JPH0352890A - 4,7-dihydrothieno(2,3-b)pyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is lower alkyl or phenylalkyl; R<2> is lower alkyl, (substituted) phenyl, cycloalkyl or cycloalkylalkyl]. EXAMPLE:(+)-Methyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)thieno[2,3- b]pyridine-5-carboxylate [(+)-III]. USE:The compound expressed by formula I is a calcium blocking medicine and used as a remedy for circulatory disease such as angina pectoris, hypertonia, cerebral blood flow or arrhythmia. PREPARATION:2-tert.-Butoxycarbonyl derivative expressed by formula II is treated with trimethylsilyl chloride and iodide of alkali metal and the treated material is hydrolyzed.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to 4,7-dihydroche/[2.3-b]hyridine derivatives.

[Prior art formula (■): (wherein l'{+ is lower alkyl or phenylalkyl, Rt is lower alkyl, phenyl optionally substituted with one or more halogen or alkoxy,
4,7-dihydrothieno[2.3-b]pyridine derivatives represented by
It has various effects such as increasing cerebral blood flow and dilating coronary vessels, causing angina pectoris,
It is expected to be useful as a therapeutic agent for a wide range of circulatory system diseases such as hypertension, cerebral blood flow disorders, and arrhythmia.

We have discovered that many 4,7-dihydrothieno[2.3
-b] To synthesize pyridine derivatives, to clarify that they have pharmacological effects such as antihypertensive action and coronary vasodilatory action, and to disclose the clinical applicability range and dosage, JP-A-62-10087 ). In addition, through animal experiments, we demonstrated the affinity of the above derivatives with calcium channels in the cerebral cortex, confirming the existence of calcium blocking effects, and at the same time conducted detailed studies on the coronary vasodilatory and antihypertensive effects of various compounds [Adachi et al. et al., Chem. Pharm.
Bull. 3 6 (1 1) 4 3 8 9-44
02 (1988)]. This study revealed that the carunium blocking effect of compounds having optical isomers is unevenly distributed in one isomer. For example, the above formula (
In), R1 is methyl and R2 is isobutyl (methyl 4,7-dihydro-3-inbutyl-6
-Methyl-4-(3-nitrophenyl)thieno[2.3
-b] pyridine 5-carboxylate), as well as coronary vasodilation and antihypertensive effects, are shown in the table below.
As shown in the figure, each optical isomer is significantly different (see Adachi et al., supra).

Ca blockade, coronary vasodilatory effect and antihypertensive effect of S-(+) and R-(-) derivatives S-(+)-1 R{-}-1 ±)-1 0.14 0 .14 128.5 (38)
717.7 4.62 33.
6 ( 8) 00.19 0, 22
104.0(25) 57 Abbreviation: ['H]NTD: [3H]nitrendibine CVD action
Coronary vasodilatory action CPF: Coronary vasodilator anti-HT activity: Antihypertensive activity SBP: Systolic blood pressure: K, (X 1 0-'M), K value is IC, 0
/(1+(!/K). Here, IC,. is,
The concentration that inhibits 50% of the specific binding of [3H]NTD in the rat cerebral cortex membrane fraction, C is the [3H]NTD concentration (0
．． 2 nM), K is the dissociation constant (0.2-0.23 nM).

”: Maximum increase rate (%) in CPF. Changes in CPFI were measured by the Langendorff method using an isolated heart. The test compound was administered into the coronary artery at a dose of 0.1 μ9.

The number in parentheses is the time (in minutes) required for 50% of the maximum change in CPF to recover.

”: Maximum decrease in SBP (mmHg). The test compound is orally administered at 3 m9/k9 to 5 spontaneously hypertensive rats.

”: (XIO-”M), RC5. The value is the concentration required to relax 50% of the contraction of isolated rabbit basilar artery induced by KCl2 (5 x 10-''M).

The results in Table 1 suggest that the action of the derivative represented by formula (II[) is primarily derived from the (+) enantiomer of the S configuration.

[Problems to be Solved by the Invention] As described above, the clinical effectiveness of the compound represented by formula (III) in the treatment of cardiovascular diseases is higher than that of the racemic compound.
It is expected that it will be much higher for the optically active (+) enantiomer. Therefore, this optical isomer can be stably produced,
If supplied, it would be possible to obtain a highly effective therapeutic agent for cardiovascular diseases in small amounts. Generally, an asymmetric synthesis method is used to produce optically active isomers of 1,4-dihydropyridine derivatives. However, in the case of the compound of formula (III), production by asymmetric synthesis is inefficient and yields low. Also,
Method for optically resolving (±) compounds of formula ([[) (Adachi et al., Chem. Pharm. Bull. supra)
can also be used, but such a method involves long steps, complicated operations, and has a low yield.

As described above, all conventional methods have low efficiency and are impractical, and in order to apply the above optically active isomers clinically, it is necessary to establish a production method that is more efficient and suitable for practical use. there were.

Therefore, the present inventors have developed a 2,5-diester derivative represented by formula (n) (wherein Rl and R! are according to the above definitions), which is a synthesis intermediate of the compound of formula (III). We focused on obtaining optically active isomer (III) using That is, this 2,5-
Only the 2-position t-butyl ester of diester compound (II) is hydrolyzed to obtain a 2-carboxylic acid represented by formula (I): (wherein R1 and R! are according to the above definitions), and the obtained carboxylic acid We attempted a method in which the compound was optically resolved as an appropriate salt and then decarboxylated.

The starting material for the above method is the 2,5-diester (ff
) is a known substance and is described in JP-A-62-10087 filed by the present applicant as a synthetic intermediate of the (±) compound represented by formula (III).

In this method, one problem was to selectively hydrolyze the 2-position ester bond of the diester represented by formula (1). For example, using alkaline hydrolysis, the usual means of obtaining carboxylic acids from esters, 2,
The yield becomes extremely low because the 5-position ester bond is decomposed non-selectively. On the other hand, according to the method of inducing 1-butyl ester to carboxylic acid using an acid such as trifluoroacetic acid, the ester at the 2-position can be selectively converted to carboxylic acid, but the raw material is easily decarboxylated. This will reduce the subsequent salt formation efficiency.

[Means for Solving the Problems] As a result of trying various methods to solve the above problems, the present inventors have discovered that the 2-t-butoxycarbonyl derivative represented by formula (II) can be converted into trimethylsilyl chloride. The present inventors have discovered that the 2-carboxylic acid derivative represented by formula (I) can be selectively obtained by treatment with an alkali metal iodide and subsequent hydrolysis, and have completed the present invention. The 2-carboxylic acid derivative of formula (I) is novel and extremely important as a starting material for the production of the optically active 4,7-dihydroche/[2.3-b]pyridine derivative represented by formula (II[) above. be.

Accordingly, the present invention provides a 4,7-dihydroche/[2.3-b]pyridine derivative represented by formula (I). Furthermore, the present invention provides 2-
The present invention provides a method for producing a pyridine derivative represented by formula (1), which comprises treating a t-butoxycarbonyl derivative with trimethylsilyl chloride and an alkali metal iodide, and then hydrolyzing it.

Terms used in this specification are defined below.

In the definition of R', lower alkyl refers to linear or branched C
．． -C. means an alkyl group, examples include methyl, ethyl\propyl, isopropyl, butyl, isobutyl, S
-Butyl, etc. can be mentioned.

Phenylalkyl refers to the above linear lower alkyl bound to phenyl, and examples of such phenyl include phenethyl, phenylprobyl, phenylbutyl, and the like.

In the definition of R'', lower alkyl refers to straight or branched C
．． -C. means an alkyl group, examples include methyl, ethyl, proyl, isobrobyl, butyl, isobutyl, S
-butyl, t-butyl and the like.

(2) In phenyl optionally substituted with two halogens or alkoxy, examples of the halogen include fluoro, chloro, and bromo, and examples of the lower alkoxy include methoxy, ethoxy, and the like. These may be the same or different, and examples of such phenyl include m,p-dimethoxyphenyl and p-chlorophenyl.

Cycloalkyl means 03-C7 cycloalkyl, and examples include cycloprobyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

Cycloanolekinoleanolekinore is the upper three C, ~C
77 means a linear C1-C4 lower alkyl substituted with chloroalkyl.

In the compound of the present invention, -No. is attached to either the 2nd or 3rd position.

As described above, the 4,7-dihydrothieno[2.3-b]pyridine derivative represented by formula (1) of the present invention is optically resolved as a suitable salt, and then decarboxylated to obtain optically active formula (III). can be obtained.

For this purpose, a recrystallized purified product of the compound of formula (I) may be used, but the compound of formula (1) is unstable, and some decarboxylation occurs during recrystallization, resulting in compound (I[ Since a racemate of I) is produced, it is convenient to use the crude product as it is without purification by recrystallization.

Although various base salts can be considered as salts suitable for this optical resolution step, cinchonine salts are most preferred.

That is, a 2-t-butoxycarbonyl derivative represented by formula (It) H is treated with trimethylsilyl chloride and an alkali metal iodide, and then hydrolyzed to form 4,7 dihydrothieno[2, 3 b] A pyridine derivative is obtained, and then this 2-carboxylic acid derivative is optically resolved as a cinchonine salt, and then subjected to decarboxylation treatment with an acid to obtain an optically active 4,7-dihydrothieno compound represented by the formula (■):H. [23-b
] A pyridine derivative is obtained. In each of the above formulas, R+ and R2
follows the above definition.

According to the invention, compounds of formula (I) are obtained, and further compounds of formula (II) are obtained.
A series of steps for producing the optically active 4,7-dihydrothieno[2.3-b copyridine derivative I) will be explained according to the following reaction formula.

■ ■ ■ (In the formula, R' and R2 are according to the above definition, and M represents an alkali metal.) Ifu1 Carboxylic acid of 2-position t-butyl ester (1
) When the compound of formula (n) is treated with trimethylsilyl chloride and an alkali metal iodide and ice water is added, the 2-carboxylic acid 5-ester is selectively obtained in a high yield. It will be done. Potassium or lithium can also be used as the alkali metal, but the latter is sparingly soluble. In addition, C
H. SiC (2-M In place of I, CH.Sil may be used although it is expensive. The reaction is carried out in a suitable medium such as acetonitrile, acetone, dichloromethane or chloroform at a temperature of O to 30°C. The reaction is preferably carried out at room temperature for about 1 to 8 hours with stirring. Then, ice water is added to precipitate the desired 2-carboxylic acid (I).

The starting material for this reaction, the 2,5-diester compound (■), is a known substance, and is used as a synthetic intermediate for the (±) compound represented by formula (III) in JP-A No. 62-1995, filed by the present applicant.
It is described in Publication No. 10087.

Step 2 After heating and dissolving equimolar amounts of 2-carboxylic acid (1) and cinchonine in an appropriate solvent and optical resolution of diastereomeric salt of 2-carboxylic acid (1). , when left to cool (+)
-1-/Nkonin salt is precipitated. This is filtered, washed with ethanol, dried, and has an optical purity of 95%ee or higher (+
)-1 is obtained.

By concentrating the mother liquor and subjecting it to appropriate treatments such as neutralization and ether extraction, crude (-)-1 is obtained.

As the reaction solvent, alcohols such as ethanol, methanol, n-probanol, or isobrobanol can be used.

Engineering [3 (+) -1-Cinchonine salt oyohi (-) ■
-(+)-1 and (-) by decarboxylation of cinchonine salts
Preparation of -I In a suitable solvent, each cinchonine salt was decarboxylated separately by heating to reflux in the presence of an acid, and then water was added, resulting in (+)-. I
I[ and (-)-III isomers are precipitated.

The crystals are separated and purified by recrystallization from a solvent such as ethanol. Cinchonine can be recovered and reused.

As the solvent that can be used in this step, mention may be made of methanol, ethanol or propanol. Also,
Suitable acids include hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and the like.

Effect of the invention] According to the invention, optically active 4,7-dihydrothieno[2
．． 3-b] is a useful starting material for pyridine derivatives.
Carboxylic acid derivative (1) can be easily obtained, and this 2-carboxylic acid derivative can be used to treat cardiovascular diseases such as angina, hypertension, cerebral blood flow disorder, and arrhythmia by having a calcium blocking effect. optically active 4, which is widely useful as a therapeutic agent for
．． 7-dihydrothieno[2.3-b]pyridine derivative (
III) can be produced with high purity and high yield by a simple method.

EXAMPLES The present invention will be explained in detail by giving Examples and Reference Examples below.

Example 1 4,7-dihydro-3-isobutyl 5-methoxycarbonyl-6-methyl-1-(3-nitrophenyl)thieno[2.3-b]pyridine 2-carboxylic acid (1
) 2-t-Butyl5-methyl4,7-dihydro3-ynebutyl-6-methyl-4-(3-nitrophenyl)thieno[2.3-b]pyricine-2,5-dicarboquinole}
(It) 1 0 8. 8g (0.224mol)
, 67.0 g (0.447 mol) of sodium iodide, and 500 a+4 acetonitrile were added dropwise with stirring at room temperature to 48.6 g (0.447 mol) of 1. Stir for an hour.

Add 1,1 Lot (1,10%) of water to the reaction mixture.
Fifty volumes of NazSzO3 solution were sequentially added dropwise, and the precipitated crystals were collected by filtration, washed with water, and dried to obtain 2-carphonic acid (1) 98.49% as yellow crystals. mp17
3-174°C0 The purity of this product by HPLC is approximately 96
．． 1%, and the yield of compound (I) in this reaction is 9
It is 8.2%.

Compound (I): I R (Nujol): 3306 (NH), 2596 (COOH), 1649 (
Co), 1342(NO,)'H-NMR (d.DMs
o) δ: 0.7 5 (3H, d, J = 7Hz), 0.85 (
3H, d, J = 7Hz), 1.69 (IH, n+), 2. 1 3 (IH, dd, J = 7, l lHz
), 2.30 (3H, s), 2.88 (LH.dd, J =7.13Hz), 3.5
7 (3H, s), 5. 2 1 (l H, S), 7.
53-8.08 (4H, i) Elemental analysis value (as C,,H,,N.O,S) Calculated value;
C: 58.59, H: 5.15, N: 6.51 Actual 6t value; C: 58.29, H: 5.16, N: 6.
40 HPLC: tR4.8min [7'7 Ram:TSK-GEL ODS-120T, 5
μN (4.OX250); Mobile phase: methanol, 0.
5 z (1/min; detection: UV254nm; 3
5 atm 1 Using the crude product obtained in Example 1, optically active 4,7-dihydroche/[2. 3
-b] A pyridine derivative was obtained.

Reference example l (+) monomethyl 4,7-dihydro-3in butyl-6-methyl-4-(3-nitrophenyl)thieno [2.3-b]pyridine-5-carboxylate [(
+)-II1] and (1)1-methyl 4,7-dihydro-3-inbutyl-6-methyl-4-(3nitrophenyl)thieno [2.3-bl pyridine-5-carboxylate [(-)-I[ I] [1 piece (.+)-4.7-
dihydro-3-isobutyl-5-methoxycarbonyl-6
-Methyl-4-(3-nitrophenyl)che/[2.
3-b] pyridine = 2-carboxylic acid-cinchonine J (+
)-1-cinchonine salt] 2-carboxylic acid (+) 97.19 (
0.224 mol), cinchonine 6 5. 99 (0.
A mixed solution of 24 moles of ethanol) and 5001 ff of ethanol was heated under reflux for 10 minutes to dissolve the raw materials, and then left at room temperature for 20 hours. Collect the precipitated crystals by filtration and add 100 ml of ethanol.
After washing twice with ZC, dry. (+)-r-cinchonine salt 69.2y was obtained as pale yellow crystals. mp=2
24-226°C (decomposition). Yield 42.8%.

(C=0.5 1 3, DMSO) I R (Nujol) 23226 (NH), 1668 (Co), 1 3 4 2
cr-'(Not) [2] (-)-4.7-dihydro-3-inbutyl-5-methoxycarbonyl-6-methyl-4-(3nitrophenyl)che/ [2. 3-b]pyridine=2-
Carboxylic acid [(-)-11 In the above [1], the filter limb from which the (+)-1-cinchonine salt was separated is concentrated, and the residue is neutralized with Q and INHcQ when cold, and then extracted with ether. After washing the ether extract with ice water, Q. Extract with 5N NaOH solution a260i&. The aqueous extract is acidified with 1NHCQ while cold, and the precipitated crystals are collected by filtration, washed with water, and dried. (1)-1 49.19 was obtained as pale yellow crystals. Yield 50.9%.

This product was used as it was in the next step without purification.

[3] (10) Monomethyl 4,7-dihydro-3-isobutyl-6-methyl-4-(3-nitrophenyl)cheno [2,3-b]pyridine-5-carboxylate [(+)-■] Top 64.4 g (0.089 mol) of (→-)-1-cinchonine salt prepared with i2J2] and 320 g of methanol.
14 x ff (0.2 x sulfuric acid) was added to the solution of
7. Drip Mok). Thereafter, the mixture is heated to gradually raise the temperature and refluxed for 15 minutes. After cooling, 650 ml of water is added, and the precipitated crystals are collected by filtration, washed with water, and dried. The desired (+)-I[[,47. I got 59. This product was purified by recrystallization from ethanol to obtain 32.09 yellow plate crystals. mp=173~175°C0 yield 93.0%.

(+)-11I: (C=1.Ol9, EtOH) Elemental analysis value (as CZ.H, 1N, O.S) Calculated value;
C: 62.16, H: 5.74, N: 7.25 Actual value; C: 62.04, H: 5.67, N: 7.28 I R (Nujol): 3305 (NH), 1630 ( C=O), 1 342c
r' (NCL) 'H-NMR (CDCi23) δ: 0.72 (3H, d, J=6) {z), 0. 8 8
(3 H, d, J = 6 Hz), 1. 6 0
(IH, m), 2.02 (IH, dd, J-7.15Hz), 2.13
(LH, dd, J=7.15Hz), 2. 3 7 (
3 H, s), 3.63 (3 H, s), 5. 2 5(
l H,s), 6. 2 2(l H,s), 7.
35-8.08 (4H, m) HPLC: ta 15.5min [Column SUMIPAX OA2000, 5μI (
4. OX250 (l); Mobile phase: hexane isopropyl alcohol (9:l), 1. OxQ/min; Detection: UV248 nm; 40 atm] [4] (-) Monomethyl 4.7-dihydro-3-inbutyl-6-methyl-4-(3-nitrophenyl)thieno [2.3-b]
Pyridine-5-carpoxylate [(-)-111] Crude (-)-1 prepared in [2 above] 49.0y (
About 0.114 mol), methanol 320111& is added dropwise to a solution of sulfuric acid 14JI& at room temperature with stirring, the temperature is gradually raised, and the mixture is refluxed for 15 minutes. After cooling,
650 Misaki of ice water is added and the precipitated crystals are collected by filtration, washed with water, and then recrystallized from ethanol (repeated three times). 338 g of (-)-1I[, was obtained as yellow plate crystals. n
p=175-177°C0 yield 76.8%.

(-)-III: (C=1.014, EtOH) Elemental analysis value (C,. As H2, N, 03) Calculated value: C
:62.16, H:5.74, N:7.25 Actual value. C: 62.01, H 5 65, N: 7. 2
7 I R (Nujol): 3305 (NH), 1 6 3 0 (C10), 1
34 2cr' (No.) 'H-NMR (CDC&3) δ: 0.7 2 (3H, d, J = 6Hz), 0.88 (3
H, d, J = 6 Hz), 1.60 (IH, +++), 2.02 (IH, dd, J = 7.15 Hz), 2.1
3 (IH, dd, J = 7.1 5Hz), 2. 3
7 (3 H, s), 3. 6 3 (3 H, s),
5.25 (LH, s), 6.22 (IH, s), 7.3
5-8.08 (4H, m) HPLC: ta 13.5min [Column: SUMI PAX OA2000, 5μ shoulder (4.Ox250ul): Mobile phase; Hexane-in-bupal (9:1); Detection: UV248nIII; 40
Atmospheric pressure]

Claims (1)

[Claims] 1. Formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R^1 is lower alkyl or phenylalkyl, R^2 is lower alkyl, 1 or A 4,7-dihydrothieno[2,3-b]pyridine derivative represented by phenyl, cycloalkyl or cycloalkylalkyl optionally substituted with the above halogen or alkoxy. 2. Formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R^1 and R^2 follow the above definitions) The 2-t-butoxycarbonyl derivative represented by trimethylsilyl chloride 4. The method according to claim 1, wherein the treatment is performed with an alkali metal iodide and then hydrolyzed.
A method for producing a 7-dihydrothieno[2,3-b]pyridine derivative.