JP4535238B2 - Retinoic acid ester of psicose and method for producing the same - Google Patents
Retinoic acid ester of psicose and method for producing the same Download PDFInfo
- Publication number
- JP4535238B2 JP4535238B2 JP2004077127A JP2004077127A JP4535238B2 JP 4535238 B2 JP4535238 B2 JP 4535238B2 JP 2004077127 A JP2004077127 A JP 2004077127A JP 2004077127 A JP2004077127 A JP 2004077127A JP 4535238 B2 JP4535238 B2 JP 4535238B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- psicose
- retinoic acid
- acid
- 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.)
- Expired - Lifetime
Links
- 229930002330 retinoic acid Natural products 0.000 title claims description 93
- 229960001727 tretinoin Drugs 0.000 title claims description 92
- -1 Retinoic acid ester Chemical class 0.000 title claims description 91
- 238000004519 manufacturing process Methods 0.000 title claims description 9
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 80
- SHGAZHPCJJPHSC-YCNIQYBTSA-N retinoic acid group Chemical group C\C(=C/C(=O)O)\C=C\C=C(\C=C\C1=C(CCCC1(C)C)C)/C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 claims description 63
- BJHIKXHVCXFQLS-PUFIMZNGSA-N psicose group Chemical group OCC(=O)[C@H](O)[C@H](O)[C@H](O)CO BJHIKXHVCXFQLS-PUFIMZNGSA-N 0.000 claims description 21
- 150000003192 psicose derivatives Chemical class 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 11
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000011968 lewis acid catalyst Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical class OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 9
- 239000002537 cosmetic Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
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- RFSUNEUAIZKAJO-JDJSBBGDSA-N D-psicofuranose group Chemical group OCC1(O)[C@H](O)[C@H](O)[C@H](O1)CO RFSUNEUAIZKAJO-JDJSBBGDSA-N 0.000 description 7
- 230000001588 bifunctional effect Effects 0.000 description 7
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
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- 125000006239 protecting group Chemical group 0.000 description 5
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- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 4
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-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
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
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- 229910052736 halogen Inorganic materials 0.000 description 4
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- 235000020944 retinol Nutrition 0.000 description 4
- 239000011607 retinol Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 206010000496 acne Diseases 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 3
- 150000002243 furanoses Chemical class 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
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- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 description 2
- SJQBHNHASPQACB-ONEGZZNKSA-N (e)-1,2-dimethoxyethene Chemical group CO\C=C\OC SJQBHNHASPQACB-ONEGZZNKSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
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- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- SHGAZHPCJJPHSC-ZVCIMWCZSA-N 9-cis-retinoic acid Chemical compound OC(=O)/C=C(\C)/C=C/C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-ZVCIMWCZSA-N 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RFSUNEUAIZKAJO-VRPWFDPXSA-N D-Fructose Natural products OC[C@H]1OC(O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-VRPWFDPXSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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- LKDRXBCSQODPBY-AMVSKUEXSA-N L-(-)-Sorbose Chemical compound OCC1(O)OC[C@H](O)[C@@H](O)[C@@H]1O LKDRXBCSQODPBY-AMVSKUEXSA-N 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 125000003545 alkoxy group Chemical group 0.000 description 2
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000004122 cyclic group Chemical group 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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Description
本発明は、プシコースのレチノイン酸エステル、ならびにその製造方法及び中間体化合物に関する。 The present invention relates to a retinoic acid ester of psicose, a method for producing the same, and an intermediate compound.
レチノイン酸はビタミンＡ１（レチノール）の誘導体であり、しわやシミの改善、乾性や角化性の皮膚の治療、ニキビの治療等を期待して化粧品に配合されている。レチノイン酸の効能及び効果は、基本的にレチノールが体内でレチノイン酸に変化して作用するのでレチノールの効果及び効能と同じであるが、外用する場合、レチノールの数百倍の効果があり、作用が強い。そのためレチノイン酸は肌質によっては刺激が強すぎて使用に適さない場合がある。日本国内では、催奇性があることが理由となり、しわやシミの改善、乾性や角化性の皮膚の治療、ニキビの治療等の用途で、医薬品や化粧品としての許可がない成分である。しかし外国では、しわとり成分として注目されたことから、日本でも皮膚科医で研究用として取り扱うところがでてきた。 Retinoic acid is a derivative of vitamin A1 (retinol), and is incorporated into cosmetics in the hope of improving wrinkles and spots, treating dry and keratinized skin, treating acne and the like. The effects and effects of retinoic acid are basically the same as those of retinol because retinol acts in the body by changing to retinoic acid, but when applied externally, there are several hundred times the effect of retinol. Is strong. Therefore, retinoic acid may not be suitable for use because it is too irritating depending on the skin quality. In Japan, because of its teratogenicity, it is an ingredient that is not approved as a pharmaceutical or cosmetic product in applications such as improving wrinkles and spots, treating dry and keratinized skin, and treating acne. However, in foreign countries, it has been attracting attention as a wrinkle-removing ingredient, and even in Japan it has come to be handled for research purposes by dermatologists.
医薬品分野において、レチノイン酸は、細胞の分化を促進することで増殖を抑制し、ガン細胞に自然死を起こさせる分化誘導剤として市販されている（トレチノイン：急性前骨髄球性白血病の治療薬）。レチノイン酸は、前骨髄球の段階で分化が停止した急性前骨髄球性白血病（ＡＰＬ）細胞を前骨髄球以降へ分化誘導することにより自・他覚症状の改善、末梢血所見を正常化に導く。
また全トランス型レチノイン酸の幾何異性体である９−シス−レチノイン酸は、レチノイドＸ受容体（ＲＸＲ）のすべてのタイプ及びレチノイン酸受容体（ＲＡＲ）に対して結合作用及びトランス作用を示す作用機序により、ＡＩＤＳ関連カポジ肉腫を適応とし、医薬品として市販されている（Ａｌｉｔｒｅｔｉｎｏｉｎ：抗癌剤）。
In the pharmaceutical field, retinoic acid is marketed as a differentiation-inducing agent that suppresses proliferation by promoting cell differentiation and causes spontaneous death in cancer cells (Tretinoin: a therapeutic agent for acute promyelocytic leukemia) . Retinoic acid induces differentiation of acute promyelocytic leukemia (APL) cells whose differentiation has stopped at the promyelocytic stage to the promyelocytic and subsequent stages, thereby improving autologous and objective symptoms and normalizing peripheral blood findings Lead.
In addition, 9-cis-retinoic acid, which is a geometric isomer of all-trans retinoic acid, exhibits binding and trans effects on all types of retinoid X receptor (RXR) and retinoic acid receptor (RAR). Due to the mechanism, AIDS-related Kaposi's sarcoma is indicated and marketed as a pharmaceutical (Alitretinoin: anticancer agent).
レチノイン酸は、脂溶性ビタミンの一種であり、それ自体は水に不溶性である。そのため取り扱いを容易にするため、またレチノイン酸の毒性を下げる等、皮膚科剤として有効に使用できるようにするため、レチノイン酸の水溶性を高めることは大変意義があると考えられる。特許文献１には、水溶性の高い単糖又は二糖をレチノイン酸に付加することにより水溶性レチノイン酸誘導体を合成することが記載されている。特許文献１に記載される合成方法は、クロロエナミン等の塩素化剤を用いてレチノイン酸を反応性誘導体に変換する工程、水酸基で保護した糖を付加し脱保護する工程からなっている。 Retinoic acid is a kind of fat-soluble vitamin and is itself insoluble in water. Therefore, in order to facilitate handling and to enable effective use as a dermatological agent, such as to reduce the toxicity of retinoic acid, it is considered to be very significant to increase the water solubility of retinoic acid. Patent Document 1 describes that a water-soluble retinoic acid derivative is synthesized by adding a highly water-soluble monosaccharide or disaccharide to retinoic acid. The synthesis method described in Patent Document 1 comprises a step of converting retinoic acid into a reactive derivative using a chlorinating agent such as chloroenamine, and a step of adding and deprotecting a sugar protected with a hydroxyl group.
一方、Ｄ−グルコースやＤ−フラクトースなどの単糖と比べて脂肪合成を促進せず、体脂肪、特に腹腔内脂肪を蓄積させない糖として、Ｄ−プシコースが注目されている（非特許文献１）。また、Ｄ−プシコースの有効エネルギー価はほぼゼロであることも報告されている（非特許文献２）。
特許文献２には、プシコースに様々な保護基を付けた化合物及びそれらを合成する方法が記載されているが、二官能性水酸基保護基で保護されたプシコースを、プシコースを出発原料として合成する方法については何ら記載されていない。また、プシコースとレチノイン酸のエステルについても、水酸基を保護したプシコースから保護基を除去する方法についても記載されていない。
Patent Document 2 describes compounds in which various protective groups are attached to psicose and a method for synthesizing them. A method for synthesizing psicose protected with a bifunctional hydroxyl protecting group using psicose as a starting material. Is not described at all. In addition, regarding the ester of psicose and retinoic acid, there is no description on a method for removing the protecting group from the psicose whose hydroxyl group is protected.
本発明は、医薬品及び化粧品の分野で有用な水溶性レチノイン酸誘導体を提供することを目的とする。本発明は、レチノイン酸エステル化合物およびその製造方法を提供することを目的とする。本発明は、レチノイン酸エステル化合物を含む、化粧料組成物または医薬組成物を提供することを目的とする。 An object of the present invention is to provide a water-soluble retinoic acid derivative useful in the field of pharmaceuticals and cosmetics. An object of this invention is to provide a retinoic acid ester compound and its manufacturing method. An object of this invention is to provide the cosmetic composition or pharmaceutical composition containing a retinoic acid ester compound.
本発明者らは、鋭意研究を重ねた結果、以下の（ア）〜（ウ）のプシコースとレチノイン酸のエステルによって上記課題が解決できること、ならびに以下の（エ）、（オ）の金属ハロゲン化物ならびにホウ素ハロゲン化物及びその錯体から選択される一種以上の触媒の存在下、酸で処理することにより、水酸基が保護されたプシコースとレチノイン酸のエステルから水酸基保護基を除去できることを見出し本発明を完成するに至った。
（ア）式I
で表されるレチノイン酸エステル化合物。
（イ）プシコース残基の水酸基が二官能性の水酸基保護基で保護されている上記（ア）記載の化合物。
（ウ）プシコース残基がＤ−プシコフラノース残基であり、Ｄ−プシコフラノース残基の１位と２位、３位と４位の炭素原子に結合する水酸基がそれぞれ二官能性の水酸基保護基で保護されている、上記（ア）記載の化合物。
（エ）式I
で表されるレチノイン酸エステル化合物の製造方法であって、プシコースの水酸基の少なくとも一部が水酸基保護基で保護されたプシコース誘導体を製造し、該プシコース誘導体をレチノイン酸とエステル結合させてレチノイン酸エステルを製造し、及び該レチノイン酸エステルをルイス酸触媒の存在下に酸で処理することによりプシコース誘導体部分の水酸基保護基を除去することを含む、該方法。
（オ）プシコースがＤ−プシコフラノースである（エ）記載の方法。
即ち、本発明は以下の（１）のレチノイン酸エステル化合物を要旨とする。
（１）式II
As a result of intensive studies, the present inventors have found that the above problems can be solved by the following (a) to (c) psicose and retinoic acid esters, and the following (e) and (e) metal halides: In addition, the present invention was completed by finding that a hydroxyl protecting group can be removed from a hydroxyl group-protected psicose and retinoic acid ester by treatment with an acid in the presence of one or more catalysts selected from boron halides and complexes thereof. It came to do.
( A ) Formula I
A retinoic acid ester compound represented by the formula:
(B) the hydroxyl groups of the psicose residue is protected with a bifunctional hydroxyl-protecting group (A) compound described.
( C ) The psicose residue is a D-psicofuranose residue, and the hydroxyl groups bonded to the 1st, 2nd, 3rd and 4th carbon atoms of the D-psicofuranose residue are bifunctional hydroxyl protecting groups, respectively. The compound according to ( a ) above, which is protected with
( D ) Formula I
Wherein a psicose derivative in which at least a part of hydroxyl groups of psicose is protected with a hydroxyl protecting group is produced, and the psicose derivative is ester-bonded with retinoic acid to form a retinoic acid ester. And removing the hydroxyl protecting group of the psicose derivative moiety by treating the retinoic acid ester with an acid in the presence of a Lewis acid catalyst.
(E) psicose is a D- Pushiko furanose (d) the method described.
That is, the gist of the present invention is the following (1) retinoic acid ester compound.
( 1 ) Formula II
また、本発明は以下の（２）のレチノイン酸エステル化合物の製造方法を要旨とする。
（２）式II
Moreover, this invention makes the summary the manufacturing method of the retinoic acid ester compound of the following (2).
(2) Formula II
本発明のレチノイン酸エステル化合物により、肥満や糖尿病患者への悪影響を与えずにレチノイン酸を利用することが可能になる。また、本発明の方法により、レチノイン酸エステル化合物を簡便に合成することができる。 The retinoic acid ester compound of the present invention makes it possible to use retinoic acid without adversely affecting obesity or diabetic patients. Moreover, a retinoic acid ester compound can be easily synthesized by the method of the present invention.
本発明のレチノイン酸エステル化合物は、以下の式Iで表される。
式I
プシコース残基とは、プシコースのいずれかの水酸基とレチノイン酸がエステル結合することにより形成される糖残基を意味する。
そして、水酸基の少なくとも一部が保護されたプシコース残基とは、前記プシコース残基において、レチノイン酸とエステル結合した水酸基以外の水酸基の少なくとも１個が保護されたプシコース残基を意味し、好ましくはレチノイン酸とエステル結合した水酸基以外の水酸基すべてが保護されたプシコース残基を意味する。
以下、Ｒが、プシコース残基であるレチノイン酸エステル化合物をレチノイン酸プシコースと称し、Ｒが、水酸基が保護されたプシコース残基であるレチノイン酸エステル化合物をレチノイン酸プシコース誘導体と称する。
The retinoic acid ester compound of the present invention is represented by the following formula I.
Formula I
The psicose residue means a sugar residue formed by an ester bond between any hydroxyl group of psicose and retinoic acid.
The psicose residue in which at least a part of the hydroxyl group is protected means a psicose residue in which at least one hydroxyl group other than the hydroxyl group ester-bonded to retinoic acid is protected in the psicose residue, It means a psicose residue in which all hydroxyl groups other than the hydroxyl group ester-bonded to retinoic acid are protected.
Hereinafter, a retinoic acid ester compound in which R is a psicose residue is referred to as a retinoic acid psicose, and a retinoic acid ester compound in which R is a psicose residue with a hydroxyl group protected is referred to as a retinoic acid psicose derivative.
本発明のレチノイン酸エステル化合物において、レチノイン酸とエステル結合しているプシコースとしては、直鎖状プシコース、プシコフラノースのα体及びβ体、ならびにプシコピラノースのα体及びβ体が挙げられる。プシコースは、Ｄ体及びＬ体でもよいが、好ましくはＤ体である。好ましくは環状構造を有するプシコースであり、より好ましくはフラノース構造を有するプシコースであり、特に好ましくはプシコフラノースである。プシコースは、１位〜６位のいずれの炭素原子に結合する水酸基で、レチノイン酸とエステル結合していてもよいが、６位の水酸基でレチノイン酸とエステル結合しているものが好ましい。 In the retinoic acid ester compound of the present invention, examples of the psicose having an ester bond with retinoic acid include linear psicose, α-form and β-form of psicofuranose, and α-form and β-form of psicopyranose. The psicose may be D-form and L-form, but is preferably D-form. Psicose having a cyclic structure is preferable, psicose having a furanose structure is more preferable, and psicose furanose is particularly preferable. Psicose is a hydroxyl group bonded to any carbon atom at the 1st to 6th positions, and may be ester-bonded to retinoic acid, but is preferably an ester bond to retinoic acid at the 6th-position hydroxyl group.
本発明においては、Ｄ−プシコフラノースが６位の水酸基でレチノイン酸とエステル結合したレチノイン酸プシコースが好ましい。当該化合物は、以下の式IIで表される。
本発明はまた、レチノイン酸とプシコースがエステル結合した化合物において、プシコースのエステル結合した水酸基以外の水酸基が保護されたレチノイン酸プシコース誘導体に関する。レチノイン酸プシコース誘導体におけるプシコースについては、上記と同様である。このレチノイン酸プシコース誘導体は、レチノイン酸プシコースを製造するための中間体として重要である。
水酸基が保護されたとは、水酸基の水素原子が保護基で置換されていることを意味する。ここで、水酸基保護基としては、特に制限されないが、例えば、ベンジル基、ｐ−メトキシベンジル基、２，４−ジメトキシベンジル基、ｐ−クロロベンジル基、ｍ−ブロモベンジル基、ｐ−ニトロベンジル基、ベンズヒドリル基、ジ−ｐ−アニシルメチル基、トリチル基等のアリールメチル基；トリメチルシリル基、トリエチルシリル基、トリプロピルシリル基、ｔ−ブチルジメチルシリル基等のシリル基；メチル基、エチル基、プロピル基、イソプロピル基、ブチル基等のアルキル基；ホルミル基、アセチル基、トリフルオロアセチル基、ピバロイル基、ベンゾイル基、ｐ−メトキシベンゾイル基、ｐ−クロロベンゾイル基、メトキシカルボニル基、エトキシカルボニル基、ベンジルオキシカルボニル基、ｔ−ブトキシカルボニル基等のアシル基；アリル基、メトキシメチル基、２−メトキシエトキシメチル基、ベンジルオキシメチル基、メチルチオメチル基、２，２，２−トリクロロエトキシメチル基、２−（トリメチルシリル）エトキシメチル基、テトラヒドロピラニル基、１−エトキシエチル基などを例示することができる。
保護されたプシコース残基においては、互いに隣接する２つの水酸基が、二官能性の水酸基保護基で保護されているのが好ましい。二官能性の水酸基保護基としては、２つの水酸基における２つの水素原子を置換する保護基を意味し、特に限定されないが、二価の有機基、例えば、炭素数１〜７の直鎖状、分枝状又は環状の置換されていてもよいアルキリデン基、置換されていもよいベンジリデン基、炭素数１〜３の直鎖状又は分枝状の置換されていてもよいアルキレン基等が挙げられる。置換基としては、炭素数１〜４のアルキル基、例えば、メチル、エチル、プロピル、ブチルなど；ハロゲン、例えば、塩素、臭素、フッ素、ヨウ素など；ならびにアリール基など各種官能基が挙げられる。
二官能性の水酸基保護基の具体例としては、イソプロピリデン基、１−メチルプロピリデン基、１−メチルブチリデン基、シクロペンチリデン基、シクロヘキシリデン基、ベンジリデン基、ｐ−メトキシベンジリデン基、ｐ−クロロベンジリデン基、１−メチルベンジリデン基、１−エチルベンジリデン基、ジフェニルメチリデン基、メチレン基、エチレン基、プロピレン基、ｔ−ブチルメチリデン基、１−ｔ−ブチルエチリデン基、１−フェニルエチリデン基、１−（４−メトキシフェニル）エチリデン基、２，２，２−トリクロロエチリデン基、アクロレイン基、シクロへプチリデン基、２，４−ジメトキシベンジリデン基、３，４−ジメトキシベンジリデン基、２−ニトロベンジリデン基、４−ニトロベンジリデン基、メトキシメチレン基、エトキシメチレン基などが挙げられ、イソプロピリデン基、ベンジリデン基、エチレン基、ｔ−ブチルメチリデン基、１−ｔ−ブチルエチリデン基、１−フェニルエチリデン基、１−（４−メトキシフェニル）エチリデン基、２，２，２−トリクロロエチリデン基、アクロレイン基、シクロへプチリデン基、２，４−ジメトキシベンジリデン基、３，４−ジメトキシベンジリデン基、２−ニトロベンジリデン基、４−ニトロベンジリデン基、メトキシメチレン基、エトキシメチレン基が好ましい。
レチノイン酸プシコース誘導体の具体例としては、１，２：３，４−ジ−Ｏ−イソプロピリデン−β−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−イソプロピリデン−α−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−ベンジリデン−β−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−ベンジリデン−α−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−プロピリデン−β−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−プロピリデン−α−Ｄ−プシコフラノース、１，２：３，４−ジ−Ｏ−エチレン−β−Ｄ−プシコフラノース又は１，２：３，４−ジ−Ｏ−エチレン−α−Ｄ−プシコフラノースが６位の炭素原子に結合する水酸基でレチノイン酸とエステル結合した化合物が挙げられる。
例えば、１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノースとレチノイン酸とのエステルは、以下の式IIIで表される。
That the hydroxyl group is protected means that the hydrogen atom of the hydroxyl group is substituted with a protecting group. Here, the hydroxyl protecting group is not particularly limited, but examples thereof include benzyl group, p-methoxybenzyl group, 2,4-dimethoxybenzyl group, p-chlorobenzyl group, m-bromobenzyl group, p-nitrobenzyl group. Arylmethyl groups such as benzhydryl group, di-p-anisylmethyl group and trityl group; silyl groups such as trimethylsilyl group, triethylsilyl group, tripropylsilyl group and t-butyldimethylsilyl group; methyl group, ethyl group and propyl group Alkyl groups such as isopropyl group and butyl group; formyl group, acetyl group, trifluoroacetyl group, pivaloyl group, benzoyl group, p-methoxybenzoyl group, p-chlorobenzoyl group, methoxycarbonyl group, ethoxycarbonyl group, benzyloxy Carbonyl group, t-butoxycarbonyl group, etc. Sil group; allyl group, methoxymethyl group, 2-methoxyethoxymethyl group, benzyloxymethyl group, methylthiomethyl group, 2,2,2-trichloroethoxymethyl group, 2- (trimethylsilyl) ethoxymethyl group, tetrahydropyranyl group And 1-ethoxyethyl group can be exemplified.
In the protected psicose residue, the two adjacent hydroxyl groups are preferably protected with a bifunctional hydroxyl protecting group. The bifunctional hydroxyl-protecting group means a protecting group that replaces two hydrogen atoms in two hydroxyl groups, and is not particularly limited, but a divalent organic group, for example, a straight chain having 1 to 7 carbon atoms, Examples thereof include a branched or cyclic optionally substituted alkylidene group, an optionally substituted benzylidene group, and a linear or branched optionally substituted alkylene group having 1 to 3 carbon atoms. Examples of the substituent include alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and butyl; halogens such as chlorine, bromine, fluorine, and iodine; and various functional groups such as aryl groups.
Specific examples of the bifunctional hydroxyl protecting group include isopropylidene group, 1-methylpropylidene group, 1-methylbutylidene group, cyclopentylidene group, cyclohexylidene group, benzylidene group, p-methoxybenzylidene group, p-chlorobenzylidene group, 1-methylbenzylidene group, 1-ethylbenzylidene group, diphenylmethylidene group, methylene group, ethylene group, propylene group, t-butylmethylidene group, 1-t-butylethylidene group, 1-phenylethylidene group 1- (4-methoxyphenyl) ethylidene group, 2,2,2-trichloroethylidene group, acrolein group, cycloheptylidene group, 2,4-dimethoxybenzylidene group, 3,4-dimethoxybenzylidene group, 2-nitrobenzylidene group Group, 4-nitrobenzylidene group, methoxymethyle Group, ethoxymethylene group and the like, isopropylidene group, benzylidene group, ethylene group, t-butylmethylidene group, 1-t-butylethylidene group, 1-phenylethylidene group, 1- (4-methoxyphenyl) ethylidene group, 2,2,2-trichloroethylidene group, acrolein group, cycloheptylidene group, 2,4-dimethoxybenzylidene group, 3,4-dimethoxybenzylidene group, 2-nitrobenzylidene group, 4-nitrobenzylidene group, methoxymethylene group, An ethoxymethylene group is preferred.
Specific examples of retinoic acid psicose derivatives include 1,2: 3,4-di-O-isopropylidene-β-D-psicofuranose, 1,2: 3,4-di-O-isopropylidene-α-D. -Psicofuranose, 1,2: 3,4-di-O-benzylidene-β-D-psicofuranose, 1,2: 3,4-di-O-benzylidene-α-D-psicofuranose, 1,2: 3,4-di-O-propylidene-β-D-psicofuranose, 1,2: 3,4-di-O-propylidene-α-D-psicofuranose, 1,2: 3,4-di-O— Examples include compounds in which ethylene-β-D-psicofuranose or 1,2: 3,4-di-O-ethylene-α-D-psicofuranose is ester-bonded to retinoic acid at the hydroxyl group bonded to the 6th carbon atom .
For example, an ester of 1,2: 3,4-di-O-isopropylidene-D-psicofuranose and retinoic acid is represented by the following formula III.
本発明はまたレチノイン酸プシコースの製造方法に関する。本発明のレチノイン酸プシコースの製造方法は、１）プシコースの水酸基の少なくとも一部が水酸基保護基で保護されたプシコース誘導体を製造する工程、２）該プシコース誘導体をレチノイン酸とエステル結合させてレチノイン酸エステルを製造する工程、３）該レチノイン酸エステルをルイス酸触媒の存在下に酸で処理することによりプシコース誘導体部分の水酸基保護基を除去する工程を含む。
まず、プシコースの水酸基が水酸基保護基で保護されたプシコース誘導体を製造する。本発明においてプシコース誘導体とは、プシコースの水酸基の少なくとも一部が保護された化合物を意味する。好ましくは、１つの水酸基を除いて、プシコースの水酸基が保護された化合物を意味する。プシコースの水酸基を水酸基保護基で保護することによりプシコース誘導体を製造する場合、出発原料であるプシコースは、天然由来のものを使用してもよいし、特許３３３３９６９号公報に記載の方法によって合成したものを使用してもよい。好ましくは、Ｄ−プシコフラノースを用いる。
プシコースを酸触媒存在下、水酸基保護試薬の存在下で反応させることにより、プシコースの水酸基を保護することができる。水酸基保護試薬とは、上記で述べたような水酸基保護基を付加するのに好適な試薬を意味し、当業者であれば付加する保護基によって適宜選択できる。例えば、２，２−ジメトキシプロパン、２，２−ジエトキシプロパン、２，２−ジプロポキシプロパン、２，２−ジエトキシブタン、３，３−ジメトキシペンタン、３，３−ジエトキシペンタン、１，１−ジメトキシシクロペンタン、１，１−ジエトキシシクロペンタン、１，１−ジメトキシシクロヘキサン、１，１−ジエトキシシクロヘキサン、ベンズアルデヒドジメチルアセタール、ベンズアルデヒドジエチルアセタール、ｐ−メトキシベンズアルデヒドジメチルアセタール、ｐ−クロロベンズアルデヒドジメチルアセタール、ベンゾフェノンジメチルアセタール、アセトフェノンジメチルアセタール、プロピオフェノンジメチルアセタール、１，２−ジメトキシエチレン、ジアルキルアセタール類及びジアルキルケタール類、アセトン、２−ブタノン、３−ペンタノン、シクロペンタノン、シクロヘキサノン等のケトン類、ならびにアルキル基等と結合したアルデヒド類等が例示されるが、好適には２，２−ジメトキシプロパン、ベンズアルデヒドジメチルアセタール、１，２−ジメトキシエチレンが用いられる。これらは、溶媒として用いることもできる。
酸触媒としては、塩酸、硫酸、硝酸、過塩素酸、フッ化水素酸、臭化水素酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ−トルエンスルホン酸、トリフルオロメタンスルホン酸、フルオロスルホン酸等の有機酸及び無機酸が例示されるが、好適には、ｐ−トルエンスルホン酸、過塩素酸が用いられる。
反応は溶媒中で行われ、用いられる溶媒としては、反応に影響を及ぼさないものであれば特に制限されないが、例えば、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム、１，２−ジクロロエタン等のハロゲン化炭化水素系溶媒及びベンゼン、トルエン、キシレン等の芳香族炭化水素系溶媒が用いられ、好適には、トルエンが用いられる。反応は、通常−２０〜１５０℃、好ましくは−５〜１０℃で行う。
反応後、反応液を中和して減圧下溶媒を留去し、得られた残留物を溶解後、生成物を有機溶媒から晶析するのが好ましい。残留物を溶解する溶媒として好ましくは、酢酸エチルが挙げられる。晶析に用いる溶媒としては、ヘキサン、ヘキサン−酢酸エチル混合溶液が挙げられる。
The present invention also relates to a process for producing retinoic acid psicose. The method for producing psicose retinoic acid according to the present invention comprises 1) a step of producing a psicose derivative in which at least a part of hydroxyl groups of psicose is protected with a hydroxyl protecting group, and 2) esterifying the psicose derivative with retinoic acid to form retinoic acid. A step of producing an ester, and 3) a step of removing the hydroxyl protecting group of the psicose derivative portion by treating the retinoic acid ester with an acid in the presence of a Lewis acid catalyst.
First, a psicose derivative in which the hydroxyl group of psicose is protected with a hydroxyl protecting group is produced. In the present invention, the psicose derivative means a compound in which at least a part of the hydroxyl group of psicose is protected. Preferably, it means a compound in which the hydroxyl group of psicose is protected except for one hydroxyl group. When producing a psicose derivative by protecting the hydroxyl group of psicose with a hydroxyl protecting group, the psicose as a starting material may be naturally derived or synthesized by the method described in Japanese Patent No. 3333969. May be used. Preferably, D-psicofuranose is used.
The hydroxyl group of psicose can be protected by reacting psicose in the presence of an acid catalyst and in the presence of a hydroxyl protecting reagent. The hydroxyl protecting reagent means a reagent suitable for adding a hydroxyl protecting group as described above, and can be appropriately selected by those skilled in the art depending on the protecting group to be added. For example, 2,2-dimethoxypropane, 2,2-diethoxypropane, 2,2-dipropoxypropane, 2,2-diethoxybutane, 3,3-dimethoxypentane, 3,3-diethoxypentane, 1, 1-dimethoxycyclopentane, 1,1-diethoxycyclopentane, 1,1-dimethoxycyclohexane, 1,1-diethoxycyclohexane, benzaldehyde dimethyl acetal, benzaldehyde diethyl acetal, p-methoxybenzaldehyde dimethyl acetal, p-chlorobenzaldehyde dimethyl Acetal, benzophenone dimethyl acetal, acetophenone dimethyl acetal, propiophenone dimethyl acetal, 1,2-dimethoxyethylene, dialkyl acetals and dialkyl ketals, acetone Examples include ketones such as 2-butanone, 3-pentanone, cyclopentanone, and cyclohexanone, and aldehydes bonded to an alkyl group, and the like. Preferably, 2,2-dimethoxypropane, benzaldehyde dimethyl acetal, 1, 2-dimethoxyethylene is used. These can also be used as a solvent.
Acid catalysts include hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrofluoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, etc. Examples of the organic acid and inorganic acid are p-toluenesulfonic acid and perchloric acid.
The reaction is performed in a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction. For example, ether solvents such as tetrahydrofuran and dioxane, dichloromethane, chloroform, 1,2-dichloroethane and the like. And an aromatic hydrocarbon solvent such as benzene, toluene, xylene, etc., preferably toluene. The reaction is usually carried out at -20 to 150 ° C, preferably -5 to 10 ° C.
After the reaction, the reaction solution is neutralized, the solvent is distilled off under reduced pressure, the resulting residue is dissolved, and the product is preferably crystallized from an organic solvent. A preferable solvent for dissolving the residue is ethyl acetate. Examples of the solvent used for crystallization include hexane and hexane-ethyl acetate mixed solution.
水酸基の保護されたプシコースは、フルクトース又はＬ−ソルボースを出発原料とし、公知の有機化学的方法、例えばE．J．Prisbe et．al., J．Org．Chem., Vol．41, No．41 (1976)に記載の方法に準じて製造することもできる。例えば、３位以外の水酸基がすべて水酸基保護基で保護されたプシコースはフルクトースから、４位以外の水酸基がすべて水酸基保護基で保護されたプシコースはＬ−ソルボースから合成することができる。また、プシコノースを酸触媒存在下、水酸基保護試薬と反応させ、水酸基が保護されたプシコフラノースとともに合成された、５位の水酸基以外の水酸基が保護されたプシコピラノースをカラム分離することにより、５位の水酸基以外の水酸基が保護されたプシコピラノースを得ることができる。
Ｄ−プシコフラノースを上記の方法により、例えば２，２−ジメトキシプロパンと反応させると、１位及び２位の炭素原子に結合した水酸基、ならびに３位及び４位の炭素原子に結合した水酸基が、それぞれ２，２−ジメトキシプロパンと一緒になってジメチルメチレンジオキシ基を形成したＤ−プシコフラノース誘導体（以下の式ＩＶで表される）が得られる。
そして、レチノイン酸プシコース誘導体を、ルイス酸触媒の存在下に、酸で処理することにより、水酸基保護基を除去することによりレチノイン酸プシコースが得られる。
本発明において、ルイス酸触媒とは、反応する相手から電子対を受容する活性を有する触媒であって、通常の酸性触媒（例えば、塩酸及び硝酸等の無機酸、ならびに酢酸及びリン酸等の有機酸）を除くものを意味する。ルイス酸触媒としては、金属又はホウ素とハロゲン、アルキル基、アリール基又はアルコキシル基とが結合した化合物及びその錯体が挙げられる。金属としては、遷移金属及び希土類金属が好ましい。金属とハロゲンが結合した金属ハロゲン化物としては、Ｚｎ、Ｔｉ、Ｓｎ、Ｆｅ、Ａｌ及びランタノイドのハロゲン化物、例えば、フッ化物、塩化物、臭化物、ヨウ化物、好ましくは塩化物が挙げられる。具体的には、ＺｎＣｌ２、ＴｉＣｌ４、ＳｎＣｌ２、ＦｅＣｌ３、ＡｌＣｌ３、ＳｍＣｌ３、ＹｂＣｌ３等が挙げられ、好適にはＺｎＣｌ２を用いる。金属ハロゲン化物の錯体としては、上記金属ハロゲン化物のアミン、エーテル、エステル、ホスフィン類との錯体などが挙げられる。ホウ素とハロゲンが結合したホウ素ハロゲン化物としては、ＢＦ３等が挙げられる。ホウ素ハロゲン化物の錯体としては、上記ホウ素ハロゲン化物のアミン、エーテル、エステル、ホスフィン類との錯体などが挙げられ、特にＢＦ３・ＯＥｔ２が好ましい。金属とアルキル基、アリール基又はアルコキシル基とが結合した化合物としては、ＣＨ３ＴｉＣｌ３、Ｔｉ｛ＯＣＨ（ＣＨ３）２｝、Ｃ６Ｈ５Ｔｉ（ＯＣＨＭｅ２）３が挙げられる。これらは単独で用いてもよいし、複数種を組み合わせて用いてもよい。
酸としては、特に制限されないが、塩酸、硫酸、硝酸、過塩素酸、フッ化水素酸、臭化水素酸、酢酸、トリフルオロ酢酸、メタンスルホン酸、ｐ−トルエンスルホン酸、トリフルオロメタンスルホン酸、フルオロスルホン酸、ピリジニウムｐ−トルエンスルホナート等が例示されるが、好適には、酢酸が用いられる。
反応は溶媒中で行われ、用いられる溶媒としては、反応に影響を及ぼさないものであれば特に制限されないが、例えば、テトラヒドロフラン、ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム、１，２−ジクロロエタン等のハロゲン化炭化水素系溶媒及びメタノール、エタノール等のアルコール類が用いられ、好適には、テトラヒドロフランが用いられる。反応は、通常−８０〜１５０℃、好ましくは５０〜７０℃で行う。
例えば、上記の式IIIで表されるレチノイン酸プシコース誘導体を、テトラヒドロフラン、酢酸及び水の混合溶媒に溶解後、触媒としてＺｎＣｌ２を添加して反応させると、式IIで表されるプシコースのレチノイン酸エステル、すなわちレチノイン酸プシコースが得られる。
通常、糖の水酸基を保護した水酸基保護基は、酢酸、塩酸、硫酸等の酸を用いて除去できるが、レチノイン酸プシコース誘導体における水酸基保護基、特に二官能性水酸基保護基は、酸を用いる従来の方法では除去できなかった。しかし、ＺｎＣｌ２等の触媒を酸と共存させることにより、水酸基保護基を除去し、高い収率でレチノイン酸プシコースを得ることが可能となった。
詳細なメカニズムは現時点では不明であるが、環状構造をとったときのプシコースの特異的な立体配座が影響していると考えることもできる。
The hydroxyl-protected psicose is obtained by using fructose or L-sorbose as a starting material, and known organic chemical methods such as E. coli. J. Prisbe et. al., J. et al. Org. Chem., Vol. 41, no. 41 (1976). For example, psicose in which all hydroxyl groups other than the 3-position are protected with a hydroxyl-protecting group can be synthesized from fructose, and psicose in which all hydroxyl groups other than the 4-position are protected with a hydroxyl-protecting group can be synthesized from L-sorbose. In addition, by reacting psyconose with a hydroxyl protecting reagent in the presence of an acid catalyst and synthesizing together with psicofuranose having a hydroxyl group protected, the psicopyranose protected with a hydroxyl group other than the 5-position hydroxyl group is separated by column. Thus, it is possible to obtain a pseudopyranose having a hydroxyl group other than the hydroxyl group protected.
When D-psicofuranose is reacted with, for example, 2,2-dimethoxypropane by the above method, a hydroxyl group bonded to the 1st and 2nd carbon atoms and a hydroxyl group bonded to the 3rd and 4th carbon atoms are D-psicocofuranose derivatives (represented by the following formula IV), each of which forms a dimethylmethylenedioxy group together with 2,2-dimethoxypropane, are obtained.
Then, retinoic acid psicose is obtained by treating the retinoic acid psicose derivative with an acid in the presence of a Lewis acid catalyst to remove the hydroxyl protecting group.
In the present invention, the Lewis acid catalyst is a catalyst having an activity of accepting an electron pair from a reaction partner, and is an ordinary acidic catalyst (for example, inorganic acids such as hydrochloric acid and nitric acid, and organic acids such as acetic acid and phosphoric acid) Means acid). Examples of the Lewis acid catalyst include a compound in which a metal or boron is bonded to a halogen, an alkyl group, an aryl group, or an alkoxyl group, and a complex thereof. As metals, transition metals and rare earth metals are preferred. Examples of metal halides in which a metal and a halogen are bonded include Zn, Ti, Sn, Fe, Al, and lanthanoid halides such as fluoride, chloride, bromide, iodide, preferably chloride. Specifically, ZnCl 2, TiCl 4, SnCl 2, FeCl 3, AlCl 3, SmCl 3, YbCl 3 , and the like, preferably using ZnCl 2. Examples of the metal halide complex include complexes of the metal halide with amines, ethers, esters, and phosphines. Examples of the boron halide in which boron and halogen are bonded include BF 3 . Examples of the boron halide complex include complexes of the above boron halides with amines, ethers, esters, phosphines, and the like, and BF 3 .OEt 2 is particularly preferable. Examples of the compound in which a metal and an alkyl group, an aryl group, or an alkoxyl group are bonded include CH 3 TiCl 3 , Ti {OCH (CH 3 ) 2 }, and C 6 H 5 Ti (OCHMe 2 ) 3 . These may be used alone or in combination of two or more.
The acid is not particularly limited, but hydrochloric acid, sulfuric acid, nitric acid, perchloric acid, hydrofluoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, Examples include fluorosulfonic acid, pyridinium p-toluenesulfonate, and acetic acid is preferably used.
The reaction is performed in a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction. For example, ether solvents such as tetrahydrofuran and dioxane, dichloromethane, chloroform, 1,2-dichloroethane and the like. And halogenated hydrocarbon solvents and alcohols such as methanol and ethanol are used, and tetrahydrofuran is preferably used. The reaction is usually performed at −80 to 150 ° C., preferably 50 to 70 ° C.
For example, when the retinoic acid psicose derivative represented by the above formula III is dissolved in a mixed solvent of tetrahydrofuran, acetic acid and water and then reacted by adding ZnCl 2 as a catalyst, the retinoic acid of the psicose represented by the formula II Esters, ie retinoic acid psicose, are obtained.
Usually, the hydroxyl-protecting group protecting the hydroxyl group of the sugar can be removed using an acid such as acetic acid, hydrochloric acid, sulfuric acid, etc., but the hydroxyl-protecting group in the retinoic acid psicose derivative, particularly the bifunctional hydroxyl-protecting group, uses an acid. This method could not be removed. However, by allowing a catalyst such as ZnCl 2 to coexist with an acid, it was possible to remove the hydroxyl protecting group and obtain retinoic acid psicose in high yield.
Although the detailed mechanism is unknown at present, it can also be considered that the specific conformation of psicose when the ring structure is taken influences.
本発明はまた、本発明のレチノイン酸プシコースを含む医薬組成物及び化粧料組成物に関する。
本発明のレチノイン酸プシコースを含む医薬組成物又は化粧料組成物は、適当な担体とともに製剤化し、錠剤、顆粒、カプセル剤、糖衣錠、軟膏、クリーム、チンキ、ローション、溶液、懸濁物、ヒドロゲル、リポソーム又は泡スプレーの形態で投与又は施用することができる。
適当な担体の例は、各種乳化剤、分散剤、安定剤、香油、酸化防止剤、増粘剤、希釈剤、湿潤剤、フィラー、浸透圧を変えるための塩類、緩衝剤及びこれらの混合物などである。例えば、ゼラチン、ラクトース、スターチ、脂肪酸塩、タルク、アラビアゴム、ポリアルキレングリコール及びその他の非毒性賦形剤が挙げられる。
本発明の医薬組成物及び化粧料組成物における活性成分であるレチノイン酸プシコースの濃度は、投与形態に依存するが、通常０．１〜９９．８重量％である。
レチノイン酸は、皮膚の治療及び改善、例えば、しわやシミの改善、乾性や角化性の皮膚の治療、ニキビの治療、紫外線防止において効果を有することが知られていることから、本発明のレチノイン酸プシコースを含む化粧料組成物又は医薬組成物もまた、皮膚の治療及び改善のために使用できる。
さらに、レチノイン酸は、癌の治療（例えば、前骨髄球性白血病の治療薬）、ＡＩＤＳ関連カポジ肉腫の治療にも効果を有することから、本発明のレチノイン酸プシコースを含む医薬組成物もまた、これらの用途に使用できる。
生体内でレチノイン酸プシコースが加水分解されレチノイン酸とプシコースに分離したとき、前述のとおりプシコースは他の糖に比べ腹腔内脂肪を蓄積させず、有効エネルギー価がほぼゼロであることから、肥満や糖尿病患者への悪影響を与えずにレチノイン酸を利用することができる。
さらに、生体内において、Ｄ−プシコースは、Ｄ−グルコースやＤ−フラクトースと比べ異なった生理活性作用を及ぼすことから、レチノイン酸プシコースは、グルコース、ガラクトース、マンノースのレチノイン酸エステル等とは異なる生理活性作用を及ぼすと考えられる。
The present invention also relates to a pharmaceutical composition and a cosmetic composition comprising the retinoic acid psicose of the present invention.
The pharmaceutical composition or cosmetic composition containing the retinoic acid psicose of the present invention is formulated with a suitable carrier, and is made into tablets, granules, capsules, dragees, ointments, creams, tinctures, lotions, solutions, suspensions, hydrogels, It can be administered or applied in the form of liposomes or foam sprays.
Examples of suitable carriers are various emulsifiers, dispersants, stabilizers, perfume oils, antioxidants, thickeners, diluents, wetting agents, fillers, salts for changing osmotic pressure, buffers and mixtures thereof. is there. Examples include gelatin, lactose, starch, fatty acid salts, talc, gum arabic, polyalkylene glycols and other non-toxic excipients.
The concentration of retinoic acid psicose, which is an active ingredient in the pharmaceutical composition and cosmetic composition of the present invention, depends on the dosage form, but is usually 0.1 to 99.8% by weight.
Retinoic acid is known to have an effect in the treatment and improvement of skin, such as wrinkles and spots, dry and keratinized skin, acne treatment, and prevention of ultraviolet rays. Cosmetic or pharmaceutical compositions containing retinoic acid psicose can also be used for skin treatment and improvement.
Furthermore, since retinoic acid is also effective in the treatment of cancer (for example, a therapeutic agent for promyelocytic leukemia) and the treatment of AIDS-related Kaposi's sarcoma, the pharmaceutical composition containing the retinoic acid psicose of the present invention is also It can be used for these applications.
When retinoic acid psicose is hydrolyzed in vivo and separated into retinoic acid and psicose, as mentioned above, psicose does not accumulate intraperitoneal fat compared to other sugars, and the effective energy value is almost zero. Retinoic acid can be used without adversely affecting diabetic patients.
Further, in vivo, D-psicose exerts a different physiological activity than D-glucose and D-fructose, so that retinoic acid psicose is different from glucose, galactose, mannose retinoic acid ester, etc. It is thought to have an effect.
１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノースの合成
Ｄ−プシコース（１００ｇ、０．５６ｍｏｌ）のアセトン溶液（１０００ｍｌ）に２，２−ジメトキシプロパン（１７３ｇ、１．６６ｍｏｌ）を加え、液温を０℃に冷却し、過塩素酸（７０％水溶液）（２２．０ｇ、０．１５７ｍｏｌ）を加えて６時間撹拌する。反応溶液を濃アンモニア水で中和し、減圧下溶媒留去する。得られた残留物を酢酸エチル（３００ｍＬ）に溶解後、水（２５０ｍＬ）で洗浄する。有機層を無水硫酸マグネシウムで乾燥し、減圧下溶媒留去する。得られた残渣をヘキサン−酢酸エチルで晶析し、得られた白色結晶を減圧乾燥して１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（５２．０ｇ、純度 ９９％以上、収率 ３６．０％）を得た。
IR νmax (KBr):3560cm-1及び3200-2850cm-1;1H-NMR δ:1.33, 1.41, 1.45, 1.51(3H×4, each s), 3.16(1H, dd), 3.60-3.69(3H, m), 4.07(1H, d), 4.34(1H, d), 4.65(1H, d)及び4.92(1H,dd); 13C-NMR : 24.87, 26.20, 26.38, 26.52, 63.99, 69.97, 81.69, 85.89, 86.87, 111.78, 112.38, 113.50; MS(m/z):理論値；C11H17O6:245(M+-15)、実測値；245(M+-15)。
Synthesis of 1,2: 3,4-di-O-isopropylidene-D-psicofuranose D-psicose (100 g, 0.56 mol) in acetone solution (1000 ml) 2,2-dimethoxypropane (173 g, 1.66 mol) ), The liquid temperature is cooled to 0 ° C., perchloric acid (70% aqueous solution) (22.0 g, 0.157 mol) is added, and the mixture is stirred for 6 hours. The reaction solution is neutralized with concentrated aqueous ammonia, and the solvent is distilled off under reduced pressure. The obtained residue is dissolved in ethyl acetate (300 mL) and washed with water (250 mL). The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The obtained residue was crystallized from hexane-ethyl acetate, and the obtained white crystal was dried under reduced pressure to obtain 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (52.0 g, purity 99). % Or more, yield 36.0%).
IR νmax (KBr): 3560cm -1 and 3200-2850cm -1 ; 1 H-NMR δ: 1.33, 1.41, 1.45, 1.51 (3H × 4, each s), 3.16 (1H, dd), 3.60-3.69 (3H , m), 4.07 (1H, d), 4.34 (1H, d), 4.65 (1H, d) and 4.92 (1H, dd); 13 C-NMR: 24.87, 26.20, 26.38, 26.52, 63.99, 69.97, 81.69 , 85.89, 86.87, 111.78, 112.38 , 113.50; MS (m / z): theory; C 11 H 17 O 6: 245 (M + -15), Found; 245 (M + -15).
１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノースとレチノイン酸のエステルの合成
１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（０．８１ｇ、３．１０ｍｍｏｌ）、ビタミンＡ酸（１．３８ｇ、４．６１ｍｍｏｌ）、ジシクロヘキシルカルボジイミド（１．４６ｇ、７．０６ｍｍｏｌ）及び４−Ｎ，Ｎ−ジメチルアミノピリジン（０．２０ｇ、１．６３ｍｍｏｌ）のトルエン（１６０ｍｌ）溶液を５℃に冷却し、６０時間撹拌する。反応溶液に飽和塩化アンモニウム溶液（５０ｍｌ）を加えて生じた沈殿をろ別し、ろ液を分液する。得られた有機層を減圧下溶媒留去後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２４：１（ｖ／ｖ））に付し、レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース１．４０ｇ（収率８３．２％）を得た。
IR νmax (KBr):3150-2800cm-1及び1730cm-1;1H-NMR δ:1.03(6H, s), 1.33(3H, s), 1.37(3H, s), 1.44-1.49(12H, m), 1.72(3H, s), 2.00-2.04(5H, m), 2.36(1H, s), 4.05-4.35(5H, m), 4.70(2H, dd), 5.81(1H, s), 6.12-6.31(4H, m)及び7.02(1H, dd)。
Synthesis of 1,2: 3,4-di-O-isopropylidene-D-psicofuranose and ester of retinoic acid 1,2: 3,4-di-O-isopropylidene-D-psicofuranose (0.81 g, 3.10 mmol), vitamin A acid (1.38 g, 4.61 mmol), dicyclohexylcarbodiimide (1.46 g, 7.06 mmol) and 4-N, N-dimethylaminopyridine (0.20 g, 1.63 mmol) in toluene. (160 ml) Cool the solution to 5 ° C. and stir for 60 hours. Saturated ammonium chloride solution (50 ml) is added to the reaction solution, the resulting precipitate is filtered off, and the filtrate is separated. The obtained organic layer was evaporated under reduced pressure, and then subjected to silica gel column chromatography (hexane: ethyl acetate = 24: 1 (v / v)) to give retinoic acid-1,2: 3,4-di-O. -1.40 g of isopropylidene-D-psicofuranose was obtained (yield 83.2%).
IR νmax (KBr): 3150-2800cm -1 and 1730cm -1 ; 1 H-NMR δ: 1.03 (6H, s), 1.33 (3H, s), 1.37 (3H, s), 1.44-1.49 (12H, m ), 1.72 (3H, s), 2.00-2.04 (5H, m), 2.36 (1H, s), 4.05-4.35 (5H, m), 4.70 (2H, dd), 5.81 (1H, s), 6.12- 6.31 (4H, m) and 7.02 (1H, dd).
プシコースレチノイン酸エステルの合成
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（０．２０ｇ、０．３７０ｍｍｏｌ）をテトラヒドロフラン（４ｍｌ）、酢酸（１２ｍｌ）及び水（４ｍｌ）の混合溶媒に溶解後、ＺｎＣｌ２（０．２０ｇ）を加え、６０℃に加温する。同温において１８時間撹拌後、減圧下溶媒留去し、これをシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９：１（ｖ／ｖ））に付し、下記化合物（２）（０．１７ｇ、収率 ８１．０％）を得る。
IRνmax (KBr): 3460cm-1,3100-2775cm-1及び1715cm-1;1H-NMR δ:1.03(6H, s), 1.71-2.36(11H, m), 3.27(1H, s), 3.39-3.41(1H, m), 3.83(1H, s), 4.10-4.42(7H, m), 5.68-6.54(5H, m)及び6.99-7.06(1H, m)。
〔比較例１〕
Synthesis of psicose retinoic acid ester Retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (0.20 g, 0.370 mmol) was added to tetrahydrofuran (4 ml), acetic acid (12 ml) and water ( 4 ml), dissolved in a mixed solvent, add ZnCl 2 (0.20 g) and warm to 60 ° C. After stirring at the same temperature for 18 hours, the solvent was distilled off under reduced pressure, and this was subjected to silica gel column chromatography (chloroform: methanol = 9: 1 (v / v)) to obtain the following compound (2) (0.17 g, yield). Rate 81.0%).
IRνmax (KBr): 3460cm -1 , 3100-2775cm -1 and 1715cm -1 ; 1 H-NMR δ: 1.03 (6H, s), 1.71-2.36 (11H, m), 3.27 (1H, s), 3.39- 3.41 (1H, m), 3.83 (1H, s), 4.10-4.42 (7H, m), 5.68-6.54 (5H, m) and 6.99-7.06 (1H, m).
[Comparative Example 1]
無機酸のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（３００ｍｇ）のテトラヒドロフラン溶液（３ｍｌ）に２Ｎ−Ｈ２ＳＯ４（０．３ｍｌ）を添加し、１８時間還流したが、水酸基保護基は除去できなかった。
〔比較例２〕
Removal of hydroxyl protecting group with only inorganic acid 2N—H 2 SO 4 (0. 0) was added to a tetrahydrofuran solution (3 ml) of retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (300 mg). 3 ml) was added and refluxed for 18 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 2]
無機酸のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（３００ｍｇ）のテトラヒドロフラン溶液（３ｍｌ）に２Ｎ−Ｈ２ＳＯ４（０．９ｍｌ）を添加し、１８時間還流したが、水酸基保護基は除去できなかった。
〔比較例３〕
Removal of hydroxyl protecting group with only inorganic acid 2N—H 2 SO 4 (0. 0) was added to a tetrahydrofuran solution (3 ml) of retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (300 mg). 9 ml) was added and refluxed for 18 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 3]
無機酸のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（３００ｍｇ）のテトラヒドロフラン溶液（３ｍｌ）に１Ｎ−ＨＣｌ（３ｍｌ）を添加し、１８時間還流したが、水酸基保護基は除去できなかった。
〔比較例４〕
Removal of hydroxyl protecting group with only inorganic acid 1N-HCl (3 ml) was added to a tetrahydrofuran solution (3 ml) of retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (300 mg). The mixture was refluxed for 18 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 4]
有機酸のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（５０ｍｇ）のギ酸溶液（２ｍｌ）に水（０．１ｍｌ）を添加し、１８時間還流したが、水酸基保護基は除去できなかった。
〔比較例５〕
Removal of hydroxyl protecting group with only organic acid Water (0.1 ml) was added to a formic acid solution (2 ml) of retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (50 mg). The mixture was refluxed for 18 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 5]
有機酸のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（４５ｍｇ、０．０８６１ｍｍｏｌ）の氷酢酸（２ｍｌ）溶液に水（０．１ｍｌ）を添加し、１８時間還流したが、水酸基保護基は除去できなかった。
〔比較例６〕
Removal of hydroxyl protecting group with only organic acid Retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (45 mg, 0.0861 mmol) in glacial acetic acid (2 ml) in water (0. 1 ml) was added and refluxed for 18 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 6]
イオン交換樹脂による水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（５０ｍｇ）のメタノール溶液（１ｍｌ）にイオン交換樹脂Ｄｏｗｅｘ ５０Ｗ（Ｈ＋） １０ｍｇを添加し、室温で２０時間撹拌したが、水酸基保護基は除去できなかった。
〔比較例７〕
Removal of hydroxyl protecting group by ion exchange resin Retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (50 mg) in methanol solution (1 ml) and ion exchange resin Dowex 50W (H +) 10 mg Was added and stirred at room temperature for 20 hours, but the hydroxyl protecting group could not be removed.
[Comparative Example 7]
塩化亜鉛のみによる水酸基保護基の除去
レチノイン酸−１，２：３，４−ジ−Ｏ−イソプロピリデン−Ｄ−プシコフラノース（５０ｍｇ）のメタノール溶液（１ｍｌ）に塩化亜鉛１０ｍｇを添加し、室温で２０時間撹拌したが、水酸基保護基は除去できなかった。
Removal of hydroxyl protecting group with zinc chloride alone 10 mg of zinc chloride was added to a methanol solution (1 ml) of retinoic acid-1,2: 3,4-di-O-isopropylidene-D-psicofuranose (50 mg) at room temperature. After stirring for 20 hours, the hydroxyl protecting group could not be removed.
プシコースを用いてレチノイン酸の水溶性を高め、得られたプシコースのレチノイン酸エステルは、医薬品及び化粧品の分野で有用であることが期待される。
Psicose is used to increase the water solubility of retinoic acid, and the obtained retinoic acid ester of psicose is expected to be useful in the fields of pharmaceuticals and cosmetics.
Claims (2)
Formula II
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| JP2004077127A JP4535238B2 (en) | 2004-03-17 | 2004-03-17 | Retinoic acid ester of psicose and method for producing the same |
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| JP5358802B2 (en) * | 2007-03-16 | 2013-12-04 | 国立大学法人 香川大学 | Process for producing novel rare sugar fatty acid diesters |
| WO2016210087A1 (en) * | 2015-06-23 | 2016-12-29 | Massachusetts Institute Of Technology | Nano-fibular nanoparticle polymer-drug conjugate for sustained dermal delivery of retinoids |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09503499A (en) * | 1993-10-06 | 1997-04-08 | チバーガイギー アクチエンゲゼルシャフト | Water soluble retinoid |
| JP3160105B2 (en) * | 1992-12-11 | 2001-04-23 | 三共株式会社 | Psicofuranose and Psicopyranose derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP3160105B2 (en) * | 1992-12-11 | 2001-04-23 | 三共株式会社 | Psicofuranose and Psicopyranose derivatives |
| JPH09503499A (en) * | 1993-10-06 | 1997-04-08 | チバーガイギー アクチエンゲゼルシャフト | Water soluble retinoid |
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