° are methyl can be produced by reacting (V) with methyl halide, dimethyl sulfate, etc. in the presence of a suitable deoxidizing agent. The deoxidizing agent is preferably an alkali carbonate or the like.This reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent may be acetone, dimethylformamide, dioxane, dimethoxyethane, or a mixture thereof, which does not participate in the reaction. Anything is fine.

Trans-〇-alkyl compound (X can be produced by treating (IX) with an appropriate base, and the base is preferably an alkali alcoholade, an alkali hydride, etc.) The reaction must be carried out in an appropriate reaction solvent. is preferable, and the reaction solvent is methanol, tetrahydrofuran,
Anything that does not participate in the reaction, such as dioxane and mixtures thereof, may be used.

The trans-〇-alkyl compound (XI) is obtained by converting transcarboxylic acid (X) into methyl halide,
It can also be produced by reacting with dimethyl sulfate, etc., and the deoxidizing agent is preferably alkali carbonate. The reaction is preferably carried out in an appropriate reaction solvent, and examples of reaction solvents include acetone, dimethylformamide, dioxane, Anything that does not participate in the reaction may be used, such as dimethoxyethane and mixtures thereof.

Transcarboxylic acid (X) can be produced by saponifying and isomerizing (IX) with an appropriate base, and any base commonly used for saponification such as alkali hydroxide or alkali carbonate can be used as the base. Can be used. This reaction is preferably carried out in a suitable reaction solvent, and preferred reaction solvents include water, ethanol, methanol, tetrahydrofuran, dioxane, and mixtures thereof.

Cisoxazoloisoquinoline (Xll) and transoxazoloisoquinoline (X1m are respectively (DO
and (Xl) can be produced by reacting with a suitable reducing agent. Preferred reducing agents include lithium borohydride and zinc borohydride.
This reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent may be any solvent that does not participate in the reaction, such as ether, tetrahydrofuran, dioxane, toluene, and mixtures thereof.

R1゜R1 of cis-oxazoloisoquinoline body (■)
is H, the cismethylol form (can also be produced by reacting Xm with a base, and the base is preferably an alkali hydride, an alkali alkoxide, etc.
This reaction is preferably carried out in a suitable reaction solvent, and the reaction solvent may be any solvent that does not participate in the reaction, such as ether, tetrahydrofuran, dioxane, toluene, and mixtures thereof.

The cismethylol compound (χIV) can be produced by reacting the cis N-carbalkoxy compound (V) with a suitable reducing agent. As the reducing agent, borane, borane-tetrahydrofuran complex, etc. are preferable. This reaction is preferably carried out in a suitable reaction solvent, and any reaction solvent may be used as long as it does not participate in the reaction, such as tetrahydrofuran, ether, dioxane, toluene, and mixtures thereof.Furthermore, according to this production method, D- Dopa, D-dopa methyl ester hydrochloride, L-
Optically active (■) by using dopa, L-dopa methyl ester hydrochloride, etc. as raw materials.

(V), (Vl), (VW), (IX), (X
), (XI), (XI).

(X III ), and (Xm) can be produced.

Also (IV), (V), (VI), (Vl),
(IX), (X), (χ■).

(XI), (XI[[) and (Xm) may each be optically resolved by an appropriate method.

[Action and effect of the invention]

The thus obtained compound (1) of the present invention exhibited strong antitumor activity and low toxicity, as shown in the following experimental examples.

Experimental Example 1: Antitumor effect on P388 leukemia 10' P388 leukemia cells (National Can
cerInstitute origin) with 6 female CDs per group.
It was intraperitoneally transplanted into FI mice (8 weeks old), and the specimen was intraperitoneally administered once a day for 5 consecutive days from the day after the transplant. The sample is 1%T
It was suspended in 0.9% physiological saline containing ween80 and administered at a dose of 0.01@Z per 1 g of mouse body weight. The survival of mice in each group was observed, and the median survival days (M S T
Ha+ediansurvival ti+we) to T/C (%) = (MST of treatment group/MST of control group) x
lQQ was calculated. It was considered effective when T/C≧125%.

The results are shown in Table 1.

Table 1 Compound name (1): Cis-1.3,4,5,10.10a-hexahydro-3-(3,4,5-trimethoxyphenyl)
-7,8-methylenedioxyoxazolo(3,4-b)
Isoquinolin-3-one [21: (5S, 10aS
)-1,3,4,5,10゜10a-hexahydro-5
-(3,4,5-trimethoxyphenyl)-7,8-methylenedioxyoxazolo(3,4-b)isoquinolin-3-one (3): Podophyllotoxin Experimental Example 2; Acute toxicity experimental example Compound 1 (11, (2)) did not show any toxic findings during the observation period up to 5 days after a single intraperitoneal administration of 300 aw/kg.

Compounds (1) and (2) of Experimental Example 1 did not show any toxic findings during the observation period up to 5 days after the first oral administration of 1000 μ/kg.

When the compound of the present invention is used as a pharmaceutical, it can be prepared by itself or mixed with pharmacologically acceptable carriers, excipients, diluents, etc. in the form of powders, granules, tablets, capsules, injections, etc. It can be administered orally or parenterally. The dosage varies depending on the target disease, symptoms, or compound used, but in the case of oral administration, it is usually about 1 to 500 f11r per day for adults.

〔Example〕

EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited thereto.

Example 1 cis-6,7-cyhydroxy-1-(3,4°5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid DL-Dopa 50. O
g and 3,4.5-trimethoxybenzaldehyde 5
7.2 g of acetic acid 150 d1 methanol 150-1 water 1
Add 50 ml of the mixture and heat under reflux for 12.5 hours. After cooling the reaction solution, the precipitate was collected by filtration to obtain 83.7 g of colorless needle crystals. Melting point: 222-223°C (decomposition) Example 2 Cis-2-benzyloxycarbonyl-6,7-cyhydroxy-1- (3,4,5-trimethoxyphenyl)
-1,2,3,4-tetrahydroisoquinoline-3-
6.5 g of carboxylic acid cis-6,7-cyhydroxy-1-(3,4°5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are suspended in 65af of water, While stirring at room temperature, 2.0 g of sodium carbonate is added thereto. Add 95 m7 of methanol, drop 2.5 parts of benzyl chlorocarbonate, and stir at room temperature for 30 minutes. The mixture was cooled with water, acidified with hydrochloric acid, extracted with chloroform, the organic layer was washed with water, dried, and the solvent was distilled off to obtain 8.9 g of a reddish-brown oil.

NMR (CDCJ3, TMS) δ near, 40-6.
40 (12H, m), 6.22-5.96 (LH
, m).

5.32-4.84 (2H, +*), 4.60-4
．． 16 (IH, +m).

4.04-3.40 (9H, m), 3.04-2.
40 (2L m).

Example 3 (Method A) Methyl cis-6,7-cyhydroxyl-
(3,4,5-trimethoxyphenyl)-1.2,3
．． 4-Tetrahydroisoquinoline-3-carboxylate hydrochloride Methanol 850I117 is cooled to -15 to -10°C, and thionyl chloride 70aZ is added dropwise over 1 hour while stirring.

After stirring for another hour at the same temperature, cis-6゜7-cyhydroxy-1-(3,4,5-trimethoxyphenyl)
Add 85 g of -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid and stir at -10°C to room temperature for 1 hour. After standing for 48 hours, stirring at 40°C for 1.5 hours,
At 0° C., 2.51 g of ether was added dropwise with stirring, and 82 g of precipitated crystals were collected by filtration. Melting point 192°C (decomposition) (Method B) DL-dopa methyl ester hydrochloride 24.
8 g and 22.6 g of 3,4.5-trimethoxybenzaldehyde were dissolved in 200 g of methanol and 7 g was dissolved at room temperature.
The reaction mixture was stirred for 2 hours and concentrated under reduced pressure to a volume of 23.5 g, and 23.5 g of precipitated crystals were collected by filtration. Melting point: 192°C (decomposition) Example 4 Methyl cis-2-benzyloxycarbonyl-6,7
-Sihydroxy-1- (3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (Method A) Cis-2-benzyloxycarbonyl = 6,7-cyhydroxy-1- (
3,4,5-trimethoxyphenyl)-1,2,3,4
-tetrahydroisoquinoline-3-carboxylic acid 25.7
Dissolve 200 g of acetone in 5.0 g of dimethyl sulfate.
Add 8.4 g of -1 potassium carbonate and heat under reflux for 3 hours.

After the reaction solution was allowed to cool, it was filtered, and the filtrate was concentrated under reduced pressure. The residual aroma obtained was subjected to silica gel column chromatography [solvent: chloroform-methanol (20:1)], and the solvent was distilled off from the eluate to obtain a colorless product. 20.9 g are obtained as oil.

(Method B) Methyl cis-6,7-cyhydroxyl-
(3,4,5-)rimethoxyphenyl)-1,2,3
, 29.8 g of 4-tetrahydroisoquinoline-3-carboxylate hydrochloride was suspended in 300 d of methylene chloride, and 1 N sodium carbonate L aqueous solution H 155 w and 11.0 af of benzyl chlorocarbonate were sequentially added dropwise under water cooling, followed by stirring at room temperature for 2 hours. do. The aqueous layer was separated and extracted with chloroform, combined with the organic layer, washed successively with 1N hydrochloric acid and water, dried, and the solvent was distilled off to obtain 36.7 g of a reddish-brown oil.

NMR (CD Cj! 3, TMS) δ near, 31 (5H, s), 7.04-6.52 (4
H, m).

6.32-6.04 (1B, m), 5.44-4
．． 94 (28, m).

4.62-4.22 (IH, m), 3.92-3.
33 (12H, s+).

3.04-2.53 (2H, Rin), Example 5 Methyl cis-2-benzyloxycarbonyl-1-(
3,4,5-1-rimethoxyphenyl) = 6.7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate dimethylformamide 20
〇-Methyl cis-2-benzyloxycarbonyl-6,7-cyhydroxy-1-(3,4,5-)rimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate15. Add 0 g of methylene dibromide 2.0-1 potassium carbonate, 6.0 g of cupric oxide, and 0.5 g of cupric oxide, heat and stir at ioo to 110°C for 4 hours. The reaction solution is allowed to cool, then filtered, and the filtrate is depressurized. The residual aroma obtained by concentration is subjected to silica gel column chromatography [
Solvent: chloroform-ethyl acetate (10:1)), and the solvent was distilled off from the eluate to give a colorless oil with a concentration of 12.0%.
get g.

NMR(CD C1s, TMS) δ Near, 33 (5H, s), 6.90-6.68 (2H
, m).

6.69 (28,s), 6.40-6.10 (L
H, m).

5.98 (2H,s), 5.46-4.84 (2
H, m)+4.64-4.25 (IH, s+), 3
．． 96-3.40 (12)1. m).

3.01-2.70 (2H, +w).

Example 6 Cis-1.3.4,5.10,10a-hexahydro-
5-(3,4,5-)rimethoxyphenyl)-7,8-
methylenedioxyoxazolo[3゜4-b]isoquinolin-3-onemethyl cis-2-benzyloxycarbonyl-1-(
Dissolve 3.4 g of 3,4,5-trimethoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate in 30-tetrahydrofuran, and add 2 moles of lithium borohydride. Add concentration tetrahydrofuran solution 10+a7, 50~5
Heat and stir at 5°C for 9 hours. Acetic acid 5-
After dropping , add chloroform 200@Z, wash with saturated potassium carbonate aqueous solution and saturated saline, dry, and distill off the solvent. Methanol is added to the residual aroma obtained, and crystals 1 are precipitated.
．． 8 g is collected by filtration. Melting point: 235°C Example 7 Methyl trans-2-benzyloxycarbonyl-1
-(3,4,5-trimethoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate methyl cis-2-benzyloxycarbonyl-1-(
9.0 g of 3,4,5-trimethoxyphenyl)-6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate was added to 1 part of anhydrous methanol.
00-, add 2g of sodium methoxide and make 6
After cooling the reaction solution heated under reflux for an hour, it was poured into a saturated ammonium chloride aqueous solution, extracted with chloroform, washed with water, dried, concentrated under reduced pressure, and the residual aroma was removed by silica gel column chromatography [solvent: n-hexane-ethyl acetate (6 : 4)
), from the eluate methyl cis-2-benzyloxycarbonyl-1-(3,4,5-trimethoxyphenyl)-6,7-methylenedioxy-1,2,3,4-
Tetrahydroisoquinoline-3-carboxylate 3.
1 g, and methyl trans-2-benzyloxycarbonyl-1-(3,4,5-)rimethoxyphenyl)
5.8 g of -6°7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate are obtained as a colorless oil.

NMR (CD C1s, TMS) δ near, 39-6.02 (IOH, m), 5.91 (2
H,s).

5.32-4.78 (3H, m), 3.84-2.
64 (14H, m).

Example 8 trans-1,3,4,5,10,10a-hexahythroa, 8-methylenedioxy-3-(3,4,5-)
rimethoxyphenyl)-oxazolo(3,4-b)isoquinolin-3-onemethyl trans-2-benzyloxycarbonyl-1-(3,4,5-)rimethoxyphenyl)-6,7-methylenedioxy-1 ,2,3,4-
Tetrahydroisoquinoline-3-carboxylate 8.
3 g was reduced in the same manner as in Example 6 with a 2 molar solution of lithium borohydride in tetrahydrofuran, and crystallized from methanol to obtain 3.0 g of colorless needle crystals. Melting point 185-186°C Example 9 Methyl cis-2-benzyloxycarbonyl-6,7
-Simethoxy1- (3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-
2.7 g of 3-carboxylate cis-2-benzyloxycarbonyl-6,7-cyhydroxy-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid acetone 3
0d dissolved in dimethyl sulfate 1.8-1 potassium carbonate 3
．． After cooling the reaction solution, add 3 g and heat under reflux for 17 hours.
The residue was poured into 1N hydrochloric acid, extracted with chloroform, washed with water, dried, and concentrated under reduced pressure. The residual aroma obtained was crystallized from isopropyl ether to obtain 2.5 g. Melting point 155-1
57°C Example 1O cis-1,3,4,5,10,10a-hexahythroa,8-dimethoxy-5-(3,4,5-trimethoxyphenyl)-oxazolo[3,4-b)isoquinoline -3-onemethyl cis-2-benzyloxycarbonyl-6,7
-Simethoxy1- (3,4,5-1-rimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (6.1 g) was added to 2 moles of lithium borohydride in the same manner as in Example 6. Reduction with 12aj of a concentration tetrahydrofuran solution and crystallization from methanol yielded 3.7g of colorless needle crystals. Melting point 180-181℃
Example 11 Trans-2-hensyloxycarbonyl-6゜7-simethoxy1-(3,4,5-1rimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-
Methyl carboxylate cis-2-benzyloxycarbonyl-6,7
-Simethoxy1-(3,4,5-)rimethoxyphenyl)-1,2,3,4-te)dihydroisoquinoline-3-carboxylate 2.8g in ethanol 2011
Dissolve in 1/2 and add 10@l of 2N potassium hydroxide,
Heat to reflux for 8.5 hours. The reaction solution was allowed to cool, then acidified with hydrochloric acid under ice cooling, and extracted with ethyl acetate. After washing with water and drying, the solvent was distilled off and the resulting residue was crystallized from ethyl acetate.
1.2.3.4-Tetrahydroisoquinoline-3-carboxylic acid was removed as crystals, and trans-2-benzyloxycarbonyl-6,7-simethoxy1-(
3,4,5-)rimethoxyphenyl)-1,2,3,4
-Tetrahydroisoquinoline-3-carboxylic acid 0.8g
is obtained as a pale brown oil.

NMR (CDCj!z, TMS) δ near, 42-5.
92 (IOH, m), 5.40-4.82 (31
1,01).

4.04-2.80 (20tl, m).

Example 12 Methyl trans-2-benzyloxycarbonyl-6
,7-Simethoxy1-(3,4,5-trimethoxyphenyl')-1,2,3,4-tetrahydroisoquinoline-3-carboxylatetrans-2-benzyloxycarbonyl-6゜7-Simethoxy1-( 3,
4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (6.8 g) was dissolved in acetone (70), dimethyl sulfate (1.5 ate,
Add 3.5 g of potassium carbonate and heat under reflux for 4.5 hours.

After cooling the reaction solution, it was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography [solvent: hexane-ethyl acetate (1:1)], and the solvent was distilled off from the eluate to obtain a colorless product. Obtain 5.5 g as oil.

N M R (CD C1s , TMS ) δ
:, 7.42-7.00 (511,m),
6.90-5.92 (5H,s+)t5.40-4
．． 82 (3)1. o+), 4.04-2.
80 (20H, +*).

Example 13 trans-1,3,4,5,10,10a-hexahythroa, 8-dimethoxy-5-(3,4°5-trimethoxyphenyl)-oxazolo[3°4-b]isoquinoline-3 -onemethyl trans-2-benzyloxycarbonyl-6
, 7-Simethoxy1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (5.5 g) was added to 2 moles of lithium borohydride in the same manner as in Example 6. The mixture was reduced with a tetrahydrofuran solution having a concentration of 12 mff1 and crystallized from methanol to obtain 2.7 g of colorless prism crystals. Melting point 159
~160°C Example 14 (53,10aS)-1,3,4,5,10°10a-
Hexahythroa, 8-methylenedioxy-5-(3,
4,5-trimethoxyphenyl)-oxazolo(3,4
-b) Isoquinolin-3-one (13,3S)-Methylcis-2-benzyloxycarbonyl-1-(5°) produced from L-dopa in the same manner as in Example 1.2.3.5. 4.5-1-rimethoxyphenyl)-6,7-methylenedioxy-1,2,
3.4 g of 3,4-tetrahydroisoquinoline-3-carboxylate was added to a 2 molar solution of lithium borohydride in tetrahydrofuran for 10 s in the same manner as in Example 6.
7 and crystallized from methanol to give colorless needle crystals 1.
．． Obtain 8g. Melting point 230-233℃, specific light intensity = -3
2,3' (c = 1.0. dimethylformamide) Example 15 (53,10aR) -1,3,4,5,10°10a
-Hexahydrol:1-5-(3,4,5-trimethoxyphenyl)-7,8-methylenedioxy-oxazolo(3,4-b)isoquinolin-3-one from L-dopa Example 1.2 (Is,3R)-methyl cis-2 produced by reacting in the same manner as in .3.5.7
-benzyloxycarbonyl-1-(3,4,5-trimethoxyphenyl)-6゜7-methylenedioxy-1,
4.5 g of 2,3,4-tetrahydroisoquinoline-3-carboxylate was added to 10 g of a 2 molar solution of lithium borohydride in tetrahydrofuran in the same manner as in Example 6.
The product was reduced in step a7 and crystallized from methanol to obtain 2.1 g of colorless needle crystals. Melting point 196-198℃, specific light intensity = +
131.1' (c=1.0. dimethylformamide) Example 16 Cis-2-benzyloxycarbonyl-6,7-cyhydroxy-3-hydroxymethyl-1-(5,4,5-)
rimethoxyphenyl)-1,2゜3.4-tetrahydroisoquinolinecis-6,7-hydroxy-2-benzyloxycarbonyl-1-(3,4,5-)rimethoxyphenyl)-
Dissolve 3.1 g of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid in 30-tetrahydrofuran,
Add 0.45 g of sodium borohydride at -15°C and stir at the same temperature. After 30 minutes, boron trifluoride ether complex salt2. Add 〇- dropwise and stir at -15° to 0° for 2 hours.

After leaving it at room temperature for 48 hours, add 1N hydrochloric acid (1 part) under water cooling.
m7 was added dropwise and stirred for 2 hours. 6. The reaction solution was extracted with chloroform, washed with water, dried, and the solvent was distilled off under reduced pressure. The residual aroma obtained was subjected to silica gel column chromatography [solvent: chloroform-methanol (20:1)] The eluate was distilled off under reduced pressure to obtain 2.5 g of white amorphous powder.

N M R (CD CI 3, T M S ) δ near,
31 (5H, s), 6.67 (18, s).

6.32 (18, s), 6.20 (III, b
rs).

5.40-5.00 (2H, m), 4.44-4.
16 (IH,s+)+3.81 (38,s), 3
．． 80-3.40 (2)1. m).

3.63 (6H,s), 2.98-2.24 (2
H, m).

Example 17 Cis-1.3,4.5,10,10a-hexahythroa,8-dihydroxy-3-(3,4,5-trimethoxyphenyl)-oxazolo[3,4-b)isoquinoline-3- on

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 and R^2 represent a hydroxyl group, an alkoxy group, or R^1 and R^2 are bonded to form an alkylene dioxy group, and X, Y, and Z are the same or different and represent a hydroxyl group or an alkoxy group.