JPS6183180A - Isochroman derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is H, lower alkyl, aryl; R<2>, R<3> are H, alkyl, aryl, aralkyl). EXAMPLE:1-[2-(N-benzylamino)propyl]isochroman. USE:Since it has powerful inhibition of gastric juice excretion, the compound is very effective in treatment or prevention for hyperacid, gastric ulcer and duodenal ulcer. PREPARATION:The reaction of 1-ethoxyisochroman with a carbonyl compound is effected, the product of formula II is allowed to react with an amine of R<3>NH2, then the resultant Schiff base of formula III is reduced to give of formula I when R<2> is H. Or the compound of formula II is reduced, then halogenated and the product of formula IV (X is halogen) is allowed to react with an amine of formula V to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (wherein R' is a hydrogen atom, a lower alkyl group or an aryl group, and Rz and R are the same or different,
6 Relating to isochroman derivatives represented by hydrogen atoms, alkyl groups, aryl groups, or aralkyl groups and their production methods In the above general formula (I), the lower alkyl group represented by R1 is, for example, a methyl group, Examples of the aryl group include ethyl JJ, n-propyl group, etc.; examples of the aryl group include phenyl group, naphthyl group, etc.; ethyl, methoxy, nidoxy, n
- Placement of propoquine, nitro, etc.? ! It may have one or two 13.

In addition, the alkyl group represented by R1 and R3 is
For example, linear alkyl groups from methyl to n-heptyl, inpropyl, isobutyl, 5ec-butyl, ta
Examples include branched alkyl groups such as rt-butyl; examples of the aryl group include phenyl groups and naphthyl groups having the same meanings as the above-mentioned examples; examples of the aralkyl groups include benzyl convex and phenethyl groups.

The isochroman derivative of the present invention represented by the general formula (1) is a new compound and can be used as a therapeutic or preventive agent for peptic ulcers. In other words, it strongly suppresses gastric acid secretion in animals such as rats and mice, and aspirin,
It suppresses the occurrence of experimental ulcers such as stress and soei, and its action is continuous, and there are no particular problems with toxicity and tolerance. Extremely effective for treatment or prevention.

Furthermore, it is important as an intermediate for making compounds with the same effect.

Compound [1] of the present invention can be produced by various methods, but the industrially advantageous production method completed by the present inventors as a result of intensive research is as described by Tsukashita.

First, a compound in which R1 is a hydrogen atom in the general formula (1) is produced by the method shown in the following reaction formula [11] [lV
] (In the formula, R1 and R are the same as above) That is, l-
Ethoquinoisochroman and the corresponding carbonyl compound were prepared by the method of Yamato et al.
ato, Chem, Pharm, Bull, 30.
1594 (1982)] and the amines (III 3) to obtain the nonov salt i (Iν), and by converting it into 15 elements, the target compound (la'l is obtained.

The reaction between compound [I+] and amine ji [111] is carried out using an excess of the amine in the absence of a solvent or in an inert solvent such as diethyl ether, chloroform, or hexane at room temperature or under heating. The return of IV) is
This can be carried out in an ether solvent using a reducing agent such as sodium borohydride, lithium aluminum hydride or sodium cyanoborohydride at room temperature or under heating. When used, the reduction reaction can be carried out subsequently without isolating compound (IV).

Moreover, the compound [1] of the present invention can be advantageously produced by the following formula.

(In the formula, X represents a halogen atom, R1, R1 and R
3 is the same as the above general formula [1]), that is, the target compound (
13 can be obtained by reducing the compound (I+) and then reacting the compound (V) obtained by halogenation with the amines 1:VI].

This reaction is carried out without a solvent or in an inert solvent such as ethers, chloroform, acetonitrile, or dimethylformamide, usually in the presence of a dehydrohalogenating agent such as potassium carbonate, and by heating or refluxing. .

Furthermore, in the general formula (+), when R' is a hydrogen atom, it may be produced by the following method.

Mll [yI rule (wherein,
(X, R'' and R3 are the same as above) That is, a compound (Mll) obtained by reacting 1-ethoxyisochroman and diethyl malonate according to the method of Yamato et al., followed by hydrolysis, decarboxylation, and halogenation. , amine r(I
Cv■] to obtain a compound (Vlll), which is reduced to obtain the target compound (Ib).

The reaction between compound (Vl'l) and amide 7 (Vll) is
Usually in an inert solvent as described above, in the presence of a dehydrohalogenating agent such as triethylamine or pyridine,
Perform at room temperature or under heating. Further, the reduction of the compound (V[I+] can be carried out in the same manner as the above-mentioned method.

The target compound (11) obtained as above.

For example, the 'ii i! +1 unit can be manufactured.

In addition, the compound of the present invention (11 can be prepared according to a known method, for example, an inorganic acid salt such as a hydrochloride, a hydrobromide, a sulfate, etc.)
Alternatively, it can be an a-acid salt or a quaternary ammonium salt such as an acetate, a maleate, a tartrate, a lyluenesulfonate, or a methanesulfonate.

The present invention will be described below with reference to Examples.

Example 1 (1) 6+nl of 47% boron trifluoride diethyl nitrate was added to a mixture of 30 g of 1-ethoquinoisochromane and 30 g of anhydrous acetone, and the mixture was heated at 40°C in a nitrogen stream.
Stir for 3 hours. The reaction product was extracted with ether, the ether layer was washed with 10% potassium bicarbonate and water, dried, and (isochroman-1-yl)acetone at bp 11B-120°C (0.05BmHg) was extracted into a viscous oil. 22.9 g (61%) of solids were obtained.

IRν=賎'cff-': 1715 (C・0)N
M R (CC1,) δ: 2.16 (3H,s, C0C
IIz), 2.97 (2H, d.

JJIIz, CIIzCOCTo), 33-5O-4
-32 (4N1+3・Ilz and 4-Hz) 5
．． 18 (lH, t, J-6Hz, 1-H), 7.13
(4H,s,Ar-H) (2) After stirring 4 g of (isochroman-1-yl)acetone and 3.4 g of hensidylamine in ether at room temperature for 4 hours, 1 g of sodium borohydride and 60 ml of anhydrous methanol were added. and further stirred at room temperature for 3 hours. Most of the solvent is distilled off, and the residue is extracted with ethyl acetate. The ethyl acetate layer was extracted with 5% hydrochloric acid, and the hydrochloric acid layer was extracted with 5% potassium hydroxide. After making alkaline with liquid 8, extract with ethyl acetate.

After washing the ethyl acetate layer with water and drying, t8ge I was distilled off.

The residue was subjected to alumina column chromatography and eluted with a mixture of ethyl acetate and petroleum ether to give ■-(2-(
N-benzylamino)propylcoisochroman 2.8
g(47χ)1).

IR Shu 7 1C Lock-’: 3340 (N11).

NMR(CG++)δ: 1.08, 1.13(b
oth 3N, d, each J=6Hz, > CIIC
Hs), 1.15-2.18 (311, m, Cl1
tCH<), 2.56-3.30 (311, m, >CH
Ct13 and 4-Ht), 3.40-4.28
(2H.

m, 3-)1t), 3.73(211,s, N11C
lh), 4.59 5.09 (IH, Tsuyoshi.

14), 7.05 (4H,s, Ar-11), 7.2
5 (5H5s, C&+Is).

M S vx/z: 28BM-).

This product was converted into hydrochloride according to a conventional method, and mp 175-
i) Crystals at 177°C (dec,).

Examples 2 to 7 All of the compounds shown in Table 1 were obtained as oils in the same manner as in Example 1.

Example 8 (1) 479A boron trifluoride/diethylnitere) in a mixture of 30 g of l-ethquine isochromane and 25 g of acetophenone? +al was added and heated at 40°C in a nitrogen stream for 2 hours.
The reaction mixture was stirred for an hour and the reaction mixture was extracted with ether. The ether layer was washed with a 5% aqueous potassium bicarbonate solution and water, dried, and the solvent was distilled off. The residue was distilled under reduced pressure, bp 16
Obtain 32 g (78%) of α-(isochroman-1-yl)acetophenone t-at 0-163°C (0.03 mmHg). Mp 43-45°C.

I Rv product SH'cva-': 1680 (CJ)
.

NMR(CCIa)δ: 2.46-3.00(2
11, lock, 4'-1h), 3.16-3.46 (2H
, a, cHzcO), 3.51-4.43 (211,
+*, 3'-L).

5.41 (III, t, J-6Hz, l'-H),
7.15 (4H, s, 8r-H), 7.26-7.
68 (311, m, 311.4-II, and 511
), 7.79 8.18 (211, m.

2-Hand 6-If).

(2) After stirring log α-(isochroman-1-yl)acetophenone and 7.2 g of phenethylamine in anhydrous ether at room temperature for 4 hours, the solvent was distilled off. After adding anhydrous Hensen to the residue and distilling off the water produced by azeotropic distillation, this anhydrous ether C8 liquid was poured into a suspension of 3.5 g of lithium aluminum hydride in anhydrous ether under water cooling. do.

After that, the mixture was heated under reflux for 5 hours, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer is washed with a 5% aqueous potassium hydrogen carbonate solution and water, and after drying, the solvent is distilled off. The residue was subjected to alumina column chromatography and eluted with petroleum ether/ethyl acetate to obtain 3.2 g (17%) of 1-(1-(N-phenethylamino)phenethylcoisochroman) as a viscous oil.

I Ry shell: 'cm-': 3350 (NH).

NMR(CC1,)δ: 1.93(Ill,s,
N11), 1.89-2.29 (28°+n, CII
tCH<), 2.54 -3.30 (611, m,
NIICIIz(:1IzPh and 4-Hz
), 3-46 -4.27 (3M, -, >CllPh
and 3-Ib) 14.50 (0,5H,t,
J-61Lz, 1-H), 4.97 (0,511,t
, J=6Hz, 1-H).

7.18 (48,s, Ar-H), 7.24-7.6
4 (10H, m, C, Hs x 2).

MS mHz: 357 (M”)- This product was converted into hydrochloride according to a conventional method, and mp +74-
1) Gather the crystals at 176°C (dec).

Example 9 4 g of α-(isochroman-■-yl)acetophenone and 5.4 g of methylamine were dissolved in 60 ml of methanol, and Ig of sodium cyanoborohydride was added thereto, followed by stirring at room temperature for 7 hours. Most of the solvent is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. 5 ethyl acetate layer
% hydrochloric acid, the hydrochloric acid layer is made alkaline with 5% sodium hydroxide solution, and extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying, the solvent was distilled off. The residue was subjected to alumina column chromatography, and petroleum ether
It was eluted with ethyl acetate and 1-(1-
(N-methylamino)phenethylcoisochroman 2.
Obtain 2g (53χ).

l RvQ::Lcm-': 3360 (lL
H)-NMR (CC1,) δ: 1.70 (III, s
, NH), 1.84-2.09 (2hm, CToCH
<), 2-22 (3H1s, NCIh) + 2.51
-2.96 (2H, m.

4-1h) l 3.56 4.18 (311, m,
CHlCII < and 3-Hz).

4.46 (0,71+, t, J=6Hz, 1-1f)+
4.98 (0,3H, t, J=6Hz, 1-H),
7.18 (4H,s, Ar-H), 7.04 (411
,s,Ar-)1), 7.18-7.65(5rr,
m, Ar-H).

M S mHz: 267 (M').

Example IO In a similar manner to Example 9, 1(1-(N-butylamino)
phenethyl isochroman was produced.

I Rv-3'cm-': 3360 (Nll), N
M R (CCL) δ: 0.80 0.98 (311
, m, C1h), 1.191.54 (4■, m, CII
zCIltCIIi), 1.74 (111,s, N1
1), 1.94-2.27 (2H, l, 3-Hri,
4.45 (0,711,t, J=711z, I-H),
4.96(0,31(,t,J=7Hz,1-It),
6.94.6.99 (both 4H, s, s, Ar
-II), 7.18-7.58 (5H, ++, Ar-
11).

M S mHz: 309 (M').

This product was converted into hydrochloride according to a conventional method, and mp 170-
Obtain crystals at 175°C (dec).

Example 11 (1) Add 6 g of (isochroman-1-yl)acetone to methanol, add 1 g of sodium borohydride, and stir at room temperature for 2 hours. 6 Most of the methanol is distilled off under reduced pressure. The residue was extracted with ethyl acetate for 4 times. After washing the ethyl acetate layer with water and drying, the solvent was distilled off, and the residue was distilled under reduced pressure.
-(isochroman-1-yl)-2-propatool 5
．． 4g (87χ) obtained 6I Rv cm-' on core: 34
40 (011).

NMR (CC1, n δ: 1.13, 1.16 (
Both 317. d, each J=6Hz, C
) Is), 1.25-2.07 (2H, m, HzC
H<), 2.60-3.60 (:llI, +i, 44
z), 3.33-3.59 (IH, br, OH),
3.62-3.89 (IH, m, >C11CHx), 3
．． 92-4.32 (2H, m, 3-1h), 4.73-
5.14 (IH, m, 1-14), 7.10 (41,
s, Ar-11).

M S Jz: 192 (M”).

(2) Dissolve 1.5 g of 1-(isochroman-1-yl)-2-propatol in 3.3 g of triphenylphosphine and 40 ml of anhydrous dimethylformamide, and add bromine to this solution under water cooling. The mixture was added dropwise until the color disappeared, and the mixture was further stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and dried, and then the solvent was distilled off. The residue was subjected to Norica gel column chromatography,
Eluted with petroleum ether/ethyl acetate, an oily substance 1-(
Isochroman-1-ylcine-2-propyl bromide (69χ) is obtained.

NMR(CC14)δ: 1.75.1.81(
hotl+ 311. d, each J=611z,
CH3, 1.96-2.44 (211,s, C
11IC1l<), 2.65-3.04(2H, +
w, 4-Ht), 3.65-4.16 (211, m
, 3-11t), 4.745.14 (111,11
, 1-11), 7.14 (411,s, ^r-If
).

-H), 7.18-7.58 (511,m, 8r-
1f).

MS mHz: 254 (M).

(3) 1-(isochroman-1-yl)-2-propyl bromide 4.3g% tert-butylamine 7
．． 4g! A mixture of 3.5 g of potassium carbonate and 20 ml of dry trimethylformamide was stirred at 60° C. for 40 hours.

The reaction solution was extracted with ethyl acetate, the ethyl acetate layer was extracted with 5% hydrochloric acid, the hydrochloric acid layer was made alkaline with 20x sodium hydroxide solution, and extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying, the solvent was distilled off. The residue was subjected to alumina column chromatography, eluted with ethyl acetate/petroleum ether, and 1.5 g (3(iχ)
obtain.

l Rv ””cm-': 3350 (Nll
).

NMR(CC1m)δ: 0.71(IH,s,N
H), 1.0H911,s, C<CI(ri3), 1.
03.1.07 (boLh 3H, d, each J=
611z,>CHCll3).

1.69-1.94 (2H, m, CHzCH<),
2.58-3.28(31(,m,C:H-C1l,
and 4-11z), 3.61-4.26 (2L
Gu, 3-tit), 4.52-4.84 (LH, gloss, 1-H), 7.04 (411, m, 8 r-) 1)
.

MS mHz: 247 (M').

Example 12 2 g of 1-(2-(N-benzylamino)propylcoisochroman and 3 ml of formalin are dissolved in a7tonitrile, and 0.75 g of sodium cyanoborohydride is dissolved in this solution.
Add under water cooling. Furthermore, acetic acid was added until the reaction solution became neutral, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under tJ&pressure, the residue was made alkaline with potassium hydroxide, and then extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying, the solvent was distilled off. The residue was subjected to alumina column chromatography, eluted with ethyl acetate/petroleum ether, and 1-
(1.3g (63χ
)obtain.

NMR((:C1,)δ: 1.Ol, 1.05
(both 3H, d, each J-6+1z, >(
:IICIh), 1.49-1. I? 1l (I
II, m,>CllCl+3n, 2.12°2.2
8 (both 311.s, NCH)), 2.58
-2.98 (2Lm, 4-L).

3.54, 3.65 (both 2!1.s, NC1h
), 3.68 4.24 (2) 1. m.

3-1lz), 4.48 5.24(Ill, m
, l-1f), 7.04 (4H, m, 8r-H).

7.22 (511, S, C, I+,).

MS mHz: 295 (M-).

Example 13 1.8 g of 1-(2-(N-benzyl-N-methylamino)propyl isochroman and 7.3 g of methyl iodide
was dissolved in 30 ml of anhydrous ether and heated under reflux for 10 hours. The precipitated crystals were collected by filtration, washed with ether, and purified with benzyl[2-(isochroman-1-yl)propan-2-yl]dimethylammonium iosito 1.7
g ([;5χ) is obtained.

NMR(CCIa)δ; 1.44-1.91(3
11, m, >CHC)I*), 2.01-2.4111
(2LI++, Cl1zCI+<), 2.54-3.
OR3Lm, 4-11tand>CHCIb), 3
．． 21(611,s,N(CIl,)z), 3.71
-4.21 (211, m, 3Jlz), i, 61
5.21(31+, m, N(:Ih and
l-11).

3-H2), 4.48-5.24(Ill, m, [-
11+, 7.04 (41(, m, Ar4+.

6.91-8.11(9)1. m, Ar4).

Example 14 (I) Add thionyl chloride!7[ to a solution of 10 g of isochroman-1-yl vinegar M in anhydrous benzene and heat under reflux for 4 hours. Thionyl chloride was distilled off under reduced pressure, and (isochroman-1-yl ) Acetyl chloride as oil 9.5
g(86X) i*ru.

I Ru', @:tcm-': 1800 (OH)
.

(2) 1.4 g of phenethylamine and 1.1 g of triethylamine in water ether) Add dropwise a solution of 2.2 g of (isochroman-1-yl)acetyl chloride in anhydrous ether. 1. Stir the reaction solution at room temperature for 30 minutes. Afterwards, it is extracted with ethyl acetate. Add ethyl acetate layer to 5% hydrochloric acid, 5%
Wash with potassium hydrogen carbonate solution and water, dry, and then evaporate the solvent. The residue was recrystallized from ether and mp
2.6 g (88.chi.) of N-phenethyl-.alpha.-(isochroman-1-yl)acetamide at 89-91 DEG C. are obtained.

I Rp:::'cm-': 3270 (Nil),
1640 (OH).

NMR((:C1,)δ:2.56-3.0H61
1,n+,Cl1zC[lNIICLCIIz)I3.
31 4.32 (4H, m, 3-1lz and 4-
11i), 5.10(11(, t, J=OH2,1
-11), 6.46 6.71 (l11.hr, c
ONH), 7.13 (511, s.

C6H3), 7.36 (4N, s, Ar-It).

MS ta/z: 295 (M').

(3) A solution of 4 g of N-phenethyl-α-(isochloro7-1-yl)acetamide in anhydrous ether was added to 2.5 g of lithium aluminum hydride. 6. Water was added to the reaction solution, which was added dropwise to an IC suspension in anhydrous tetrahydrofuran and further heated under reflux for 8 hours, and extracted with ether.

After washing and drying the ether layer, the solvent was distilled off and the residue was subjected to alumina column chromatography. It was eluted with 0 petroleum ether and ethyl acetate, and l-(2-(N-phenethylamino)ethylcoisochroman was dissolved in a viscous form. 1.1 as oil
g(29χ) is obtained.

[R',":x'cs-': 329G (Nll
).

NMR(CC1a) 6 : 1.17(LH,s
, N11), 1.80-2.20 (2H, m, cI1g
cl'1JH) + 2.30 3.22 (811, m,
clIJIlcHtcHtPhand 4-Hri, 3
．． 55-4.23 (211, m, 3-11z), 4.
76 (lIl, L.

J=6112.1-H), 7.08(411,s,A
r-It), 7.21 (5H,s, C611s).

MS Il/z: 28HM”).

This product was converted into hydrochloride according to a conventional method, and mp168-1
Obtain crystals at 70°C (dec).

Examples 15 to 17 The compounds shown in Table 2 were obtained as oils in the same manner as in Example 4.

(From the procedure chief Fu Zhengshu) January 1982! 6th

Claims (10)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a hydrogen atom, lower alkyl group, or aryl group, R^2 and R^3 are the same or different, and hydrogen an isochroman derivative represented by an atom, an alkyl group, an aryl group, or an aralkyl group. (2) The isochroman derivative according to claim 1, wherein in the general formula, R^1 is a methyl group. (3) In the above general formula, R^2 is a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms, and R^3 is a lower alkyl group having 1 to 5 carbon atoms.
The isochroman derivative according to claim 2, which is a lower alkyl group of ~7, a phenyl group, a benzyl group, or a phenethyl group. (4) The isochroman derivative according to claim 1, wherein in the general formula, R^1 is a phenyl group. (5) In the general formula, R^2 is a hydrogen atom,
R^3 is a lower alkyl group having 1 to 7 carbon atoms, a phenyl group,
The isochroman derivative according to claim 4, which is a benzyl group or a phenethyl group. (6) The isochroman derivative according to claim 1, wherein in the general formula, R^1 is a hydrogen atom. (7) In the general formula, R^2 is a hydrogen atom,
R^3 is a lower alkyl group having 1 to 7 carbon atoms, a phenyl group,
The isochroman derivative according to claim 6, which is a benzyl group or a phenethyl group. (8) General formula ▲ Numerical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a hydrogen atom, a lower alkyl group, or an aryl group) (wherein, R^3 represents an alkyl group, aryl group, or aralkyl group), the general formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ (in the formula, R^1 and R^3 is the same as above), and this compound is reduced to a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 and R^3 are the same as above) A method for producing an isochroman derivative shown in (9) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^1 represents a hydrogen atom, a lower alkyl group, and an aryl group, and X represents a halogen atom) and a compound represented by the general formula▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^2 and R^3 are the same or different and represent a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group) Reacting amines A method for producing an isochroman derivative represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R^1, R^2 and R^3 are the same as above). (10) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, X represents a halogen atom) Compounds represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^ 2 and R^3 are the same or different and represent a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group) to form the general formula ▲ mathematical formula, chemical formula, table, etc. In the formula, R^2 and R^3 are the same as above) A general formula is obtained, which is characterized by reducing this compound. There are mathematical formulas, chemical formulas, tables, etc. 2 and R^3 are the same as above).