JPS62497A - Cyclic biphenyl ether compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A cyclic biphenyl ether compound shown by the formula I (R1 is H or formyl: R2 is H or methyl; R3 is H or acetyl; R4 is lower alkyl; R5 is H or methyl; X is H or Br). EXAMPLE:A compound shown by the formula II. USE:An intermediate for synthesizing a compound shown by the formula III (R is H or OH) showing antitumor activity. PREPARATION:A compound shown by the formula IV is catalytically reduced to give a compound shown by the formula V among compounds shown by the formula I. N-Protected N, O-dimethyltyrosine is combined with L-alanine methyl ester, the amino-protecting group is removed to combine the L-alanine, further the amino group is combined with D-alanine to produce tetrapeptide, which is combined with the amino group of the compound shown by the formula II and subjected to ring closure to give a compound shown by the formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel cyclic biphenyl ether compound useful as an intermediate for the synthesis of medicinal compounds and a method for producing the same.

[Conventional technology]

Traditionally, plants grown in Mexico (Bouvardia ternifolia) or madder grass (Rubia akane) were used.
Or Rubia cordiafolia (Rubia a
ordia-folia) From the root, the following general formula (1
): (wherein R represents hydrogen or hydroxyl group) has been isolated and is known to exhibit significant antitumor activity [Journal Op.
Society (J, Am, Ohθm.

Hoe, ), ig 9q, p. 804Q (197
7), Chemical and Pharmacy Bullech 7 (C!hem, Pharm, Bull,
) Vol. 52, p. 284 (1984)].

[Problem that the invention seeks to solve]

However, the compound represented by the general formula (1) is only contained in trace amounts in natural products (for example, 12 kg
), its use is inconvenient.

An object of the present invention is to provide a novel compound that is a synthetic intermediate, with the ultimate objective of synthetically obtaining the compound represented by the general formula (1), and a method for producing the same.

[Means for solving problems]

To summarize the present invention, the first invention of the present invention relates to a novel cyclic biphenyl ether compound, which has the following general formula: It is characterized by being represented by hydrogen or an acetyl group, ``Akira'' represents a lower alkyl group, and ``Crow'' represents hydrogen or a methyl group, or hydrogen or bromine.

The second invention of the present invention is based on the following general formula (where Karasu is hydrogen or formyl group, Karasu is hydrogen or methyl group, Uma is hydrogen or acetyl group, Hiki is lower alkyl group, Karasu is hydrogen or methyl group) This invention relates to a method for producing a cyclic biphenyl ether compound represented by the following general formula (in which & is as described above), which is characterized by catalytic reduction.

Furthermore, the third invention of the present invention is based on the following general formula (where & is hydrogen or formyl group, horse is hydrogen or methyl group, crow is hydrogen or acetyl group, horse is lower alkyl group, bird is hydrogen or methyl group) The present invention relates to a method for producing a cyclic biphenyl ether compound represented by the following general formula % (wherein, is as described above) is treated with thallium (l[[) salt in a methanol-containing solvent to obtain a genone compound represented by the following general formula (wherein is as described above). This is zinc-reduced to obtain a compound represented by the following general formula (wherein the formulas are as described above), which is catalytically reduced, then acetylated and/or methylated, and further processed as desired. It is characterized by removing the membrane-retaining group.

Therefore, the method for producing one example of the compound of the present invention from tyrosine is as follows.

(1) CI'l')
(V) [■] [■] [Punishment [■]] The above reaction steps will be explained below.

Compound (1) is tyrosine, which is the starting material for this reaction. After protecting the amino group and carboxyl group of this compound (1), the compound is brominated, the amine or carboxyl protecting group is removed, and the tetrabromo form of compound V is produced by an amide bond.

This tetrabromo compound is treated with thallium (III) salt in a methanol-containing solvent to produce a methoxygenone compound (compound ①). This is one step of the method of the present invention, and is the center of the method of the present invention.

There are a few known examples of using thallium (III) salts for oxidative coupling of phenol [Advance, Organomet, Chem,
) Vol. 11, p. 147 (1973)]. The method of the invention is based thereon. As valent thallium salts, thallium acetate, thallium trifluoroacetate, thallium perchlorate, thallium nitrate, etc. are known, but the present inventors found that thallium nitrate (T
/(Non)l·5HaO) was found to be optimal in the method of the present invention. It has also been found that a methanol-dimethylformamide mixed solvent is most suitable as the methanol-containing solvent from the viewpoint of solubility. The reaction is preferably carried out at a temperature below 40°C, from the viewpoint of product decomposition and increase in by-products (-25°C to room temperature, preferably 0°C, overnight).

Next, ■ is reduced with zinc to produce ■. This step is a conventional method of zinc reduction, and may be a reaction under cooling with zinc dust and acetic acid.

Next, compound (2) is catalytically reduced to produce (2).

This step is a conventional method for debromination, and catalytic reduction using palladium on carbon in methanol is preferred.

Next, protect the hydroxyl group from ■ by acetylation (for example, using acetic anhydride-pyridine) to obtain ■, and methylate the amine group (for example, using sodium hydride-methyl iodide) to obtain X. , optionally deprotected (deformylated) to obtain X.

As mentioned above, the compound of the present invention is useful as a synthetic intermediate for the compound represented by the general formula (1), which is a natural product.

In order to produce the antitumor substance, for example, L-alanine methyl ester is combined with N-protected N,O-dimethyltyrosine using a conventional method of peptide synthesis, and the protecting group of the amino group is removed to form L. -Alanine is combined with D-alanine, and then the amino group is combined with D-alanine to produce a tetrapeptide, which is then combined with the amine group of compound X, and then the ring is closed. According to this method, antitumor substances, which conventionally relied only on extraction, can be efficiently produced by synthesis.

〔Example〕

Hereinafter, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these Examples.

The molecular weight was determined by measurement using a mass spectrometer.

Reference example 1 100f of tyrosine was mixed with 100tnt of methanol under water cooling.
Dissolved in normal hydrogen chloride-methanol 600-, 2,2-
25-dimethoxypropane was added. Heat this to 4℃ for 12
After holding the reaction for 2 hours at 45°C, the wire was separated, and the residue was recrystallized from methanol/ether at 90°C. Further, 25.79 colorless needle crystals of compound (II) were obtained from the mother liquor. Melting point 184-185°C Reference example 2 C! 0OOH.

(ff) Compound 95.5 If was dissolved in a small amount of methanol and added with an excess sodium bicarbonate aqueous solution. After bubbling stopped, the mixture was concentrated under reduced pressure and azeotroped with benzene. The residue was extracted repeatedly with hot ethyl acetate, the solution was concentrated under reduced pressure, and then the residue was recrystallized from ethyl acetate-hexane to obtain the free amine as colorless prisms of 71.8 f. Melting point: 135-136°C The obtained free amine 509 was dissolved in 320 + dK of formic acid under ice-cooling, 110rnt of acetic anhydride was added dropwise over 1 hour, the reaction was allowed to proceed at room temperature for 1 hour, and the mixture was concentrated under reduced pressure at 30°C, followed by toluene azeotroping. repeated. The oily residue was crystallized from methanol/ether to obtain 16.912, and the mother liquor was concentrated. The residue was dissolved in 100 methanol, and 5.2F potassium carbonate was obtained.
was added and reacted at 0°C for 25 minutes. The reaction solution was filtered, concentrated, and recrystallized from methanol-ether to give 141
9 (I[l) compounds were obtained. Melting point 142-142.5
℃ Reference Example 3 COOOH.

0HOHN I) 4qH r CIV) (II) Compound 10f was dissolved in 200% of tetrahydrofuran, and 572% of sodium acetate was suspended under water cooling.

To this solution, 4.59 rnt of bromine was added dropwise over 5 minutes, and the mixture was reacted for 30 minutes, and further reacted for 1 hour at room temperature. The reaction solution was filtered, extracted with ethyl acetate-water (containing a small amount of sodium thiosulfate), washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crystalline residue was recrystallized from ethyl acetate-hexane to obtain CF/) compound 1a02 in the form of colorless needles. Melting point 16S5~165
℃ Reference example 4 aooc horse H! N method H dawn ct r CIV-a) (IV) Compound 5.02 was dissolved in 2N hydrogen chloride-methanol 20- and reacted for 25 minutes under heating reflux.
Repeated azeotropy with L and methanol.

The residue was recrystallized from methanol-ether to obtain 5.02 colorless needles of compound IJV-a). Melting point 119~
120°C 0OH OHCtHN H r C■-b) CF/) Compound 5. , or is dioxane (say)-
The mixture was dissolved in a mixed solvent of methanol (5-), 1N aqueous sodium hydroxide solution (26-) was added, and the mixture was reacted at room temperature for 20 minutes. Add Amberlite E R-120 (ROHM) to the reaction solution.
To the mixture was added an excess amount of H-green (manufactured by J.D. & Haas), stirred, and then filtered. Add ethanol to solution F, repeat the concentration, dissolve the residue in a small amount of ethanol, and add ether to form an amorphous solid of 4.714F (F/
-1)) Compound was obtained.

3350,3
200br, 1755, 1670br.

ax 1555.153O NMR (acetone-4) δ: 2.9-54 (2H, complex), 5.82 (IH, brdd, J-7,
515Hz), 7.45 (2Js), a20 (IH,s
) Reference Example 5 (V) (rv-b) Compound 5999 was suspended in 100-methylene chloride, and 2,2'-dipyridyl disulfide 2-88
t,N-hydroxysuccinimide 2.86tttnt
Ta. Next, 1.52 m of triphenylphosphine was added and the reaction mixture became clear yellow.
and (IV-a) Compound 4,242 were added and reacted at room temperature for 18 hours. The resulting precipitate was collected and diluted with ethyl acetate, 2%
After washing with acetic acid aqueous solution, saturated sodium bicarbonate aqueous solution and water, tetrahydrofuran-methanol (1:
Recrystallized from 1), colorless fine crystals of 4.50 f (V)
The compound was obtained.

Furthermore, the F solution and the washing liquid were combined and partitioned between ethyl acetate-water, 2% acetic acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure.

The resulting residue was dissolved in chloroform and left to stand, and the deposited precipitate was collected and recrystallized to obtain 680 m9 of compound (V).

Melting point: 254-257°C (decomposition) Example 1 [■] (V) Compound 951■ was dissolved in dimethylformamide 20-20-, methanol 600- was added, and thallium nitrate t84 t was added at once while cooling with water for 30 minutes. After keeping it,
The reaction was carried out at 2°C for 18 hours. The reaction solution was heated at 30°C or less for about 2
00 wt and the residue was poured into ca. 11 ml of ethyl acetate. This solution was washed with a 2% acetic acid aqueous solution and then with a saturated sodium bicarbonate aqueous solution, the resulting precipitate was filtered through Celite, and the F solution was washed with a saturated saline solution. The acetic acid aqueous layer was extracted with ethyl acetate, and partitioned between a saturated aqueous sodium bicarbonate solution and saturated brine. The aqueous sodium bicarbonate layer was also extracted with ethyl acetate and washed with saturated brine.

All the organic layers were combined, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting brown oily residue was developed with PTLC (developing solvent: chloroform/methanol 18:1) to obtain a solvent of chloroform/methanol (8:1). A portion corresponding to Rfα61 in the system was fractionated to obtain 34.8 Da of colorless oily compound (Vl).

[■] Compound [α] tube +894° (C!= 1.22, 0HCl,
) Elemental analysis Calculated value 011 HI@% Oy Br
g (M”) Molecular weight 649.8721 Actual molecular weight 64
9. B7A9 Engineering R Shifia ~-1: 3370, 1735, 168
5,1655θh, 1600°ax 55O NMR (ODO/,) δ: 2.5-17 (2H, complex), 520 (34θ), 53-57 (2H
, complex), xao(3H,s), 4.28
([,d,,T=3B,4.6~5.1(2H,1
), &75(1H, br, d, J=12H
2), 6.85 (1a, a, J=3Hz), 7.20 (
1H, s), 7.25 (1a, a, overlapping with solvent signal), 7.68 (1H, br.

d, J=12Hz), a32 (IH, s) Furthermore, R
A brown oily mixture [■-Tomoe] containing an amorphous solid soluble in acetone and sparingly soluble in ethyl acetate, chloroform, methanol, etc. was obtained from the 159 parts.

[■]

(Vl) Compound 25■ was dissolved in tetrahydrofuran 2-, washed with 3N hydrochloric acid for 2 minutes while cooling with water, then washed with distilled water until the supernatant became neutral, washed with ethanol and ether, and then washed under reduced pressure. 50 m9 of dried zinc dust was suspended. While stirring vigorously, acetic acid [11-] was added dropwise, and after 12 minutes, acetic acid (LO5-) was added dropwise again.
The reaction was allowed to proceed for 5 minutes. The resulting insoluble matter was filtered and partitioned between ethyl acetate and seminal vesicle brine, and the organic layer was dried over sodium sulfate and concentrated. This was purified by PTLC (developing solvent chloroform/methanol 1[]:1) to obtain 22.8 ㎡ of a colorless oily [■] compound.

Further, the mixture (vl-a) sas In9 was treated in the same manner to obtain 29.7■ [■] compound.

[α] Tube +72.7° (0=1.14 0HO/, )
Elemental analysis Calculated value Os Hsq N! Oa Brs.
(M”) Molecular weight 619.8615 Actual value Molecular weight 619
．． 8614 Engineering R Shifil "ylH-": 3400,1
735,1690sh, 1680,1660゜ax j580.1505 NMR (CD(!ls)δ: 2.3-2.6
(2H, Conflex), 53-16 (2H.

Conflex), 3.75 (3H, 8), a, 4
~5.1 (4H, Conflex), 5.10 (IH,
d, J=IH2), 5.15(1H,br,d,,T=
9Hz), 6.90 (1a, a, y=1Hz), 6.
95 (IH, br, d, J = 9H2), 7.25 (IH
.

overlap with solvent signal), 7.68 (IH, d, J=I
H2), s, 1y (IHl 8) Example 2 [■] 407 mg of the compound was dissolved in methanol 15 containing 30 μ of sodium acetate, and a catalytic amount of 55 palladium/
After adding carbon, the atmosphere in the system was replaced with hydrogen, and catalytic reduction was performed overnight at room temperature.

The reaction solution was filtered, and solution F was partitioned between an ethyl acetate-2% aqueous acetic acid solution and a saturated aqueous sodium bicarbonate solution, washed with saturated brine, dried over sodium sulfate, and concentrated.

PTLC the resulting residue! The mixture was developed and fractionated using (J [solvent chloroform/methanol 15:1)] to obtain a colorless prismatic crystal [■] compound of 2L4W.

A portion was recrystallized from acetone as a sample for analysis.

Melting point 156-158°C [α] 1+137.6° (0 = (L91, methanol) Example 3 [■] Compound 1a2 da was dissolved in acetic anhydride-pyridine (each 1-)
The mixture was dissolved in water, reacted at room temperature for 8 hours, and azeotropically treated with toluene. The resulting residue was purified by PTLC (developing solvent chloroform-methanol 15:1) to obtain colorless oily [phantom compound] 193.

[α] +84° (C α84, aHctm) Elemental analysis Calculated value C□4. Horse OF (M+) molecular weight 426.1
425 Actual value Molecule j1426,1422 Film -l.

Engineering Rν, aX, , 3400.1745tlr,
1670, 1590.1505 Example 4 (IX) Compound 17.3■ was placed in a corrugated flask and azeotropically treated with benzene twice. Next, the system was made to have a fulvone atmosphere, then dissolved in dimethylformamide 3-, and while cooling with water, 50 μl of methyl iodide was added, and then sodium hydride (60% in mineral oil, 1 μl) was added with vigorous stirring. Allowed to react for minutes. Acetic acid 1-
was added to stop the reaction, and after foaming was completed,
Ethyl acetate - 2% acetic acid aqueous solution, saturated hydrogen carbonate) IJ
The mixture was partitioned between aqueous sodium chloride solution and saturated brine, and the organic layer was dried over sodium sulfate. The concentrated residue was purified by Rfo using PTLO (developing solvent chloroform-methanol 19:1).
6 and Rfo, the colorless oil of 41 was added to each (X-a) compound (
&Om9), (Xb) was fractionated as compound (7,3q).

Both of these compounds are partially isomerized at room temperature, so
I couldn't get it purely.

(X-a) Compound NMR (cDcr,) δ: 2.3? (3H,s),
2.6-57 ([, complex), 2.71,
2.75 (total 3H, a), 2.89, 2.9
4() → Ru 3H, s), 572,176 (Togota k
5H, B), X76 (3H, a), 4.25 (1H,
d, :r=1Hz), 4.41-s, 1 (aa, conflux), 6.6-7.6 (7H, cox, overlapping with solvent signal), 7.80. aoo()-, tal
jH,s), (X-1)) Compound NMR (ODO/,) δ: 2.35 (3H,
8), 2.73, 2.79 () = Tal 3H.

a), 2.87, 2.90 ()-tal 5H, a),
16~! L7 (AH, - complex), 575 (
3H, θ), 573. 575 (total 3H, s)
, 4.7~a 1 (2Ht Kombuchus), 5.0
8 (1B,'br,g), 6.5-7.7 (7H.

overlap with solvent signal), aoo, A12()-le I
H, 8) Equilibrium Mixture Engineering R Shi7ko S Tan-”: 1760sh, 1740
, 1660 , 1650° 1590 , 1500 Elemental analysis Calculated value c, 4Tl@, 01 Horse (M+) Molecular weight 454.1738 Actual value 454.1730 Example 5 Equilibrium mixture y of (X-a) and (X-1)) , a
After adding qK 2 normal hydrogen chloride-methanol 1- and heating under reflux for 4 hours and 30 minutes, concentration under reduced pressure and addition of methanol and concentration were repeated several times. PTLO the residue (
, llJ solvent chloroform-methanol 8:1) to obtain a colorless semi-crystalline solid of Rfrl, A2 and Rfl153 as an equilibrium mixture (i71rI9).

Engineering 'fly height cm-': 210 (1-3
700br, 1745,1660.

ax 1595, 1525, 1505 NMR (O knee OD) δ: 2. ．． 60,
2.63 ()-ru 3H,s), z94.

513 (total 3H, day), 2.60-4.0 (
complex, overlap with solvent signal), 4.35
, 5.20 (Total IH, br.

8), 6.5-7.8 (7H, complex) Elemental analysis Calculated value On H**+ Os N* (M"-
HC/) Molecular weight: 384°1684 Actual value: 3134.1700 [Effects of the Invention] As explained above, according to the present invention, a compound useful as a synthetic intermediate for medicinal compounds and a method for producing the same are provided.

Claims (1)

[Claims] 1. The following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 is hydrogen or formyl group, R_2 is hydrogen or methyl group, R_3 is hydrogen or acetyl group, R_4 is lower alkyl A cyclic biphenyl ether compound, characterized in that R_5 is hydrogen or a methyl group, and X is hydrogen or bromine. 2. The following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 is hydrogen or formyl group, R_2 is hydrogen or methyl group, R_3 is hydrogen or acetyl group, R_4 is lower alkyl group, R_5 is hydrogen or Cyclic biphenyl ether represented by the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (wherein R_1 to R_5 are as above), which is characterized by catalytic reduction of a compound represented by (representing a methyl group) Method of manufacturing the compound. 3. A compound represented by the following general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. A dienone compound represented by the formula ▲ has mathematical formulas, chemical formulas, tables, etc. ▼ (in the formula, R_4 is as above), and this is reduced with zinc to form the following general formula ▲ mathematical formulas, chemical formulas, tables, etc. ▼ ( The following general formula ▲ is characterized by obtaining a compound represented by the formula (in which R_4 is as described above), subjecting it to catalytic reduction, then acetylating and/or methylating it, and further removing the protecting group if desired. , chemical formulas, tables, etc.
2, at least one of R_3 and R_5 represents a group other than hydrogen).