JPH02250899A - Production of muramyl-tripeptide derivative - Google Patents
Production of muramyl-tripeptide derivativeInfo
- Publication number
- JPH02250899A JPH02250899A JP7013489A JP7013489A JPH02250899A JP H02250899 A JPH02250899 A JP H02250899A JP 7013489 A JP7013489 A JP 7013489A JP 7013489 A JP7013489 A JP 7013489A JP H02250899 A JPH02250899 A JP H02250899A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- reacting
- group
- benzyl
- 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.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 claims abstract description 9
- 150000003512 tertiary amines Chemical class 0.000 claims abstract description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000001118 alkylidene group Chemical group 0.000 claims abstract description 3
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 claims abstract 3
- 125000001424 substituent group Chemical group 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- -1 (substituted) benzyl Chemical group 0.000 abstract description 2
- 239000002671 adjuvant Substances 0.000 abstract 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 125000006307 alkoxy benzyl group Chemical group 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- YGOAYNVRTAEAAI-GKZUZGRISA-N (2R)-2-[(3R,4R,5S,6R)-2-acetyl-3-amino-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoic acid Chemical compound C(C)(=O)C1(O)[C@H](N)[C@@H](O[C@@H](C(=O)O)C)[C@H](O)[C@H](O1)CO YGOAYNVRTAEAAI-GKZUZGRISA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 108700018454 CDC15 Proteins 0.000 description 1
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010040880 Skin irritation Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 101150081467 cdc15 gene Proteins 0.000 description 1
- 229940126179 compound 72 Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 206010024378 leukocytosis Diseases 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- JKRHDMPWBFBQDZ-UHFFFAOYSA-N n'-hexylmethanediimine Chemical compound CCCCCCN=C=N JKRHDMPWBFBQDZ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000036556 skin irritation Effects 0.000 description 1
- 231100000475 skin irritation Toxicity 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
Landscapes
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
本発明は、式（Ｉ）
は前記に同じ）
でホ
（式中、Ａｌａはアラニン残基を、 ｎはｌＯ〜２０の
整数を、Ｒ３は低級アルキル基又は置換基を有すること
もあるベンジル基を意味する）で示される化合物と反応
させることを特徴とする式（ｒＶ）（式中％ ＦＩＺは
ｒｌ置換基有することもあるベンジル基を、Ｒ２は低級
アルキリデン基又は置換基を有することもあるベンジリ
デン基を意味する）で示される化合物を三級アミンの存
在下Ｎ、Ｎ′−ジスクシンィミジルカルボナートと反応
させて式（ＩＩ）（式中、Ｒ１及びＲ２は前記に同じ）
で示される化合物を製し、次いで、これを式（ＩＩＩ）
（式中、Ｒ１，Ｒ２，Ｒ３，Ａｌａ及びｎは前記に同じ
）で示される化合物の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the formula (I) (wherein Ala is an alanine residue, n is an integer of 10 to 20, and R3 is a lower alkyl group or a substituent) R2 is a lower alkylidene group or A compound represented by the formula (II) (in which R1 and R2 is the same as above)
A compound represented by formula (III) is prepared and then converted into formula (III)
(wherein R1, R2, R3, Ala and n are the same as above).
〈産業上の利用分野〉
本発明は、優れたアジュバント効果、感染防御効果及び
白血球増多作用を有する式（Ｖ）（Ｎ）
（Ｖ）
（式中、 Ａｌａ及びｎは前記に同じ）で示される化合
物（特公昭６２−２７０７９号公報参照）の製造中間体
とし・て重要な式（ＩＶ）の化合物の工業的製造法とし
て有用なものである。<Industrial Application Field> The present invention provides a compound represented by the formula (V) (N) (V) (wherein Ala and n are the same as above) that has an excellent adjuvant effect, infection prevention effect, and white blood cell increase effect. It is useful as an intermediate for the production of a compound of formula (IV) (see Japanese Patent Publication No. 62-27079) and as an industrial process for the production of the compound of formula (IV).
〈従来の技術〉
式（ｒＶ）の化合物の製造法としては、式（Ｉ）の化合
物をジシクロへキシルカルボジイミドと反応させて対応
する活性エステルを製し、次いで、これを式（１１１）
の化合物と反応させる方法が知られτ゛いる（特開昭５
８−１７２３９９号公報）、シかしながら、本製造法は
、（１）使用するジシクロへキシルカルボジイミドが皮
膚刺激性を有する、（２）副生ずるＮ。トジシクロへキ
シルウレアの除去が困難であり、生成物中に混入すると
いう問題点があった。<Prior art> As a method for producing a compound of formula (rV), a compound of formula (I) is reacted with dicyclohexylcarbodiimide to produce a corresponding active ester, which is then converted into a compound of formula (111).
There is a known method of reacting with the compound of
8-172399), however, the present production method is characterized in that (1) dicyclohexylcarbodiimide used has skin irritation, and (2) N is produced as a by-product. There was a problem in that it was difficult to remove dicyclohexylurea and it was mixed into the product.
〈発明が解決しようとする問題点〉
本発明者等は上記問題点を解決すべく鋭意検討ｌノた結
果、本発明を完成した。<Problems to be Solved by the Invention> The present inventors have completed the present invention as a result of intensive studies to solve the above problems.
〈発明の構成〉
本発明は、式（１）の化合物を三級アミンの存在下、Ｎ
、Ｎ−ジスクシンイミジルヵルボナート（以下、ＤＳＣ
と称す）と反応させて式（ＩＩ ）の化合物を製し、次
いでこれを式（ｒｎ ）の化合物と反応させることから
なる式（ＩＶ）の化合物の製造法に関する。<Structure of the Invention> The present invention provides the compound of formula (1) in the presence of a tertiary amine,
, N-disuccinimidyl carbonate (hereinafter referred to as DSC)
A process for preparing a compound of formula (IV), which comprises reacting with a compound of formula (rn) to prepare a compound of formula (II), which is then reacted with a compound of formula (rn).
式（ＩＶ）において、置換基を有することもあるベンジ
ル基としては、４−ニトロベンジル基、４−低級アルコ
キシベンジル基等を、又、置換基を有することもあるベ
ンジリデン基としては、４−ニトロベンジリデン基、４
−低級アルコキシベンジリデン基等をあげることができ
る。In formula (IV), examples of the benzyl group which may have a substituent include 4-nitrobenzyl group and 4-lower alkoxybenzyl group, and examples of the benzylidene group which may have a substituent include 4-nitrobenzyl group, 4-lower alkoxybenzyl group, etc. benzylidene group, 4
-Lower alkoxybenzylidene groups, etc. can be mentioned.
次に、本発明の詳細な説明する。Next, the present invention will be explained in detail.
式（Ｉ）の化合物を三級アミンの存在下ＤＳＣと反応さ
せることにより式（＋＋ ）の化合物を製造することが
できる。前記三級アミンとしては、トリエチルアミン、
Ｎ−メチルモルホリン、４−ジメチルアミノピリジン等
を、好ましくは４−ジメチルアミノピリジンをあげるこ
とができる。該アミンの使用量は、触媒量（通常、式（
Ｈの化合物に対し１／ｌｏ 〜１／１００倍モル）程度
でよい、又、ＤＳＣは式（Ｉ）の化合物に対し、通常１
．０〜１．５倍モル量使用される０反応溶媒としては、
ジクロロメタン、クロロホルム、１．４−ジオキサン、
テトラヒドロフラン、ジメチルホルムアミド等をあげる
ことができ、その使用量は、式（Ｉ）の化合物に対し、
通常２０〜５０倍重量部である０反応は通常室温程度で
１０分程度〜数時間行われる。このようにして製される
式（Ｉりの化−金物は、通常精製することなく式（ＩＩ
Ｉ）の化合物と反応させることができるが、カラムクロ
マト、再結晶等の通常の精製手段を適宜組み合わせて精
製してもよい。Compounds of formula (++) can be prepared by reacting compounds of formula (I) with DSC in the presence of a tertiary amine. As the tertiary amine, triethylamine,
Examples include N-methylmorpholine, 4-dimethylaminopyridine, and the like, preferably 4-dimethylaminopyridine. The amount of the amine to be used is a catalytic amount (usually a formula (
1/lo to 1/100 times the mole of the compound of formula (I).
．． The reaction solvent used in 0 to 1.5 times the molar amount is as follows:
dichloromethane, chloroform, 1,4-dioxane,
Tetrahydrofuran, dimethylformamide, etc. can be mentioned, and the amount used is based on the compound of formula (I).
The reaction, which is usually 20 to 50 parts by weight, is usually carried out at about room temperature for about 10 minutes to several hours. The metal products of the formula (II) produced in this way are usually produced without purification.
Although it can be reacted with the compound I), it may be purified by appropriately combining ordinary purification means such as column chromatography and recrystallization.
次に、式（Ｉｆ）の化合物を式（ＩＩＩ）の化合物と反
応させることからなる式（ｍＶ）の化合物の製造法を説
明する６反応溶媒としては、ジメチルホルムアミド等の
非プロトン性溶媒をあげることができ、その使用量は、
式（１１）の化合物に対し通常３０〜６０倍重量部であ
る。又、式（ＩＩＩ ）の化合物の使用量は式（ＩＩ）
の化合物に対し、通常０．９〜１．０倍モルである０反
応は、通常室温〜６０℃程度の温度で数時間〜数十時間
性われる０反応終了後、カラムクロマト、再結晶等の精
製手段を適宜組み合わせることにより式（ＩＶ）の化合
物を単離することができる。Next, we will explain the method for producing the compound of formula (mV), which consists of reacting the compound of formula (If) with the compound of formula (III).6 Examples of the reaction solvent include aprotic solvents such as dimethylformamide. and its usage is
The amount is usually 30 to 60 times the weight of the compound of formula (11). In addition, the amount of the compound of formula (III) to be used is the amount of compound of formula (II)
The 0 reaction, which is usually 0.9 to 1.0 times the mole of the compound, is usually carried out at a temperature of about room temperature to 60°C for several hours to several tens of hours.After the 0 reaction is completed, column chromatography, recrystallization, etc. The compound of formula (IV) can be isolated by appropriately combining purification means.
このようにして製される式（ｒｌ／）の化合物は特開昭
５８−１７２３９９号公報に示された方法により式（Ｖ
）の化合物とすることができる。The compound of formula (rl/) produced in this way is prepared by the method disclosed in JP-A-58-172399.
) can be a compound.
次に、上記式（ＩＩＩ）の原料化合物の製造法を説明す
る。Next, a method for producing the raw material compound of formula (III) above will be explained.
（Ｖｌ）
（■）
一一一→（ＩＩＩ ）
（式中、Ｒ４は第三級ブトキシカルボニル基、ベンジル
オキシカルボニル基等のアミノ基の保護基を意味し、＾
ｌａ、Ｒ３及びｎは前記に同じ）即ち、式（Ｖｌ）の化
合物をジクロへキシルカルボジイミドと１−ヒドロキシ
ベンゾトリアゾール又はＮ−ヒドロキシスクシンイミド
の組み合わせ等からなる活性エステル法を用いてジクロ
ロメタン、１．４−ジオキサン、テトラヒドロフラン、
ジメチルホルムアミド等の非プロトン性溶媒中０〜５０
℃で数時間〜数十時間反応させることにより式（Ｖｌ）
の化合物の活性エステルを得ることができる。これを、
テトラヒドロフラン等の非プロトン性溶媒中０〜５０℃
で式（■）の化合物と反応させることにより式（■）の
化合物を製造することができる。得られた式（■）の化
合物を、臭化水素酸と酢酸との組み合わせ、塩酸と蟻酸
又はジオキサンとの組み合わせ、三フッ化ホウ素・エー
テル錯体と酢酸又はトリフルオロ酢酸との組み合わせか
らなる試薬を用いてジクロロメタン、テトラヒドロフラ
ン等の溶媒中−１０℃〜室温の温度で反応させることに
より式（ＩＩＩ ）の化合物を製造することができる。(Vl) (■) 111 → (III) (In the formula, R4 means a protecting group for an amino group such as a tertiary butoxycarbonyl group or a benzyloxycarbonyl group,
(la, R3 and n are the same as above) That is, the compound of formula (Vl) is mixed with dichloromethane, 1.4 -dioxane, tetrahydrofuran,
0-50 in aprotic solvents such as dimethylformamide
By reacting for several hours to several tens of hours at °C, formula (Vl)
Active esters of compounds of can be obtained. this,
0-50℃ in an aprotic solvent such as tetrahydrofuran
A compound of formula (■) can be produced by reacting with a compound of formula (■). The obtained compound of formula (■) was treated with a reagent consisting of a combination of hydrobromic acid and acetic acid, a combination of hydrochloric acid and formic acid or dioxane, and a combination of boron trifluoride/ether complex and acetic acid or trifluoroacetic acid. The compound of formula (III) can be produced by reacting the compound in a solvent such as dichloromethane or tetrahydrofuran at a temperature of -10°C to room temperature.
又、上記反応における式（■）の原料化合物は、以下の
ようにして製造することができる。Further, the raw material compound of formula (■) in the above reaction can be produced as follows.
（式中、ｎ及びＲツは前記に同じ）
即ち、式（ＩＸ）の化合物をベンゼン、トルエン等の溶
媒中８３０Ｈと酸触媒の存在下反応させることにより式
（■）の化合物を製造することができる０反応は、室温
〜１５０℃の温度で数時間〜数十時間程度行われる。前
記酸触媒としては、塩酸、硫酸等の鉱酸、パラトルエン
スルホン酸、ショウノウ−１０−スルホン酸、メタンス
ルホン酸の如き有機酸をあげることができ、その使用量
は式（■）の化合物に対し、通常１７１００〜２倍当量
である。(In the formula, n and R are the same as above.) That is, the compound of formula (■) is produced by reacting the compound of formula (IX) with 830H in a solvent such as benzene or toluene in the presence of an acid catalyst. This reaction is carried out at a temperature of room temperature to 150° C. for several hours to several tens of hours. Examples of the acid catalyst include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as para-toluenesulfonic acid, camphor-10-sulfonic acid, and methanesulfonic acid, and the amount used is determined according to the compound of formula (■). On the other hand, it is usually 17,100 to 2 times equivalent.
〈発明の効果〉
本発明の製造法により、優れた白血球増多作用を有する
式（Ｖ）の化合物の重要製造中間体である式（ｒＹ）の
化合物を緩和な反応条件下、短い反応時間°で、操作性
よく且つ高収率に製造することができる。従って、本発
明の製造法は、式（ＩＶ）の化合物の工業的製造法とし
て優れたものである。<Effects of the Invention> According to the production method of the present invention, the compound of formula (rY), which is an important production intermediate of the compound of formula (V), which has an excellent leukocytosis effect, is produced under mild reaction conditions and in a short reaction time. It can be manufactured with good operability and high yield. Therefore, the production method of the present invention is excellent as an industrial production method for the compound of formula (IV).
以下、本発明を更に参考例及び実施例により説明するが
、本発明はこれにより限定されるものではない。Hereinafter, the present invention will be further explained by reference examples and examples, but the present invention is not limited thereto.
参考例ｌ
Ｎ６−スチアロイルーし一リジン ベンジルエステベン
ゼン６００ａ＋ｌにＮ６−スチアロイルーＬ−リジン８
８．６ｇ 、パラトルエンスルホン酸１ 水和物５３．
１ｇ及びベンジルアルコール１１１．６ｇを加え、約２
２時間ディーンースタルクの装置を用いて共沸脱水しな
がら加熱還流した０反応終了後、溶媒を減圧留去し、残
渣にイソプロピルエーテル２．５βを加えて、析出する
結晶を濾取し Ｎ８−ステアロイル−Ｌ−リジン ベン
ジルエステルのパラトルエンスルホン酸塩を得た。これ
を、クロロホルムＩＪ２に懸濁し、５９６炭酸水素ナト
リウム水６００■ｌを加えて攪拌した後、クロロホルム
層を分液した０次に、クロロホルム層を５＊炭酸水素ナ
トリウム水及び飽和食塩水で洗浄後、無水硫酸ナトリウ
ムで乾燥した。溶媒を留去して標記化合物の結晶７２．
５ｇを得た。Reference example 1 N6-styaroyl-L-lysine Benzyl estebenzene 600a+l and N6-styaroyl-L-lysine 8
8.6g, para-toluenesulfonic acid monohydrate 53.
Add 1g and 111.6g of benzyl alcohol, about 2
After the reaction was completed, the solvent was distilled off under reduced pressure, 2.5β of isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration. A para-toluenesulfonate salt of stearoyl-L-lysine benzyl ester was obtained. This was suspended in chloroform IJ2, 600 μl of 596 sodium bicarbonate water was added and stirred, and the chloroform layer was separated. Next, the chloroform layer was washed with 5* sodium hydrogen carbonate water and saturated saline. , dried over anhydrous sodium sulfate. The solvent was distilled off to give crystals of the title compound 72.
5g was obtained.
融点： ７８．０〜８０．０℃
ＮＭＲ（９０ＭＨｚ、ＣＤ５ＯＤ）δ；０．８８（３Ｈ
，ｔ）
５．１６（２Ｈ，Ｓ）
７．３７ （５Ｈ，ｓ）
参考例２
第三級ブトキシカルボニル−し−アラニル−Ｄ−イソグ
ルタミン６２．３ｇをテトラヒドロフラン４００ｍ１に
溶解し、水冷攪拌下ジシクロへキシルカルボジイミド４
２．５ｇ及び１−ヒドロキシベンゾトリアゾール２９．
２ｇを一度に加え、３０分攪拌後、徐々に室温に戻し、
５時間攪拌した。次に、Ｎ６−スチアロイルーＬ−リ
ジン ベンジルエステル１０３．６ｇをテトラヒドロフ
ラン１．６ｋに溶解した溶液を先の反応系に加えた。そ
の後、−夜装置し、析出した結晶を濾取した。得られた
結晶をメタノールｌでスラリー洗浄後、乾燥して標記化
合物の白色結晶１４５．９ｇを得た。Melting point: 78.0-80.0°C NMR (90MHz, CD5OD) δ; 0.88 (3H
,t) 5.16 (2H,S) 7.37 (5H,s) Reference Example 2 62.3g of tertiary-butoxycarbonyl-d-alanyl-D-isoglutamine was dissolved in 400ml of tetrahydrofuran, and dicyclodioxide was dissolved under stirring under water cooling. Hexylcarbodiimide 4
2.5g and 1-hydroxybenzotriazole29.
Add 2g at once, stir for 30 minutes, then gradually return to room temperature.
Stirred for 5 hours. Next, a solution of 103.6 g of N6-stiaroyl-L-lysine benzyl ester dissolved in 1.6 k of tetrahydrofuran was added to the above reaction system. Thereafter, the apparatus was left overnight, and the precipitated crystals were collected by filtration. The obtained crystals were slurry washed with methanol 1 and dried to obtain 145.9 g of white crystals of the title compound.
融点；１７８〜１８０℃
ＮＭＲ（５００ＭＨ２，ＣＤＣｌ３＋ ＣＤ５ＯＤ）δ
；０．８９ （３Ｈ，ｔ、Ｊ−６，１１）ＩＺ）１．３
４ （３Ｈ，ｄ、Ｊ−７，ＩＨ２）１．４５ （９）１
．３）
５．１６．５．２０（２Ｈ，ＡＢｑ、Ｊ＝ｔ１．９Ｈｚ
）７゜３２〜７．３９（５）１．ｍ）
実施例１
ジルエステル
１−α−０−ベンジル−４，６−０−ベンジリデン−Ｎ
−アセチルムラミン酸３０．９ｇをジメチルホルムアミ
ド５５０ｍ１に溶解し室温下、ＤＳＣ１７，６ｇ及び４
−ジメチルアミノピリジン０．８ｇを一度に・加え、
１時間激しくｔｌ拌した（人波）０次に、Ｎ２−（第三
級ブトキシカルボニル−し−アラニル−Ｄ−イソグルタ
ミニル） −Ｎ６−スチアロイルーし一リジン ベンジ
ルエステル５０．０ｇをジクロロメタン１００ｍＩＬに
懸濁し、水冷攪拌下トリフルオロ酢酸１５５ａｕを少量
ずつ加えた。同温にて３０分攪拌後、室温に戻し、 １
時間攪拌した。Melting point: 178-180℃ NMR (500MH2, CDCl3+ CD5OD) δ
;0.89 (3H,t,J-6,11)IZ)1.3
4 (3H, d, J-7, IH2) 1.45 (9) 1
．． 3) 5.16.5.20 (2H, ABq, J=t1.9Hz
)7°32~7.39(5)1. m) Example 1 Dyl ester 1-α-0-benzyl-4,6-0-benzylidene-N
- 30.9 g of acetylmuramic acid was dissolved in 550 ml of dimethylformamide, and DSC 17.6 g and 4
- Add 0.8 g of dimethylaminopyridine all at once,
After stirring vigorously for 1 hour (human wave), 50.0 g of N2-(tert-butoxycarbonyl-dis-alanyl-D-isoglutaminyl)-N6-styaroyl-lysine benzyl ester was suspended in 100 mL of dichloromethane. While cooling with water and stirring, 155 au of trifluoroacetic acid was added little by little. After stirring at the same temperature for 30 minutes, return to room temperature, 1
Stir for hours.
試薬及び溶媒を留去した後、ジメチルホルムアミド Ｎ
２を加えて溶解し、トリエチルアミンで中和してＮ２−
（Ｌ−アラニル−Ｄ−イソグルタミニル） −ＮＩＳ−
ステアロイル−Ｌ−リジン ベンジルエステルを得た。After distilling off the reagent and solvent, dimethylformamide N
2 was added and dissolved, neutralized with triethylamine and N2-
(L-alanyl-D-isoglutaminyl) -NIS-
Stearoyl-L-lysine benzyl ester was obtained.
この溶液を先の反応液（＾液）と混合し、室温にて一夜
攪拌した。析出した結晶を濾取し、水１．２Ｊｌ及びメ
タノール１．２ｆＬでスラリー洗浄後乾燥して標記化合
物の白色結晶６７．４ｇ（９３，δ零）を得た。This solution was mixed with the previous reaction solution (^ solution) and stirred at room temperature overnight. The precipitated crystals were collected by filtration, slurry washed with 1.2 Jl of water and 1.2 fL of methanol, and dried to obtain 67.4 g (93, δ zero) of the title compound as white crystals.
融点：２５０〜２５８℃（分解）
ＮＭＲ（５００ＭＨｚ、ＣＤＣｌ３＋ ＣＤ３０Ｄ）δ
：０．８８（３）１．ｔ、Ｊ−６，８）ＩＺ）１．９４
（３Ｈ，Ｓ、）
４．９９ （ＩＨ，ｄ、Ｊ−４，０）ＩＺ）５．１４．
５．１８（２）１．ＡＢＱ、Ｊ−１１，９Ｈｚ）７．３
１〜７．４８（１５Ｈ，ｍ）
実施例２
Ｎ’−（１−α−０−ベンジル−４，６−０−ベンジリ
デンジルエステル
実施例１と同様の方法により１−α−０−ベンジル４．
６−０−ベンジリデン−Ｎ−アセチルムラミン酸３．Ｏ
ｇとＮ２− （第三級ブトキシカルボニル−し−アラニ
ル−Ｄ−イソグルタミニル）−Ｎ６−パルミドイル−し
一リジン ベンジルエステル４．７ｇとから標記化合物
６．３ｇ（９２零）を得た。Melting point: 250-258°C (decomposition) NMR (500MHz, CDCl3+ CD30D) δ
:0.88(3)1. t, J-6, 8) IZ) 1.94
(3H,S,) 4.99 (IH,d,J-4,0)IZ)5.14.
5.18(2)1. ABQ, J-11,9Hz) 7.3
1-7.48 (15H, m) Example 2 N'-(1-α-0-benzyl-4,6-0-benzylidenezyl ester 1-α-0-benzyl 4 by the same method as Example 1 ．．
6-0-Benzylidene-N-acetylmuramic acid3. O
6.3 g (92 zero) of the title compound were obtained from 4.7 g of N2-(tert-butoxycarbonyl-d-alanyl-D-isoglutaminyl)-N6-palmidoyl-d-lysine benzyl ester.
融点： ２５３．３〜２５７．３℃（分解）ＮＭＲ（
５００ＭＨ２，ＣＤＣ１５＋ＣＤ５ＯＤ）δ；０．８８
（３Ｈ，ｔ、Ｊ−７，１）ＩＺ）１．９５ （３Ｈ，
ｓ）
５．００（ＩＨ，ｄ、Ｊ−３，２Ｈｚ）５．１４．５．
１８（２Ｈ，＾Ｂｑ、Ｊ−１２．７Ｈｚ）７．３１〜７
．４９ （１５Ｈ，■）
実施例３
ジルエステル
実施例１と同様の方法により１−α−０−ベンジル−４
，６−０−ベンジリデン−Ｎ−アセチルムラミン酸５．
８ｇとＮ２− （第三級ブトキシカルボニル−Ｌ−アラ
ニル−Ｄ−イソグルタミニル）−Ｎ６−アラキドイルー
Ｌ−リジン ベンジルエステル１０．０ｇとから標記化
合物１３．２ｇ（９３零）を得た。Melting point: 253.3-257.3°C (decomposition) NMR (
500MH2, CDC15+CD5OD) δ; 0.88
(3H, t, J-7, 1) IZ) 1.95 (3H,
s) 5.00 (IH, d, J-3, 2Hz) 5.14.5.
18 (2H, ^Bq, J-12.7Hz) 7.31~7
．． 49 (15H, ■) Example 3 Dyl ester 1-α-0-benzyl-4 was prepared in the same manner as in Example 1.
, 6-0-benzylidene-N-acetylmuramic acid5.
8g and 10.0g of N2-(tert-butoxycarbonyl-L-alanyl-D-isoglutaminyl)-N6-arachidoyl-L-lysine benzyl ester, 13.2g (93 zero) of the title compound was obtained.
融点： ２４８．８〜２５８．３℃（分解）ＮＭＲ（
５００Ｍ）ｌｚ、ＣＤＣｌ５ ＋ ＣＤ５ＯＤ）δ：０
．８８（３Ｈ，ｔ、Ｊ−７，１Ｈ２）１．９３（３）１
．ｓ）
４．９９ ＣＩＨ，ｄ、Ｊ−４，０Ｈ１Ｉ５．１３．
５．１８（２Ｈ，八Ｂｑ、Ｊ−１２，７Ｈｚ）貢７．３
１〜７．４８（１５）１．ｍ）Melting point: 248.8-258.3°C (decomposition) NMR (
500M) lz, CDCl5 + CD5OD) δ: 0
．． 88 (3H, t, J-7, 1H2) 1.93 (3) 1
．． s) 4.99 CIH, d, J-4,0H1I5.13.
5.18 (2H, 8Bq, J-12, 7Hz) Contribution 7.3
1-7.48 (15) 1. m)
Claims (1)
を、Ｒ＿２は低級アルキリデン基又は置換基を有するこ
ともあるベンジリデン基を意味する）で示される化合物
を三級アミンの存在下、Ｎ，Ｎ′−ジスクシンイミジル
カルボナートと反応させて式（II）▲数式、化学式、表
等があります▼（II） （式中、Ｒ＿１及びＲ＿２は前記に同じ）で示される化
合物を製し、次いで、これを式（III） ▲数式、化学式、表等があります▼（III） （式中、Ａｌａはアラニン残基を、ｎは１０〜２０の整
数を、Ｒ＿３は低級アルキル基又は置換基を有すること
もあるベンジル基を意味する）で示される化合物と反応
させることを特徴とする式（IV） ▲数式、化学式、表等があります▼（IV） （式中、Ｒ＿１、Ｒ＿２、Ｒ＿３、Ａｌａ及びｎは前記
に同じ）で示される化合物の製造法[Claims] Formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R_1 is a benzyl group that may have a substituent, and R_2 is a lower alkylidene group or has a substituent. A compound represented by the formula (which sometimes means a benzylidene group) is reacted with N,N'-disuccinimidyl carbonate in the presence of a tertiary amine to form formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 and R_2 are the same as above) A compound represented by the formula (III) is prepared. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, Ala is Formula (IV), which is characterized by reacting an alanine residue with a compound represented by n is an integer of 10 to 20, and R_3 is a lower alkyl group or a benzyl group that may have a substituent. There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) Method for producing the compound represented by (in the formula, R_1, R_2, R_3, Ala and n are the same as above)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7013489A JP2756135B2 (en) | 1989-03-22 | 1989-03-22 | Method for producing muramyl tripeptide derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP7013489A JP2756135B2 (en) | 1989-03-22 | 1989-03-22 | Method for producing muramyl tripeptide derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH02250899A true JPH02250899A (en) | 1990-10-08 |
| JP2756135B2 JP2756135B2 (en) | 1998-05-25 |
Family
ID=13422792
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP7013489A Expired - Fee Related JP2756135B2 (en) | 1989-03-22 | 1989-03-22 | Method for producing muramyl tripeptide derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2756135B2 (en) |
-
1989
- 1989-03-22 JP JP7013489A patent/JP2756135B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP2756135B2 (en) | 1998-05-25 |
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