JPS59225136A - 1-(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its preparation - Google Patents
1-(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its preparationInfo
- Publication number
- JPS59225136A JPS59225136A JP58083748A JP8374883A JPS59225136A JP S59225136 A JPS59225136 A JP S59225136A JP 58083748 A JP58083748 A JP 58083748A JP 8374883 A JP8374883 A JP 8374883A JP S59225136 A JPS59225136 A JP S59225136A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- dihydroxyphenyl
- oxo
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
- C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、医薬およびその中間体として有用な新規1〜
(3,4−ジヒドロキシフェニル)−3−ヒドロキン(
または3−オキソ)アルカンおよびその製造法に関する
。DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel compounds useful as pharmaceuticals and intermediates thereof.
(3,4-dihydroxyphenyl)-3-hydroquine (
or 3-oxo)alkane and its production method.
本発明の化合物は1次の一般式(I)で示される。The compound of the present invention is represented by the following general formula (I).
0■
CH2CH2−Y−R
3乃至15個からなる直鎖状または枝分れしたアルキル
基をそれぞれ意味する。)上記一般式において、Rの意
味する直鎖状のアルキル基としてはたとえば、プロピル
基、ペンチル基、ヘキシル基、オクチル基、ノニル基。0■ CH2CH2-Y-R Each means a linear or branched alkyl group consisting of 3 to 15 members. ) In the above general formula, examples of the linear alkyl group meant by R include a propyl group, a pentyl group, a hexyl group, an octyl group, and a nonyl group.
デシル基、ウンデシル基等である。また、枝分れしたア
ルキル基とは、アルキル基の1位および/またはその他
の部位に炭素数1乃至6個の低級アルキル基を有するも
のであり、たとえば。These include decyl group and undecyl group. Further, a branched alkyl group is one having a lower alkyl group having 1 to 6 carbon atoms at the 1-position and/or other positions of the alkyl group, for example.
1−メチルヘキシル基、1−エチルペンチル基。1-methylhexyl group, 1-ethylpentyl group.
1.5−ジメチルヘキシル基、2,3.5−)リメチル
へフテル基、4−フロビルノニル基、1−ヘキシルヘプ
チル基等を挙げることができる。Examples include 1.5-dimethylhexyl group, 2,3.5-)limethylhephther group, 4-furobylnonyl group, and 1-hexylheptyl group.
Yがヒドロキシメチレン基を意味するとき。When Y means a hydroxymethylene group.
およびRが枝分れしたアルキル基を意味し、枝分れのあ
る炭素原子に異1にるアルキル基が結合するときは、上
記一般式の化合物には不斉炭素原子が存在する。本発明
の目的化合物は、これらの不斉炭素原子にもとづく立体
異性体の分離されたものおよびこれらの混合物を包含す
る。and R means a branched alkyl group, and when a different alkyl group is bonded to a branched carbon atom, an asymmetric carbon atom is present in the compound of the above general formula. The target compounds of the present invention include separated stereoisomers based on these asymmetric carbon atoms and mixtures thereof.
本発明の目的化合物はS RS −A (Slow r
eactingsubstance of anaph
ylaxis )の産生、放出を強力に抑制する。The target compound of the present invention is S RS -A (Slow r
acting substances of anaph
ylaxis) production and release.
ヒトのアレルギー性喘息やその他のアトピー性疾患、あ
るいは動物のアナフィラキシ−ショックにおいて2種々
の化学伝達物質が肺やその他の組織から遊離され、気管
支筋、肺静脈などの平滑筋を収縮したり、皮膚血管の透
過性を充瓶するなどして生体に障害をひきおこすと考え
られてし・る。このような化学伝達物質としてヒスタミ
ンおよび5R3−Aがあげられる。ヒスタミンはモルモ
ットのアナフィキシーショノクにおいては重要な役割を
はたしているが、ヒトアレルギー性喘息にお見・てはあ
まり重要でない(Eiser、 Rharmac、 T
her、、 17. 239 250(1982))。In allergic asthma and other atopic diseases in humans, or in anaphylactic shock in animals, two types of chemical mediators are released from the lungs and other tissues, contracting smooth muscles such as bronchial muscles and pulmonary veins, and contracting smooth muscles in the skin. It is thought that it may cause damage to living organisms by blocking the permeability of blood vessels. Such chemical mediators include histamine and 5R3-A. Histamine plays an important role in guinea pig anaphylaxis, but is less important in human allergic asthma (Eiser, Rharmac, T.
her,, 17. 239 250 (1982)).
一方。on the other hand.
5R8−Aがヒトのアレルギー性喘息において最も重要
な化学伝達物質であることを示唆する多くの証拠かある
( Brocklehurst、 J、 Physio
l、+ 151.416−435 (1960) ;
Au5tenおよびOrange、 Am、 Rev、
Re5p、 Dis、。There is considerable evidence to suggest that 5R8-A is the most important chemical mediator in human allergic asthma (Brocklehurst, J, Physio
l, + 151.416-435 (1960);
Au5ten and Orange, Am, Rev,
Re5p, Dis,.
1.2.423−436(1975) ; Adams
およびLichtenste in+J、 Imrnu
nol、、耳名、 555−562(1979) )。1.2.423-436 (1975); Adams
and Lichtenstein in+J, Imrnu
nol,, Tumina, 555-562 (1979)).
アレルギー性反応の症状を予防し、除去し。Prevent and eliminate symptoms of allergic reactions.
または軽減するための薬剤の開発はかかる化学伝達物質
の産生、放出を遮断、抑制することまたはそ」1らの効
果に拮抗することを目標として行われていた。ヒスタミ
ンの放出を遮断、抑制する薬剤としてはジンジウム り
ロモグリケート(disodium cromogly
cate )が著名であり、ヒスタミンに拮抗する薬剤
としては、多数の抗ヒスタミン剤が市販さねている。一
方、 5R3−Aは、ヒスタミンが速効性で持続時間
が短い化学伝達体であるのに対し、遅効性で持続時間が
長見・化学伝達体として知もねていたが、最近Samu
elssonが構造決定したロイコトリエンC4,D4
およびE4と同一物質であることが明らかにされた。5
R3−A即ちロイコトリエン(Leukotricns
)は多価不飽和脂肪酸(特にアラキドン酸)のりボキ
シゲナーゼによる代謝物であり、前記アレルギー性反応
における化学伝達体としての作用以外に粘液分泌亢進作
用、繊毛運動低下作用、冠血管収縮作用、心収縮力低下
作用等の作用があることが明らかにされている。このよ
うな5R8−Aの産生。The development of drugs to reduce or alleviate the effects of these chemical mediators has been aimed at blocking or suppressing the production and release of such chemical mediators, or antagonizing their effects. An example of a drug that blocks or suppresses the release of histamine is disodium cromoglycate.
cate) is well known, and many antihistamines are commercially available as drugs that antagonize histamine. On the other hand, while histamine is a fast-acting and short-lasting chemical mediator, 5R3-A was known as a slow-acting and long-lasting chemical mediator, but recently Samu
Leukotriene C4, D4 whose structure was determined by Elsson
It was revealed that it is the same substance as E4. 5
R3-A or leukotrienes
) is a metabolite of polyunsaturated fatty acids (especially arachidonic acid) by glue boxygenase, and in addition to acting as a chemical mediator in the allergic reaction, it also has the effect of increasing mucus secretion, decreasing ciliary movement, constricting coronary vessels, and constricting the heart. It has been clarified that it has effects such as force reduction effect. Production of such 5R8-A.
放出を遮断、抑制する薬剤または反対にそれらの効果に
拮抗する薬剤は現在迄わずかの物質しか知られておらず
、現在臨床的には使用されて(・な(・。Until now, only a few substances are known to block or suppress the release or, conversely, to antagonize their effects, and they are not currently in clinical use.
本発明者等は5R3−Aの産生、放出を遮断な(・し抑
制する薬剤またはこれらの効果に拮抗する薬剤の探索を
進めて来た。その結果1本発明化合物(I)が5R8−
Aの産生、放出を極めて強力に抑制し、抗5R8−A剤
として有用であることを見出し2本発明を完成した。The present inventors have been searching for drugs that block (or suppress) the production and release of 5R3-A, or drugs that antagonize these effects. As a result, the present compound (I) has been found to be 5R8-A.
The present invention was completed based on the discovery that the present invention extremely strongly suppresses the production and release of 5R8-A and is useful as an anti-5R8-A agent.
本発明化合物(I)は前述のとおり、 5RS−Aの
産生、放出を極めて強力に遮断ないし抑制いしかも低置
性であるのでS R8−Aに起因する種々のアレルギー
症(例えば気管支喘息、アレルギー性鼻炎、じん麻疹)
や5R3−Aに起因する虚血性疾患、炎症などの予防、
治療に有用である。As mentioned above, the compound (I) of the present invention very strongly blocks or inhibits the production and release of 5RS-A, and is low-lying, so it is effective against various allergic diseases caused by SR8-A (e.g., bronchial asthma, allergies). rhinitis, hives)
Prevention of ischemic diseases, inflammation, etc. caused by 5R3-A,
Useful for treatment.
本発明化合物(■)は、そのままもしくは自体公知の薬
学的に許容さねうる担体、賦形剤などと混合した医薬組
成物C例9錠剤、カプセル剤(ソフトカプセル、マイク
ロカプセルを含む)。The compound of the present invention (■) is used as it is or mixed with a known pharmaceutically acceptable carrier, excipient, etc. to prepare a pharmaceutical composition C Example 9 tablets and capsules (including soft capsules and microcapsules).
散剤、坐剤〕として経口的もしくは非経口的に安全に投
与することができる。投与量は投与対象、投与ルート、
症状などによっても異なるが1通常成人1日当り1〜5
00 mgであり、これを1日2〜3回に分けて経口ま
たは非経口投与する0
本発明の化合物はつぎの反応式で示さJする方法により
製造さfする。It can be safely administered orally or parenterally as a powder or suppository. The dose depends on the subject, route of administration,
It varies depending on the symptoms, etc., but usually 1 to 5 doses per day for adults.
The compound of the present invention is produced by the method shown in the following reaction formula.
OR’
(1)
(式中、R′は還元てより容易に除去さJ″lる水酸基
の保護基を、Y′はヒドロキシメ
チレン基またはカルボニル基を意味
する。また、YおよびRは前記と同
じ意味を示す。OR' (1) (wherein, R' is a hydroxyl protecting group that is more easily removed by reduction, and Y' is a hydroxymethylene group or a carbonyl group. In addition, Y and R are as defined above. indicate the same meaning.
この方法は9式(n)で示さねるI−(3,4−ジ置換
フェニル)−3−ヒドロキシ(または3−オキソ)アル
ケンを還元して対応する 1−(3,4−ジヒドロキシ
フェニル)−3−ヒドロキシ(または3−オキソ)アル
カン(I)を製造するものである。この還元には、(イ
)水酸基の保護基R′の除去、(ロ)不飽和結合の飽和
(ビニ(2HH)への変換が含まれる。こねらの還元は
。This method reduces I-(3,4-disubstituted phenyl)-3-hydroxy (or 3-oxo) alkene shown in formula (n) to the corresponding 1-(3,4-dihydroxyphenyl)- 3-hydroxy (or 3-oxo) alkane (I) is produced. This reduction includes (a) removal of the protecting group R' of the hydroxyl group, and (b) conversion of the unsaturated bond to saturation (viny(2HH)).
任意の順序で行うことができる。また1条件を適宜選択
づ−ることにより2部分的な還元に止める合があること
を考慮して1式中で区別して使用したものである。Can be done in any order. In addition, in consideration of the fact that by appropriately selecting one condition, it may be possible to limit the reduction to only two parts, they are used separately in one formula.
(イ)の水酸基の保護基の除去は、保護基の種類によっ
て異なる。The removal of the hydroxyl protecting group in (a) differs depending on the type of protecting group.
本発明の製造法では、保護基としてベンシル基、p−メ
トキ7ベンジル基、ペンンルオキシ力ルホニル基、メト
キシメチル基、ヘンジイル基等が採用され、その除去は
通常、パラジウム−炭素を触媒とする接触還元または液
体アンモニア中金属すl・リウムによる還元、酸加水分
解ある(・はアルカリ加水分解が採用される。In the production method of the present invention, benzyl group, p-methoxybenzyl group, pennyloxysulfonyl group, methoxymethyl group, hendiyl group, etc. are employed as protective groups, and their removal is usually carried out by catalytic reduction using palladium-carbon as a catalyst. Alternatively, reduction with metal sulfur and lithium in liquid ammonia, acid hydrolysis (. is used for alkaline hydrolysis).
マタは、(ロ)のビニレン(−CH=CH−)のエチレ
ン(−CH2CH2−)への還元は、常法によりパラジ
ウム−炭素、ラネーニッケル2 白金黒等による接触還
元が行わ」する。The reduction of vinylene (-CH=CH-) to ethylene (-CH2CH2-) in (b) is carried out by catalytic reduction using palladium-carbon, Raney nickel 2, platinum black, etc. in a conventional manner.
ミニラムリチウム(LiAlH4)、水素化ホウ素ナト
リウム(Na BH,l)等を用いる化学還元あるいは
バランラム炭素等を用いる接触還元により常法にしたが
って行わ」する。It is carried out according to a conventional method by chemical reduction using minilum lithium (LiAlH4), sodium borohydride (NaBH,l), etc., or catalytic reduction using balanrum carbon, etc.
つぎに2本発明の化合物およびその製造法をさらに説明
するため実施例を掲記するが1本発明はこの実施例に限
定されるものでない。Next, two examples will be described to further explain the compound of the present invention and the method for producing the same, but the present invention is not limited to these examples.
なお、以下の実施例で使用する原料化合物には、新規化
合物も含ま望1て(・るので、その製法を参考例で説明
する。It should be noted that the raw material compounds used in the following examples may include new compounds, so the production method thereof will be explained using reference examples.
参考例 1(a)
油性水素化すトリウム(60%)4QQmgと1.2−
/Jトギンxタン50mZの#、敵にかきまぜながらジ
メチル−(3−メチル−2−オキシ)−へプチルポスホ
ネー)2.36gどジメトキシエタン5 mlの混液を
200〜25°Cで滴下する。滴下後2時間室温でかき
1ぜた後反応液ヲ5°〜7′″Cに冷却し、3,4−ノ
ペンジルオキシベ/ズーγルデヒド23gどゾメドキン
エタン5m4の混液を滴下する。Reference example 1(a) Oily thorium hydrogenation (60%) 4QQmg and 1.2-
/J Togin After the dropwise addition, the reaction mixture was stirred at room temperature for 2 hours, cooled to 5° to 7'''C, and a mixed solution of 23 g of 3,4-nopenzyloxybe/zuldehyde and 5 m4 of dozomedquinethane was added dropwise.
室温で2時間かき捷ぜた後5反応液に水300mLを加
えトルエン−n−ヘキサノ(1:1.)50+T+Zで
抽出し、水洗後、硫酸マグネシウムで乾燥後減圧濃縮し
てアメ状物を得る。ノリ力ゲル(70mZ使用)カラム
クロマトグラフィーに付し、n−ヘキサノ−エーテル(
4:1)で溶出し、1−(3,4−ジベンジルオキ7フ
エニル)−4−メチル−1−オクテン−3−オン1,2
gを得た。融点62〜64゜1 (b) ((実施例
1の原料))水素化リチウムアルミニウム01gをエー
テル20m1に加えた混液に水冷下1−(3,4−7ペ
ンンルオキシフエニル)−1−オクテン−3オン0.5
5 gを加え、室温で1時間攪拌する。反応液に10%
HC]10m1を徐々に加えた後エーテル層を分取、水
洗後減圧濃縮して固形物を得る。エーテル−〇−ヘキサ
ン(1:3)混液で洗って]、−(,3,4−ジベンジ
ルオキシフェニル)−4−メチル−1−オクテン−3−
オール0,4gを得た。融点77〜78°C0つきの参
考例2(a)および2(b)の化合物を、参考例1(a
)および1(b)と同様にして、1だ、参考例3〜7の
化合物を参考例1(a)と同様にして得た。After stirring at room temperature for 2 hours, add 300 mL of water to the reaction solution and extract with toluene-n-hexano (1:1) 50 + T + Z. After washing with water, dry over magnesium sulfate and concentrate under reduced pressure to obtain a candy-like substance. . It was subjected to column chromatography using Noriyoku gel (using 70 mZ), and n-hexano-ether (
4:1), 1-(3,4-dibenzylox7phenyl)-4-methyl-1-octen-3-one 1,2
I got g. Melting point 62-64゜1 (b) ((Example
1 raw material)) Add 0.5 g of 1-(3,4-7pennyloxyphenyl)-1-octen-3one to a mixture of 01 g of lithium aluminum hydride and 20 ml of ether while cooling with water.
Add 5 g and stir at room temperature for 1 hour. 10% to reaction solution
After gradually adding 10 ml of HC], the ether layer was separated, washed with water, and concentrated under reduced pressure to obtain a solid. Wash with ether-〇-hexane (1:3) mixture], -(,3,4-dibenzyloxyphenyl)-4-methyl-1-octene-3-
0.4 g of oar was obtained. The compounds of Reference Examples 2(a) and 2(b) with a melting point of 77 to 78°C were added to Reference Example 1(a).
) and 1(b), and 1. Compounds of Reference Examples 3 to 7 were obtained in the same manner as Reference Example 1(a).
参考例 2(a)((実施例3の原料))1−(3,4
−7ペンンルオキシフエニル)−1−ノイ・ノー:3−
オン 融点78〜80°C6元素分析値(C29H32
o、として)6% H%
理論値 81,27 7.53
実験値 81.21 7.65
参考例 2(b)((実施例2の原料))]−(3,4
−7ペン・/ルオキシフェニル)−1−ノネン−3−オ
ール 融点90〜92°Cc参考例 3 ((実施例4
の原料))
1 − (3,4−7ペンジルオキシフエニル) −
1,−ヘンタデセン−3−オン 融点81〜82゜
元素分析値) C35H1403として)6% H%
理論値 81,99 8.65
実験値 81,78 8.81
参考例 4((実施例5の原料)
]−(3,4−ジベンジルオキシフェニル)−4−エチ
ル−J−オクテン−3−オン 油状物核磁気共鳴スペ
クトル(CDC13中、TMS内部標阜+ppm)0.
86(6H)、1.1〜1.9(8H)、2.65(I
H)、5.15(4H)、6./I〜7.6(15H)
参考例 5((実施例6の原料))
1−(3,4−7ペンシルオキシフエニル)−1=ヘキ
セン−3−オン
融点 82〜84”C
元素分析値(C26H□。Olとして)0% H%
理論値 80,80 6.78
実験値 80,80 6.81
参考例6((実施例7の原料))
1−(3,4−ジベンジルオキシフェニル)−1−オク
テンー′3−オン
融点 71〜73°C
元素分析値(C28H31) Osとして)0%
H%
理論値 81,13 7.29
実験値 80,91 7.47
参考例 7 ((実施例8の原料))
3−(3,4−ジベンジルオキシフェニル)−1−デセ
ン−3−オン
融点 73〜75℃
元素分析値(C30H3403として)0% H%
理論値 81,41 7.74
実験値 81,26 7.97
なお、上記参考例で使用した。ジメチル(2−オキシ)
アルキルホスホネートの性状および調製法を以下に記す
。Reference example 2(a) ((raw material of Example 3)) 1-(3,4
-7 pennyloxyphenyl)-1-neu no:3-
On Melting point 78~80°C6 elemental analysis value (C29H32
o) 6% H% Theoretical value 81,27 7.53 Experimental value 81.21 7.65 Reference example 2(b) ((raw material of Example 2))] - (3,4
-7pen/ruoxyphenyl)-1-nonen-3-ol Melting point 90-92°Cc Reference example 3 ((Example 4
raw material)) 1 - (3,4-7penzyloxyphenyl) -
1,-Hentadecen-3-one Melting point 81-82゜Elemental analysis value) As C35H1403) 6% H% Theoretical value 81,99 8.65 Experimental value 81,78 8.81 Reference example 4 ((Raw material of Example 5) ]-(3,4-dibenzyloxyphenyl)-4-ethyl-J-octen-3-one Oil nuclear magnetic resonance spectrum (in CDC13, TMS internal standard + ppm) 0.
86 (6H), 1.1-1.9 (8H), 2.65 (I
H), 5.15 (4H), 6. /I~7.6 (15H) Reference example 5 ((raw material of Example 6)) 1-(3,4-7pencyloxyphenyl)-1=hexen-3-one Melting point 82~84''C Elemental analysis Value (as C26H□.Ol) 0% H% Theoretical value 80,80 6.78 Experimental value 80,80 6.81 Reference example 6 ((raw material of Example 7)) 1-(3,4-dibenzyloxy Phenyl)-1-octen-'3-one Melting point 71-73°C Elemental analysis value (C28H31) (as Os) 0%
H% Theoretical value 81,13 7.29 Experimental value 80,91 7.47 Reference example 7 ((raw material of Example 8)) 3-(3,4-dibenzyloxyphenyl)-1-decen-3-one Melting point 73-75°C Elemental analysis value (as C30H3403) 0% H% Theoretical value 81,41 7.74 Experimental value 81,26 7.97 Used in the above reference example. dimethyl(2-oxy)
The properties and preparation method of the alkylphosphonate are described below.
111
(CH30)2PCH2CCH2CH2CH1/メチル
メチルポスホネート12.75 gを65m1の無水テ
トラヒドロフランに溶解し、−70℃以下に冷却する。12.75 g of 111 (CH30)2PCH2CCH2CH2CH1/methyl methyl phosphonate are dissolved in 65 ml of anhydrous tetrahydrofuran and cooled to below -70°C.
窒素気流下かきまぜながら一70℃以下に冷却したn−
ブチルリチウムのへキザノ溶液(10v/′w%)67
mtを30分間で滴下し、同温度で15分間かき1せる
。次に一70°C以下に冷却したエチルn−ブチレート
5.8gの無水テトラヒドロフラン(20n+t)溶6
)j、を15分間で滴下し、同温度で15時間かき呼ぜ
、更に室温で2時間かき寸ぜる。反応液を氷冷し氷酢酸
10+++tを加えた混液を減圧上溶媒を留去したのち
、水50mtを加え。n- cooled to below -70°C while stirring under a nitrogen stream
Butyl lithium hexano solution (10v/'w%) 67
mt was added dropwise over 30 minutes and stirred at the same temperature for 15 minutes. Next, a solution of 5.8 g of ethyl n-butyrate in anhydrous tetrahydrofuran (20n+t) cooled to below -70°C 6
)j was added dropwise over 15 minutes, stirred at the same temperature for 15 hours, and further stirred at room temperature for 2 hours. The reaction solution was ice-cooled and 10++t of glacial acetic acid was added to the mixture, the solvent was distilled off under reduced pressure, and 50mt of water was added.
エチルエーテル50mtで3回抽出する。抽出液を合し
飽和食塩水20mZで2回洗ったのち、無水硫酸マグネ
/ラム乾燥後、溶媒を成田留去した残留物ヲ真空蒸留し
て/メチルー(2−オキシ)−ペンチルポスボネート9
7gを得た。Extract 3 times with 50 mt of ethyl ether. The extracts were combined and washed twice with 20 mZ of saturated saline. After drying with anhydrous magnesium sulfate/rum, the solvent was distilled off in Narita, and the residue was vacuum distilled/methyl-(2-oxy)-pentylposbonate 9.
7g was obtained.
沸点 95−97°C/ 0.9 mmmm1(法と同
様にして下式のホスボネ−1・化合物を調製した。Boiling point: 95-97°C/0.9 mmmm1 (Phosbone-1 compound of the following formula was prepared in the same manner as the method.
B法
ンメチルメチルホスホネート2.5gと15mZの無水
テトラヒドロフランの混液を一70″C以下に冷却し、
窒素気流下にかき寸ぜながら一70℃以下に冷却したn
−ブチルリチウムのヘキサン溶液(10v/W%) 1
3.5 mlを30分間で滴T L 、 同温度で1
5分間かきまぜる。エチルトリデカノエート2./I
g ト無水テトラヒドロフラン5mZの混然を10分間
でW&i下し、−70°C以下で1時間かきまぜ。Method B A mixture of 2.5 g of methyl methyl phosphonate and 15 mZ of anhydrous tetrahydrofuran was cooled to below -70"C,
Cooled to below -70°C while stirring under a stream of nitrogen.
-Butyllithium hexane solution (10v/W%) 1
Drop 3.5 ml in 30 minutes T L , 1 at the same temperature
Stir for 5 minutes. Ethyl tridecanoate 2. /I
g. Mix 5mZ of anhydrous tetrahydrofuran with W&I for 10 minutes, and stir at -70°C or less for 1 hour.
更に室温で2時間かき捷ぜる。Stir for another 2 hours at room temperature.
反応/佼を氷冷し氷酢酸2mlを加えた混液を減lf儂
縮し、エチルエーテル10m1で3回抽出する。The reaction mixture was cooled on ice, 2 ml of glacial acetic acid was added, the mixture was reduced in lf, and extracted three times with 10 ml of ethyl ether.
抽出液を飽和食塩水で洗い、無水硫酸マグネシウムで乾
燥し減圧濃縮して得られる油状物をシリカゲル(40m
l使用)カラムクロマトグラフィーにイ」シ、エチルエ
ーテルで溶出し、7メチル=(2−オキシ)−テトラデ
カノイルホスボネート2.5gを得た。The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
The mixture was subjected to column chromatography (using 1) and eluted with ethyl ether to obtain 2.5 g of 7methyl (2-oxy)-tetradecanoyl phosphonate.
融点 37〜38°C
実施例 1
1、−(3,4−ジベンジルオキシフェニル)−4−メ
チル−1−オクテン−3−オール0.4gをエタノール
20m1K溶解し、 10%パラジウム炭素C1,1
gを触媒として水素を吸収しな(なるまで接触還元する
。Melting point 37-38°C Example 1 0.4 g of 1,-(3,4-dibenzyloxyphenyl)-4-methyl-1-octen-3-ol was dissolved in 20 ml of 1K of ethanol, and 10% palladium on carbon C1,1
Catalytic reduction is performed until hydrogen is absorbed using g as a catalyst.
反応終了後、触媒を戸別し、P液を減圧濃縮して1−(
3,4−)ヒドロキンフェニル)−4−メチル−3−オ
クタツール0.23gを得た。After the reaction is completed, the catalyst is separated and the P solution is concentrated under reduced pressure to obtain 1-(
0.23 g of 3,4-)hydroquinphenyl)-4-methyl-3-octatool was obtained.
核磁気共鳴スペクトル(CDCl2中、TMS内部標準
1ppm)07〜1.8(15H)、 2.57(2T
()、 3.45(IH)、 6.4〜6.8(3H)
実施例2
] −(3,4−ジベンジルオキシフェニル)−1−ノ
ネン−3−オール0.85gを実施例1と同様に処理し
てl −(3,11−ジヒドロキシフェニル)−:3−
ノナノール04gを得た。Nuclear magnetic resonance spectra (in CDCl2, TMS internal standard 1 ppm) 07-1.8 (15H), 2.57 (2T
(), 3.45 (IH), 6.4-6.8 (3H)
Example 2 ] 0.85 g of -(3,4-dibenzyloxyphenyl)-1-nonen-3-ol was treated in the same manner as in Example 1 to obtain l -(3,11-dihydroxyphenyl)-:3-
04g of nonanol was obtained.
核磁気共鳴スペクトル(CDCl2中、TMS内部標準
+ppm)08〜1.9 (15H)、 2.55(2
H)、 3.60(IH)、 6.4〜6.8(3H)
実施例3
]−(3,4−ジベンジルオキシフェニル)−1−ノネ
ン−3−オン0.5gをエタノール10mtと酢酸エチ
ルIOmtの混液中10%パラジウム炭素0.2gを触
媒として水素の吸収が止むまで接触還元する。触媒を戸
別を減圧濃縮して得られる残留物をシリカゲルカラムク
ロマトグラフィーに伺し。Nuclear magnetic resonance spectra (in CDCl2, TMS internal standard + ppm) 08-1.9 (15H), 2.55 (2
H), 3.60 (IH), 6.4-6.8 (3H)
Example 3] -(3,4-dibenzyloxyphenyl)-1-nonen-3-one (0.5 g) was added to a mixture of 10 mt of ethanol and ethyl acetate (IOmt) using 0.2 g of 10% palladium on carbon as a catalyst to absorb hydrogen. Contact reduction until it stops. The catalyst was concentrated under reduced pressure one by one, and the resulting residue was subjected to silica gel column chromatography.
トルエン−酢酸エチル(10:1)で溶出し 1− (
3゜4−ジヒドロキシフェニル)−3−ノナノンの白色
結晶0.2gを得る。融点50〜53℃元素分析値(C
l5H2203として)0% H%
理論値 71,97 8.86
実験値 71,66 8.77
実施例4
l−(3,4−ジベンジルオキシフェニル)−1−ベン
タテセン−3−オン15gを酢酸エチル30m1とエタ
ノール5 mlに溶解し10%パラジウム炭素を触媒と
して水素の吸収が止むまで接触還元する。触媒を戸別、
P液を減圧濃縮して得られる残留物をシリカゲル(80
ml)カラムクロマトグラフィーに付し、トルエン−酢
酸エチル(10:])で溶出し、先に出てくる溶出物と
して] −(3,4−ジヒドロキシフェニル)−3−ペ
ンタデカノンの白色結晶055gを得る。融点67〜6
8℃
元素分析値(C21H340sとして)0% H
%
理論値 75.41 10.2.4実験値
7512 10.38
]−(3,4−ジヒドロキシフェニル)−3−ペンタデ
カノンが溶出し終った後、酢酸エチルで溶出し、]−(
]3.4−ジヒドロキシフェニル−3−ペンタデカノー
ルの白色結晶01gを得る。Elute with toluene-ethyl acetate (10:1) 1-(
0.2 g of white crystals of 3°4-dihydroxyphenyl)-3-nonanone are obtained. Melting point 50-53℃ Elemental analysis value (C
15H2203) 0% H% Theoretical value 71,97 8.86 Experimental value 71,66 8.77 Example 4 15 g of l-(3,4-dibenzyloxyphenyl)-1-bentatecen-3-one was dissolved in ethyl acetate. The solution was dissolved in 30 ml of ethanol and 5 ml of ethanol, and catalytically reduced using 10% palladium on carbon as a catalyst until hydrogen absorption stopped. Catalyst door to door,
The residue obtained by concentrating the P solution under reduced pressure was immersed in silica gel (80%
ml) column chromatography and elution with toluene-ethyl acetate (10:]) to obtain 055 g of white crystals of -(3,4-dihydroxyphenyl)-3-pentadecanone as the first eluate. . Melting point 67-6
8℃ Elemental analysis value (as C21H340s) 0% H
% Theoretical value 75.41 10.2.4 Experimental value
7512 10.38 After elution of ]-(3,4-dihydroxyphenyl)-3-pentadecanone was completed, elution was performed with ethyl acetate, and ]-(
] 01 g of white crystals of 3.4-dihydroxyphenyl-3-pentadecanol are obtained.
融点63〜64℃
元素分析値(C21H3603として)0% 11
%
理論値 74.95 10.78
実験値 7488 10.8]
実施例4と同様にして実施例5〜8の化合物を得プこ。Melting point 63-64℃ Elemental analysis value (as C21H3603) 0% 11
% Theoretical value 74.95 10.78 Experimental value 7488 10.8] Compounds of Examples 5 to 8 were obtained in the same manner as in Example 4.
実施例5
H
] −(3,4−ジヒドロキ7フエニル)−4−エチル
−3−オクタノン fill状物核磁気
共鳴スペクトル(CDCl2中、TMS内部標準+
pp”)06〜1.8 (14I()、 2.3 (I
H)、 2.67(4H)、 6.4〜68(3H)T
J
]−(3,4−ジヒロキ7フエニル)−4−エチル−3
−オクタツール ?白状物核磁気共鳴
スペクトル(CDC13中、TMS内部標準I PP
m)0.85 (6H)、 1..1〜L9 (17H
)、 2.67(2H)、 3.63(IH)。Example 5 H ] -(3,4-dihydroxy7phenyl)-4-ethyl-3-octanone fill nuclear magnetic resonance spectrum (in CDCl2, TMS internal standard +
pp”) 06-1.8 (14I(), 2.3 (I
H), 2.67 (4H), 6.4-68 (3H)T
J]-(3,4-dihyloki7phenyl)-4-ethyl-3
-Octatool? White matter nuclear magnetic resonance spectrum (in CDC13, TMS internal standard I PP
m) 0.85 (6H), 1. .. 1~L9 (17H
), 2.67 (2H), 3.63 (IH).
64〜5.7(3H)
実施例6
TJ
1− (3,4−ジヒドロキシフェニル)−3−ヘキサ
ノン
融点37〜39°C
元素分析値(Cl2HI603として)0%
H%
理論値 6921 7.7/1
実験値 68,94 7.91
1−(3,4−ジヒドロキシフェニル)−3−ヘキサノ
ール 、 油状物核磁気共鳴ス
ペクトル(CDCl2中、TMS内部標準、pp”)0
.9 (3H)、 t]〜1.9 (6H)、 2.6
(2H)、 3.65(]IH。64-5.7 (3H) Example 6 TJ 1-(3,4-dihydroxyphenyl)-3-hexanone Melting point 37-39°C Elemental analysis value (as Cl2HI603) 0%
H% Theoretical value 6921 7.7/1 Experimental value 68,94 7.91 1-(3,4-dihydroxyphenyl)-3-hexanol, oil nuclear magnetic resonance spectrum (in CDCl2, TMS internal standard, pp") 0
.. 9 (3H), t] ~ 1.9 (6H), 2.6
(2H), 3.65(]IH.
65〜6.9(3T()
実施例 7
TJ
1−(3,/l−ジヒドロキシフェニル)−3−オクタ
ノン
融点 53〜55°C
元素分析値(Cl4H2003として)0% H%
理論値 71.16 853
実験値 70,87 8.74
1−(3,4−ジヒドロキシフェニル)−3−オクタツ
ール ンI11状物核磁気
共鳴スペクトル(CDC13中、TMS内音IX才票準
+ ppm)0.9 (3H)、 1.1〜1.9
(IOH)、 2.6 (28)、 3.65(IH)
。65-6.9 (3T() Example 7 TJ 1-(3,/l-dihydroxyphenyl)-3-octanone Melting point 53-55°C Elemental analysis value (as Cl4H2003) 0% H% Theoretical value 71.16 0.9 3H), 1.1-1.9
(IOH), 2.6 (28), 3.65 (IH)
.
65〜6.9 (’3H)
実施例 8
i1
+−(3+4−ジヒドロキシフェニル)−3−デカノン
融点65〜66°C
元素分析値(CI 6 H24o3として)6%
H%
理論値 7269 9.15
実験値 72./12 9.48
]−(3,4−ジヒドロキシフェニル)−3−デカノー
ル 油状物核磁気共鳴ス
ペクトル(CDCI3中、TMS内部標準1 ppm
)0.9 r3H)、 1.1〜1.9 (14H)、
2.6 (2H)、 3.65(IH)。65-6.9 ('3H) Example 8 i1 +-(3+4-dihydroxyphenyl)-3-decanone Melting point 65-66°C Elemental analysis value (as CI 6 H24o3) 6%
H% Theoretical value 7269 9.15 Experimental value 72. /12 9.48]-(3,4-dihydroxyphenyl)-3-decanol Oil nuclear magnetic resonance spectrum (in CDCI3, TMS internal standard 1 ppm
)0.9 r3H), 1.1~1.9 (14H),
2.6 (2H), 3.65 (IH).
65〜6.9(3H)
特許出願人 山之内製薬株式会社
代理人(8920)長井省三
手 続 補 正 書 く自発)
昭和58年9月、30日
l 事件の表示
昭和58年特許願第83748号
2 発明の名称
]−(3,4−ジヒドロキシフェニル)−3−ヒドキシ
(または3−オキソ)アルカンおよびその製造法3 補
正をする者
事件との関係 特許出願人
住 所 東京都中央区日本橋本町2丁目5番地J名
称 (667) 山之内製薬株式会社代表者 森
岡 茂 夫
4代理人
住 所 東京都板橋区小豆沢1丁目1番8号6 補正
の対象
明細書の「発明の詳細な説明」の欄
7 補正の内容
(1) 明細書第27真下から3行の[65〜6.9
(3H)jに続けて行を改めて、つぎの実施例9〜12
を加入する。65-6.9 (3H) Patent Applicant Yamanouchi Pharmaceutical Co., Ltd. Agent (8920) Shozo Nagai Proceedings Amendment Written Spontaneous) September 30th, 1981 Indication of Case 1988 Patent Application No. 83748 No. 2 Title of the invention] -(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its manufacturing method 3 Relationship with the case of the person making the amendment Patent applicant address Nihonbashi Honmachi, Chuo-ku, Tokyo 2-5 J Name
Name (667) Yamanouchi Pharmaceutical Co., Ltd. Representative Shigeo Morioka 4 Agent Address 1-8-6 Azukizawa 1-chome, Itabashi-ku, Tokyo Column 7 of “Detailed Description of the Invention” of the specification to be amended Contents of the amendment (1) Three lines from the bottom of No. 27 of the specification [65 to 6.9
(3H) Following j, change the line and write the following Examples 9 to 12.
join.
(2)同第10頁4行の「または1」を「また、」に訂
正する。(2) Correct "or 1" in line 4 on page 10 to "also".
「実施例1と同様に処理して以下の実施例9〜IIの化
合物を得た。"The following compounds of Examples 9 to II were obtained by treatment in the same manner as in Example 1.
実施例 9
i1
H
1−(3,4−ジヒドロキノフェニル)−3−ウ/テカ
/−ル。融点45〜47°c0
元素分析値(Cl1H2JO:lとして)6% 1
1%
理論値 72.82 10.06
実験値 72.76 10.29
実施例 Jo
H
δH
■−(3,4−;ヒ1−rJキノフェニル)−3−+・
デカノール。 融点53〜55°C0
元素分析値(C19H3L+03として)C%
H%
理論値 73.43 10.27
3
実験値 日、48 10.47
実施例 11
H
I C3+4 ;ヒドロキノフェニル)−4−メチ
ル−3−7ナノール。油状物。Example 9 i1 H 1-(3,4-dihydroquinophenyl)-3-u/tekar/-. Melting point 45-47°c0 Elemental analysis value (as Cl1H2JO:l) 6% 1
1% Theoretical value 72.82 10.06 Experimental value 72.76 10.29 Example Jo H δH ■-(3,4-;H1-rJquinophenyl)-3-+・
Decanol. Melting point 53-55°C0 Elemental analysis value (as C19H3L+03) C%
H% Theoretical 73.43 10.27 3 Experimental Days, 48 10.47 Example 11 H I C3+4 ; Hydroquinophenyl)-4-methyl-3-7 nanol. Oily substance.
核磁気共鳴スペクトル(CDCl2中、 TMS内部標
準ppm)07〜1..9(16H) 、2.58(2
H) 、3.55(IH) 、6.5〜5.9(3H)
実施例3と同様に処理して以下の実施例 12の化合物
を得た。Nuclear magnetic resonance spectra (in CDCl2, TMS internal standard ppm) 07-1. .. 9 (16H), 2.58 (2
H), 3.55 (IH), 6.5-5.9 (3H)
The following compound of Example 12 was obtained by treatment in the same manner as in Example 3.
実施例 12
H
CH3CH2CCH(CH2)3 CH3CH3
I−(3,4−;・ヒI・ロキ/フェニ・し)−7+−
メチル−3−オク、タノン。油状物。Example 12 H CH3CH2CCH(CH2)3 CH3CH3 I-(3,4-;・hiI・loki/feni・shi)−7+−
Methyl-3-oc, thanone. Oily substance.
核磁気共鳴スヘクトノL(CDC13中、 TMS内部
標準。Nuclear magnetic resonance spectrum (in CDC13, TMS internal standard.
ppm)
06〜]、8(12H) 、2.5(IH) 、2.7
4(4H) 、6.4〜6.8 (3H)」ppm) 06~], 8 (12H), 2.5 (IH), 2.7
4 (4H), 6.4-6.8 (3H)”
Claims (2)
を、Rは炭素数3乃至15 個からなる直鎖状または枝分れした アルキル基を意味する。) で示される1−(3,4−ジヒドロキシフェニル)−3
−ヒドロキシ(または3−オキソ)アルカン(1) General formula % Formula % (In the formula, Y represents a hydroxymethylene group or a carbonyl group, and R represents a linear or branched alkyl group having 3 to 15 carbon atoms.) 1-(3,4-dihydroxyphenyl)-3
-Hydroxy (or 3-oxo)alkane
護基を、Y′はヒドロキシメ チレン基またはカルボニル基を、R は炭素数3乃至15からなる直鎖状ま たは枝分れしたアルキル基を意味する。)で示される1
−(3,4−ジ置換フェニル)−3−ヒドロキシ(また
は3−オキソ)アルケンを還元することおよび水酸基の
保護基R′力\残存1−るときは、これを除去すること
を特徴とする一般式%式% (式中、Yはヒドロキシメチレン基またはカルボニル基
を意味し、Rは上記と同 じ) で示される1−(3,4−ジヒドロキシフエニル)−3
−ヒドロキシ(または3−オキソ)アルカンの製造法(2) General formula % Formula % (In the formula, R' is a hydroxyl protecting group that is easily removed by reduction, Y' is a hydroxymethylene group or carbonyl group, and R is a straight chain consisting of 3 to 15 carbon atoms. (means a branched or branched alkyl group)
-(3,4-disubstituted phenyl)-3-hydroxy (or 3-oxo)alkene and removing the protective group R' of the hydroxyl group, if any, is present. 1-(3,4-dihydroxyphenyl)-3 represented by the general formula % formula % (wherein, Y means a hydroxymethylene group or a carbonyl group, and R is the same as above)
-Production method of hydroxy (or 3-oxo) alkanes
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58083748A JPS59225136A (en) | 1983-05-13 | 1983-05-13 | 1-(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its preparation |
CA000453422A CA1246610A (en) | 1983-05-02 | 1984-05-02 | Process of producing catechol derivatives |
SU843743757A SU1424729A3 (en) | 1983-05-13 | 1984-05-11 | Method of producing catechine derivatives |
KR1019840002568A KR840009283A (en) | 1983-05-13 | 1984-05-11 | Method for preparing catechol derivatives |
US06/609,144 US4618627A (en) | 1983-05-13 | 1984-05-11 | Catechol derivatives and pharmaceutical compositions thereof for inhibiting anaphylaxis (SRS-A) |
ES532455A ES8505914A1 (en) | 1983-05-13 | 1984-05-11 | Catechol derivatives, their production and intermediates therefor, and pharmaceutical compositions containing them. |
EP84303257A EP0125919A3 (en) | 1983-05-13 | 1984-05-14 | Catechol derivatives, their production and intermediates therefor, and pharmaceutical compositions containing them |
PH30698A PH19356A (en) | 1983-05-13 | 1984-05-18 | Catechol derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP58083748A JPS59225136A (en) | 1983-05-13 | 1983-05-13 | 1-(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its preparation |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS59225136A true JPS59225136A (en) | 1984-12-18 |
Family
ID=13811146
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP58083748A Pending JPS59225136A (en) | 1983-05-02 | 1983-05-13 | 1-(3,4-dihydroxyphenyl)-3-hydroxy (or 3-oxo) alkane and its preparation |
Country Status (2)
Country | Link |
---|---|
JP (1) | JPS59225136A (en) |
KR (1) | KR840009283A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01224342A (en) * | 1988-03-02 | 1989-09-07 | Terumo Corp | Catechol derivative and medical pharmaceutical containing said derivative |
WO1989008093A1 (en) * | 1988-03-02 | 1989-09-08 | Terumo Kabushiki Kaisha | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
-
1983
- 1983-05-13 JP JP58083748A patent/JPS59225136A/en active Pending
-
1984
- 1984-05-11 KR KR1019840002568A patent/KR840009283A/en not_active Application Discontinuation
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH01224342A (en) * | 1988-03-02 | 1989-09-07 | Terumo Corp | Catechol derivative and medical pharmaceutical containing said derivative |
WO1989008093A1 (en) * | 1988-03-02 | 1989-09-08 | Terumo Kabushiki Kaisha | Catechol compounds, process for their preparation and pharmaceutical preparation containing same |
Also Published As
Publication number | Publication date |
---|---|
KR840009283A (en) | 1984-12-26 |
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