JPS6256492A - Tetrahydroisoquinoline derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is H or methyl; X<1>, X<2>, Y<1> and Y<2> are as follows; X<1> is -OH, formula II or OR<2> (R<2> is lower alkyl) when X<2>, Y<1> and Y<2> are H, and X<1> and X<2> together link to form oxo group = O when Y<1> and Y<2> are H, and Y<1> and Y<2> together link to form oxo group = O when X<1> and X<2> are H]. EXAMPLE:4-Hydroxy-8-methoxy-2-methyl-6,7-methylenedioxy-1,2,3,4-tetrah ydroi soquinoline. USE:An intermediate for producing cotarnine which is a main raw material for antiallergic agents. PREPARATION:For example, N-methylbenzylaminoacetal compound expressed by formula III (R<3> and R<4> are lower alkyl) is cyclized in the presence of an acid, preferably protonic acid, to afford the aimed compound expressed by formula I (X<2>, Y<1> and Y<2> are H; X<1> is -OH or -OR<2>).

Description

[Detailed description of the invention] [Industrial application field]! The present invention relates to a novel tetrahydroisoquinoline derivative useful as a synthetic intermediate to Kotaruni, which is the main raw material of Tardada No. 3211t and Tardada No. 3r.

[Conventional technology]

Traditionally, cotalunine has been produced by oxidation of the natural alkaloid noskabine [Pharmaceutical Journal, Mu,! ! the law of nature(
/ri 30 years)].

However, noscapine is a natural product and has the disadvantage of being limited in quantity and difficult to provide stably.

[Means for solving problems]

Therefore, as a result of intensive studies in view of the above-mentioned circumstances, the present inventors found that cotalnin can be produced industrially advantageously by using the tetrahydroin quinol/derivative of the present invention as an intermediate for producing cotarnin. Reached.

That is, the gist of the present invention is the general formula (■): [In the formula, R1 represents a hydrogen atom or a methyl group, and yl
, zZ, yl and Yl are: ■ When x2, yl and Yl are hydrogen atoms, XI is -
OH, -0CCH, meaning represents OF, 2 (R'' represents a lower alkyl group), (2) When Yl and Yl are hydrogen atoms.

xl and x2 together represent an oxo group=O; ■ When XI and x2 are hydrogen atoms, yl and Yl
together represent oxo group=0. ] It exists in the tetrahydroisoquinoline derivative shown by these.

The present invention will be explained in detail below.

In the above general formula (1), R2 is preferably a lower alkyl group of 01 to C6, preferably (:!, %(!).

Specific examples of the tetrahydroisoquinoline derivatives of the present invention are shown below.

o4t-hydroxy-? -methoxy-7-,2-methyl-B,7-methylenedioxy-/,3,9-tetrahydroisoquinolinebit,r-dimethoxy-methyl-5,7-methylenethioxy-7.2,3. 'A-tetrahydroisoquinoline 6%-ethoxy-? -methoxy2-methyl-6,7-
Methylenedioxy-/, 2. J review - Tetrahydroisoquinoline o % -7' Roboxy? -methoxy-no-methyl-
6 fumethylenedioxy/, 2. ! , 4t-tetrahydroisoquinoline o4t-acetoxy-? -Methoxycomethyl-3,
7-methylenedioxy-'+J3+''-7) Lahydroisoquinoline O￥, ?-dihydroxy-comethyl-i, 7-methylenedioxy-/, 2,3.'pt-tetrahytroinquinoline og-methoxy- l-hydroxy-2-methyl-6,7
-methylenedioxy-/, 3. %-tetrahytroinquinoline o%-ethoxy- and -hydroxy-comethyl-O, 7
-methylenedioxy/, 2. ! , 4t-tetrahydroisoquinoline o%-propoxy-! -Hydroxy-2-methyl-B,
2-methylenedioxy-7,,l,3.41-tetrahydroisoquinoline o'A-7 setoxy and -hydroxy-comethyl-6
,7-methylenedioxy-7,col'19t-tetrahydroisoquinoline02.3-dihydro-and-methoxy-11methyl-6,
7-Methylene oxidase (/H)-isoquinolone 02.3-dihydro-? -Hydroxy-comethyl-2-methylenedioxy-4t(/H)-isoquinolone 6/, %-dihydro♂-methoxy=-methyl-g
,? -Methylenedioxy? (JH)-isoquinolone 0/,4t-dihydro-! -Hydroxy-2-methyl-4,7-methylenedioxy-3(,za)-isoquinolone The compound of the present invention can be obtained as a salt such as a hydrochloride or a sulfate depending on its production method.

The method for producing the compound of the present invention will be explained below.

In the above general formula (I), zZ, Yl and Y are hydrogen atoms, and Xl is -OH or 10R2 (wherein, R1 represents a hydrogen atom or a methyl group, and R3 and R4 represent a lower alkyl group) It can be obtained by cyclizing the N-methylbenzylaminoacetal compound represented by the following formula in the presence of an acid. The acid is preferably a protic acid, and specific examples thereof include mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid.

The amount of acid to be used is preferably in excess of compound (II), preferably λ~! It is θ times the mole.

Yes.

After the reaction is complete, excess acid is neutralized with an alkali, extracted with an organic solvent such as methylene chloride, the solvent is distilled off, and recrystallized to obtain the desired compound.

Compound (It) is a benzaldehyde compound represented by the following general formula (m): IO (wherein, R1 represents a hydrogen atom or a methyl group), and the following general formula (■): λ (wherein, X represents a hydrogen atom or a methyl group, and R5 and R6 represent a lower alkyl group.) After reacting with the aminoacetal compound represented by
It can be synthesized by reduction by catalytic reduction using a stoichiometric reducing agent such as AtH4 or hydrogen.

The amount of the aminoacetal compound (If/) to be used is preferably equivalent to or in excess of the benzaldehyde compound (III), and preferably 0 to 10 times the molar amount. When a stoichiometric reducing agent is used, the amount used is preferably equivalent to or in excess of the compound (In).

In the case of the catalytic reduction method, any catalyst may be used as long as it is used as a hydrogenation catalyst. Specifically, PtO
2, Pt70%Pt/alumina, Pa black, pa/
Examples include a, P(1/alumina, etc.).

The amount of catalyst used is 0.00θ with respect to compound (III)
/~10 molti is preferable. Hydrogen is used at normal or elevated pressure. Any solvent can be used as long as it is inert to the reaction.

In the above general formula [1], x2, yl and Y2O are hydrogen atoms, and Xl is -0CCH3, i.e., the following general formula (V): IO (wherein, R1 represents a hydrogen atom or a methyl group). The acetoxy compound represented by is a compound in which XI is 10H, the synthesis method of which was described in the previous section, that is, the following general formula (■): 0'H (wherein R1 represents a hydrogen atom and a methyl group). ) can be synthesized by reacting an acetylating agent with a hydroxy compound.

As the acetylating agent, acetic anhydride and acetyl chloride are preferred, and the amount used is preferably in excess of compound (M). Any solvent can be used as long as it is inert to the reaction. The reaction temperature is preferably -2θ°C to f0°C.

After the reaction is completed, the aqueous layer is made basic with alkaline water, extracted with an organic solvent such as methylene chloride, and then the solvent is distilled off to obtain the desired product.

In the above general formula (1), Yl and Y2 are hydrogen atoms, and Xl and x2 together represent an oxo group, or Xi and x2 are hydrogen atoms, and Y
A compound in which l and Y2 together represent oxo group = 0, that is, an inquinolone compound, has the following general formula (■): (wherein, R1 is as defined in general formula (I),
One of R5 and R6 represents a hydrogen atom and the other represents a water group. ) is subjected to an intermolecular hydrogen transfer reaction using a metal alkoxide as a catalyst in the presence of a hydrogen acceptor.
rg, React, , A.

207, /9/;0 year).

In the above reaction, the hydrogen acceptor is preferably a ketone such as fluorenone or cyclohexanone.

The amount to be used is preferably an excess of 7 to the hydroquine isoquinoline compound (■). A metal alkoxide is used as the catalyst, and lower alkoxides of metals such as Na, K, At, etc. (eg, methoxide, ethoxide, globoxide, butoxide, etc.) are preferred.

The amount of catalyst used is hydroxyisoquinoline compound (■)
It is preferably 0.6 to 20 times the amount by mole.

The reaction temperature is preferably room temperature to /jθ°C, and any solvent inert to the reaction can be used.

The compound of the present invention thus obtained is a useful intermediate in the production of cotalnin.

The production route for obtaining cotalunine from the tetrahydroisoquinoline derivative of the present invention is illustrated below.C! HsOoI (cotalnin (formula, where Xi, 12 Sy! and Y2 are of the general formula (
I) -1c' As defined, A- represents an anion. ), and a reduction reaction is used to lead them to compound (A). The reduction reaction takes place under acidic conditions.
It is carried out using hydrogen in the presence of a reducing catalyst.

The reduction catalyst may be any catalyst used as a hydrogenation catalyst, preferably pt black, PtO2, pt
/c, Pt/alumina, Pd black, Pa/C%Pd
/Alumina. The catalyst content is 0,000/-10 mol. As the solvent, acidic proton solvents are preferred, and examples thereof include mineral acids such as sulfuric acid and hydrochloric acid, and organic acids such as acetic acid and sulfonic acid. Hydrogen is used at normal or elevated pressure.

The reaction temperature is room temperature ~/? θ°C is preferred.

After the reaction is completed, the catalyst is separated, excess acid is neutralized with an alkali, and the desired product is obtained by extraction and distillation of the solvent.

A compound in which R1 is hydrogen in general formula (1) can be easily converted into a compound in general formula (I) in which R1 is a methyl group by the action of a methylating agent.

The methylating agent is preferably diazomethane.

Diazomethane is preferably used in an excess amount relative to the starting material (1). The reaction temperature is preferably -/θ°C to /θθ°C. Any solvent may be used as long as it is inert to the reaction, such as ethyl ether.

In the above production route, compound (A) can be induced into compound (B) using a chlorine-based oxidizing agent, and cotalunine can be obtained by hydrolyzing compound (B) in an alkaline aqueous solution. Examples of halogen-based oxidizing agents include Ku2, Br2, ct2,
Na0O4, Na0Br, NaO etc. can be used.

The solvent is preferably an alcohol-based solvent such as methanol or ethanol.

In this reaction, there is a method in which compound (B) is once taken out and then converted to cotalunine, but it can be induced to cotalunine in 5 situ.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to the following nine embodiments as long as they do not exceed the gist thereof.

Reference example 1 0CR30 (H.

Platinum oxide/. Add 0t to 700ml of ethanol and pass hydrogen through it for 30 minutes while stirring. To this - monomethoxy - 3
,9 is one methylenedioxybenzaldehyde (1)! 04 F (0.3 mol) and aminoacetaldehyde diethyl acetal (purity), 7. rr(0
, 3 mol) of ethanol/θ0tttl solution,
At room temperature while stirring? 1. Hydrogenate for j hours. After removing the catalyst, the solvent was distilled off under reduced pressure to obtain N-(2-methoxy-3,termethylenedioxybenzyl)aminoacetaldehyde diethyl acetal (2). Wa, Da 32 (yield 100%) was obtained as an oil.

工R(neat, Wzaz Cm'″1):/I30
/Hirowaj /Dagoj /2J-! 'H-NMR(6
0MHz in ODC! 4, δppm) :/
,/? (,<H,t, ,T=7Hz, -Q
C! Ff2C! H3X? )/,, rz (/H,
8,-NH)2,t? (2H, d, , T=4H
z, N(:!)I2CH(OEt), )3.3-
3β(%H, m, -OC mutually 2CH3x,
z)3.7o (,2H,R,ArCH2N)
3.9ta (J'H,8,QC!H3)tt,sz
(/H, t, J=tmz, NcH2am(o
:ct) Ri! ,♂7 (,2H,θ,
0 steps) ■ Reference example Platinum oxide θθm1 was mixed with ethanol/jd and acetic acid cod
and hydrogen is passed through it for j'θ minutes with stirring.

To this, N-(,2-methoxy-3,Hiro-methylenedioxybenzyl)aminoacetaldehyde diethyl acetal (1) t4 s t (7!θ mmol) and 3j% formalin/! the law of nature? (,22 mmol) and hydrogenation was carried out at room temperature for 7 hours and 9 tj minutes while stirring. The catalyst was removed, the solution was concentrated under reduced pressure, and methylene chloride 30-1 water/jtnl was added to the remaining oil. Add aqueous sodium hydroxide solution gradually to make the aqueous layer basic. Separate the layers, wash the methylene chloride layer with 1 srnl of water, and dry over anhydrous magnesium sulfate. When this is filtered and concentrated under reduced pressure, N
-(2-methoxy-3,termethylenedioxybenzyl)-N-methylaminoaldehyde diethyl acetal (
2) was obtained as an oil at a yield of 9%.

Engineering R (neat, yrnaXCln-'):/
Hiro70/ko1.0/θ70'H-NMR (
t OMHz 1n cDct, , δppm):
/, I9 (+H, t,, T=7Hz, QC!H20
H3X2)21.21. (3H,s,
NCH3) r, jz (,2E, a, J
=jHz, NcH2aI((ogt)2)3.3-
3.9 ('y'H, m, 0Cfi2C
H3X2)3, s2 (xH, s, A
, rCH2N )3.9t (3H,s,
QC■S)%, +j (/H, t, J
=jlz, -NCH, (4(OEt), ) Reference Example 3 0CH30CH30CH.

(1) <2) (3) Add platinum oxide θ0.2f to 20.1 g of methanol and activate by passing hydrogen. (1) 10, F/?
(1; 0 mmol) and 99% pure aminoacetaldehyde dimethyl acetal 6.37? (≦θ mmol) in 20 ml of methanol was added, and hydrogenation was carried out for 3.5 hours. Then 35% formalin j,, 2%! ! / (
Hydrogenation was carried out for 9 hours. The catalyst was removed and the ν liquid was concentrated under reduced pressure to give N-(,2-methoxy-3,termethylenedioxybenzyl)-N-methyl-
Aminoacetaldehyde dimethyl 7'cetal (3)/
Then, trst was obtained as an oil. Yield 9cheR (neat, l 12a1 Cm'''1):/
Hiro7j, 7.2dj', /θ7θ, /θj0'H-NM
R(&OMHz in 0DC4!l, δppm):
J,,21=(jH,s,N(jH
3), 2. j j (12H, 6, J=j Hz,
NC! H2CH(OCI(1)2)3,! ! (
6H, 8, C! H2CH(QC!H3)1)3.4t
y (,2H,s, Arca,N)3.9
1; (3H, s, ArOCH3)tt
,si (/H,t, J=JH2,NCH2C!H
(OCHs) 2) Examples/QC! H30CH.

N-(Nomethoxy-3-methylenedioxybenzyl)-N-methylaminoacetaldehyde diethyl acetal (1) J, 2. ．． 2 y (o, x mol) was dissolved in 6N sulfuric acid θθ1, and 74~2? Heat and stir at ℃ for 7.5 hours. This is cooled, and at 30° C. or lower, a 2j% aqueous sodium hydroxide solution is added to adjust the pH to approximately //. Extract sequentially with 0 tttl of methylene chloride and 100 td of water, wash together with water/00 td, and dry over anhydrous magnesium sulfate. After the salt has been removed from the furnace, the solution is concentrated under reduced pressure, 20 ml of ethanol is added to the residue and dissolved by heating, and upon cooling to 5°C, crystals are precipitated. This was washed with cold ethanol 30-g, and dried under reduced pressure to yield 36", 099 (yield?
0.3%) Deroxy? -Methoxycomethyl-, 7-methylenedioxy-/, 2,3. '! −
Tetrahydroisoquinoline (2) was obtained. mp,
/ j 2- J℃ENGR (KBr, Mmaz (m
-' ):/dat! rO/4tlsO/2(s!
/θri! /θHiroj'H-NMR (4θMHz, i
n CDC43, δppm): 2,! r (JH,s
, NCshi) 3.97 (3H, 8,00
3) Example N-(j-methoxy-3,termethylenedioxybenzyl)-N-methylaminoacetaldehyde dimethyl acetal (1) J-,t7t (20 mmol) to 4
Dissolved in N sulfuric acid ortti at 76-7°C /,! Heat and stir for an hour. This is cooled and 2j% hydroxide is added at 30° C. or below.) An aqueous solution of IJ is added to adjust the pH to approximately //.

Methylene chloride 3ml.

Extract sequentially with 10rnl and combine with water - 20rr
Wash with Tl and dry with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, ethanol/2.1 was added to the residue and dissolved by heating, and when the mixture was cooled to j°C, crystals were precipitated. When this is washed with three drops of cold ethanol and dried under reduced pressure, the result is 3.7/
f's Nuhydroxy♂-Methoxycomethyl-,
7-methylenedioxy-/, 2. j, 41-tetrahydroisoquinoline (2) was obtained. Yield 7t% mp,
/j Coco-°C Then, the recrystallization mother liquor was concentrated under reduced pressure, and separated and purified by silica gel column chromatography (eluent: 3% methanol/chloroform), resulting in a 0.1% backing. -dimethoxycomethyl-6,7-methylenedioxy-7,. 2, 3. Tertetrahydroisoquinoline (
3) was obtained as an oil.

Yield D, 6% Process R of compound (3) (neat, vy, z CM-'
) :/Da? θ /27θ /θza! 10
! 0 10 da O compound (3) NMR (tθMHz
, in CDC1B, δppm): λ, NuJ'
(JL8. Ncdan3)ocH.

Example 3 00H300H3QC! Hs (1) (2) (a)
N-(2-Methoxy-!, sit-ethylenedioxybenzyl)-N-methylaminoacetaldehyde diethyl acetal (1) 7 r Otr! ? (2,j mmol)
was dissolved in ethanol 7.6-, and 6N sulfuric acid jtx was added to this.
t and heated under reflux for 1 hour and 95 minutes. After cooling! j
% sodium hydroxide aqueous solution to make it basic, methylene chloride! 4. Extract sequentially with 211 tl. The combined extracts are washed with water (2d) and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was separated by silica gel column chromatography. -methoxycomethyl-6,7-methylenedioxy-/2. ! , 'I-tetrahydroisoquinoline (2
) 30711IP (yield 6/th) and derethoxy-r-methoxycomethyl-g, 7-methylenedioxy-/, 2. ! , 4t-tetrahydroinyanolin (
3) //QTPy (yield/7%): Obtained.

Compound (2) mp, / j J-4L °C (recrystallized from ethanol) Engineering R (KBr, W maz C7n) */
9#0. /HirotO, /2 ni j, 109! , /θdajNM
R (60MHz, in C!DC/4, δppm
): Ko, y (Ja, s, No Danri OH 3,97 (3H, a, QC!!!3)
n example cas compound (3) mp, 5.2-. 7℃ (recrystallized from n-hexane)
Engineering R (FCBr, “me, X cm-”):/
', trθ /da60 /3.20 7.2tj
10 de 9/θ da! 'H-NMR (tθMHz, in CDC1, δ
ppm):/, 2/ (3H, t, J=7Hz,
0CR1CH3) Ko, Hiroshi/ (3H,s,
, Nodan 3) 3, Otsuko (JH, q,
QCdanzcHs )3,qs (3H,S,
oaks) Example DAOOH,O(:JH3 derhydroxyza-methoxy-methyl-g, 7-
methylenedioxy/, 2. ! , 9t-tetrahydroisoquinoline (1 < t, 7a? (, 20 mmol), after stirring for 30!R1! of water, 2j% hydroxylation) I
Add Jum aqueous solution to make the aqueous layer basic.

After separation, the aqueous layer is extracted with methylene chloride θM, and the methylene chloride layers are combined and washed with water 3θd. After drying with anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure! , J-J f no Hiroshi-
Acetoxy! -Methoxycomethyl-6,7-methylenedioxy-/, =.

3.4t-tetrahydroisoquinoline (2) was obtained as crystals. Yield is perfect. This was recrystallized from ethanol-n-hexane. mp, 10 Ta1//θ℃ I R (KBr, v maz C!A'″1):/
730 /4tfθ /ko! 0 1030'
H-NMR (40MHz in CDC1g, δpp
m): Ko, θ? (JH, 8, COC Dan 3) x,
t<j(-ta, 8. No!!3)3,
qt (3H, s, oak3)00
Hs Example! N-(,2-hydroxy-3,termethylenedioxybenzyl)-N-methylaminoacetaldehyde dimethyl acetal (1) /,2 f (Me, 22mmot)
6N hydrochloric acid! ! When 24 is dissolved in td and left at room temperature for an hour, white needle-like crystals of p,r-dihydroxy-comethyl-4,7-methylenedioxy-/, 2,3.9t are obtained.
-Tetrahydroisoquinoline φ hydrochloride (2) was precipitated. mp, /ds-g℃ENGR(KBrd, lsk, v
maz C7n) -34t, 20/6 da θ
/da9θ/, 2. fO10 and 031.2-s,
0 (!H, m, -CH21gCdan2c
ao-) + 1- j, 7r (xH, θ, -QCC sea)
Example g - Derhydroxy? -methoxy-2-methyl-g,
7-methylenedioxy-/, 2,3. u-tetrahydroisoquinoline (1)! '93■(2,jmmoz
) and fluorenone, x,, 2s li' (/ 2.j
A dry benzene solution (;, Ogl) of 73 mmol of potassium t-butoxide (4 mm
ot) and heated under reflux for 70 minutes. After stopping the reaction by adding ice water/water, extraction is carried out with ethyl ether, and then the organic layer is extracted with an aqueous hydrochloric acid solution. After making the aqueous layer basic, the residue obtained by ether extraction, drying, filtration, and concentration was purified by silica gel column chromatography (developing solution: methanol/chloroform). Cikomethyl-6,7-methylenedioxy-4t(/F)-isoquinolone (2) is 417,7
(yield: 2%) was obtained. mp, // Goichi 9℃ Engineering R (
KBr disk, ymaz C7Ff-1):/
Otsu7s /6/θ /Hiroshi00 /300
101. t.

'H-4JMR(/θθMH2in 0DOt3, δ
ppm): Ko, Hiro♂ (3H, e, ':N
O small) a, 00 (J'H, s, -0C
I(3)! ,ri6 (-2H,8,-00H20-
)OMθ Reference example HiroH 00H30CH.

Darxy! -Methoxycomethyl-B, 2-
Methylenedioxy-/, 2,3. Tertetrahydroisoquinoline (1) /, / 9 t (r mmol) in acetic acid /! ! l! 97% sulfuric acid, 33r
mmol to tttc), 5% palladium on carbon 200
- was added and catalytic reduction was carried out at 25°C for 2 hours. Remove the catalyst from the furnace, 2! 71ml of sodium hydroxide solution and water! Add soy sauce and concentrate under reduced pressure. Add 10 td of water to the residue, make basic with s% sodium hydroxide solution under water cooling, and add 70 td of methylene chloride. - Extract sequentially. Add the extract to water.
After washing with water and drying with anhydrous magnesium sulfate, it was concentrated under reduced pressure to give % i, oz t? -methoxyco-methyl-6
,7-methylenedioxy-/,2,3,4t-tetrahytroinquinoline was obtained. Yield 93% Reference example j OCH300'H3 Hiro-acetoxy? -methoxycomethyl-6,7-
Methylenedioxy-/, 2,3. Ditetrahydroisoquinoline (1) θ, 279 (/mmol) was added to ethanol l1t-, and this! Chipalladium-carbon/θom
g and hydrogenated at room temperature. After the reaction is completed, the catalyst is removed, the solvent is distilled off under reduced pressure, water is added to the residue, and the mixture is made basic with an aqueous IJ solution. This was extracted with 5 g of methylene chloride/X-2, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. -Methoxycomethyl-6,7-methylenedioxy-/,,
2. J,4t-tetrahydroisoquinoline (2) was obtained as crystals. yield? 6% Reference example g 00H300H3 Derethoxy? -methoxyj-mef-7-methylenedioxy/, 2,3. %-tetrahydroisoquinoline (1) θ,, 27 t (/, 0.2 mmol) was dissolved in acetic acid/j″ml and 5% palladium-carbon 200
Add 7 ml of 19 and 97% sulfuric acid theta and hydrogenate at 75° C./hour for 0 minutes. After cooling, the catalyst is removed from the furnace and hydroxylated) A small amount of IJium aqueous solution is added and concentrated under reduced pressure. 10 ml of water on the residue! and make basic with an aqueous solution of sodium hydroxide. This was extracted with 2 methylene chloride, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. of? -methoxy 2-methyl-g,
7-methylenedioxy-/,2,3.4t-tetrahydroisoquinoline (2) was obtained as crystals. yield! Tati reference example 7? -Hydroxy-comethyl-6,7-methylenedioxy-/, 2,3. ! -Tetrahydroisoquinoline hydrochloride (1) 70. θη is 2t% ammonia water/, J-II
When added to tl, it dissolves once, but immediately crystals precipitate. The crystals were filter washed (JJ'% aqueous ammonia), dried, and ethyl ether containing excess diazomethane was washed with 1m
When stirred with l at room temperature, the reaction proceeds and the crystals dissolve. When the ether is distilled off after j hours, j/■ (yield t0
．． 0%)? -methoxy2-methyl-6,7-methylenedioxy-/2. j,91-tetrahydroisoquinoline (2) was obtained.

Reference example?・OCH30(J3 CJ, 0 0H(1>
(2) (3)? -Methoxy-111-methyl-6,7-methylenedioxy-/2.
J, It-tetrahytroinquinoline (1) 2 J
/ 1Ni (/mmol) and potassium acetate 10r■
(/,/mmol) is dissolved in ethanol 2td3, and while heating this to about 7j℃, iodine Jjllt■ (7
A solution of 2,4 mmol of ethanol is added dropwise over a period of /j minutes. After heating at 75°C for 700 minutes, ethanol was distilled off under reduced pressure, a water bottle was added to the residue, and 4 tzl of a 2j% aqueous sodium hydroxide solution θ was added under water cooling. 3 at room temperature
The extruded crystals were stirred and extruded for 0 minutes, washed twice with water θ, and dried to obtain 1.2/7 gi of cotalunine. Yield 9
/% [Effects of the Invention] The compound of the present invention is useful as an intermediate for the synthesis of cotarnin, which is the main raw material for the production of tritoqualin, which is useful as a pharmaceutical.

Sender: Mitsubishi Chemical Industries, Ltd. Representative Patent Attorney Hase-yo - 7 others

Claims (1)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 represents a hydrogen atom or a methyl group, and
^1, X^2, Y^1 and Y^2 are, [1] When X^2, Y^1 and Y^2 are hydrogen atoms,
X^1 represents -OH, ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or OR^2 (R^2 represents a lower alkyl group), and [2] Y^1 and Y^2 are hydrogen atoms. When X^1 and X^2 together represent oxo group = 0, [3] When X^1 and X^2 are hydrogen atoms, Y^1 and Y^2 together represent oxo group = 0. Represents base=0. ] Tetrahydroisoquinoline derivative represented by