JP2012051836A - Production method of hydroxyproline derivative - Google Patents
Production method of hydroxyproline derivative Download PDFInfo
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- JP2012051836A JP2012051836A JP2010195623A JP2010195623A JP2012051836A JP 2012051836 A JP2012051836 A JP 2012051836A JP 2010195623 A JP2010195623 A JP 2010195623A JP 2010195623 A JP2010195623 A JP 2010195623A JP 2012051836 A JP2012051836 A JP 2012051836A
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- hydroxyproline
- trans
- benzyloxycarbonyl
- general formula
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- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical class O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 title claims abstract description 56
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 claims abstract description 31
- -1 alkali metal bicarbonate Chemical class 0.000 claims abstract description 19
- 229960002591 hydroxyproline Drugs 0.000 claims abstract description 17
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 239000002585 base Substances 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 8
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 5
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims abstract description 5
- 150000008041 alkali metal carbonates Chemical class 0.000 claims abstract description 5
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims abstract description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 230000006181 N-acylation Effects 0.000 claims description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 3
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 15
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000005886 esterification reaction Methods 0.000 description 9
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 8
- 230000032050 esterification Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 235000019445 benzyl alcohol Nutrition 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- WWVCWLBEARZMAH-MNOVXSKESA-N (2s,4r)-4-hydroxy-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1=CC=CC=C1 WWVCWLBEARZMAH-MNOVXSKESA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- ZFTFAPZRGNKQPU-UHFFFAOYSA-N dicarbonic acid Chemical compound OC(=O)OC(O)=O ZFTFAPZRGNKQPU-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 0 *C(C1)NCC1O Chemical compound *C(C1)NCC1O 0.000 description 1
- VVKAGQHUUDRPOI-NEPJUHHUSA-N 1-o-benzyl 2-o-methyl (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1=CC=CC=C1 VVKAGQHUUDRPOI-NEPJUHHUSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 229910000032 lithium hydrogen carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
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- Pyrrole Compounds (AREA)
Abstract
Description
本発明は医薬や農薬の原料として有用なヒドロキシプロリン誘導体の工業的に有利な製造法に関する。 The present invention relates to an industrially advantageous process for producing hydroxyproline derivatives useful as raw materials for pharmaceuticals and agricultural chemicals.
ヒドロキシプロリン誘導体の製造法としてはトランス−４−ヒドロキシ−Ｌ−プロリンを出発原料とし、Ｎ−アシル化した後、エステル化することでトランス−４−ヒドロキシ−Ｌ−プロリン誘導体を得る方法が示されている（特開２００５−１１２７６１号公報実施例）。 As a method for producing a hydroxyproline derivative, a method is described in which trans-4-hydroxy-L-proline is used as a starting material, N-acylation is performed, and esterification is performed to obtain a trans-4-hydroxy-L-proline derivative. (Examples of JP 2005-112761 A).
特許文献１記載の方法は、トランス−４−ヒドロキシ−Ｌ−プロリンを誘導化する際、アミノ基、カルボキシル基の順で誘導化している。この方法はアミノ基の誘導化は水溶液系で行い、次のカルボキシル基の誘導化は非水溶液系で行うため、抽出を行い、さらに共沸脱水を行い系内から水を除くため、工程数、及び溶媒使用量が多い。また、Ｎ位を誘導化した化合物はトルエン等の芳香族炭化水素に対しては溶解度が低いため、抽剤には高価なテトラヒドロフラン（以下、ＴＨＦと略す）やシクロペンチルメチルエーテル（以下、ＣＰＭＥと略す）等のエーテル系溶媒を使用する必要があり、製造コストが高かった。 In the method described in Patent Document 1, trans-4-hydroxy-L-proline is derivatized in the order of an amino group and a carboxyl group. In this method, derivatization of amino groups is carried out in an aqueous solution system, and the subsequent derivatization of carboxyl groups is carried out in a non-aqueous solution system. And a large amount of solvent is used. In addition, since the compound derivatized at the N position has low solubility in aromatic hydrocarbons such as toluene, the extractant is expensive in tetrahydrofuran (hereinafter abbreviated as THF) or cyclopentyl methyl ether (hereinafter abbreviated as CPME). ) And the like, and the production cost was high.
本発明の目的は、工業的に簡便かつ安価なヒドロキシプロリン誘導体を製造する方法を提供することにある。 An object of the present invention is to provide an industrially simple and inexpensive method for producing a hydroxyproline derivative.
本発明者らは前記課題を解決する方法について鋭意検討した結果、上記目標を達成できることを見いだし、本発明を完成するに至った。 As a result of intensive studies on a method for solving the above problems, the present inventors have found that the above-mentioned goal can be achieved, and have completed the present invention.
すなわちヒドロキシプロリンをエステル化して一般式（１） That is, hydroxyproline is esterified to form the general formula (1)
（式中、Ｒ１は炭素数１〜６のアルキル基、アリール基、アラルキル基のいずれかを示す。）に示される化合物にした後、アルカリ金属炭酸塩、アルカリ土類金属炭酸塩、アルカリ金属炭酸水素塩、アルカリ土類金属炭酸水素塩から選ばれる、少なくとも１種類以上の塩基共存下において、Ｎ−アシル化して一般式（２） (Wherein R 1 represents any one of an alkyl group having 1 to 6 carbon atoms, an aryl group, and an aralkyl group), and then an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal N-acylation is carried out in the presence of at least one base selected from hydrogen carbonate and alkaline earth metal hydrogen carbonate.
（式中、Ｒ１は炭素数１〜６のアルキル基、アリール基、アラルキル基のいずれかを示し、Ｒ２は炭素数が１〜６のアルキルカルボニル基、アリールカルボニル基、アルコキシカルボニル基、アリールオキシカルボニル基、アラルキルオキシカルボニル基のいずれかを示す）で表されるヒドロキシプロリン誘導体を製造するヒドロキシプロリン誘導体の製造法である。 (In the formula, R 1 represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, and an aralkyl group, and R 2 represents an alkylcarbonyl group having 1 to 6 carbon atoms, an arylcarbonyl group, an alkoxycarbonyl group, and an aryl group. This is a method for producing a hydroxyproline derivative for producing a hydroxyproline derivative represented by an oxycarbonyl group or an aralkyloxycarbonyl group.
ヒドロキシプロリンを出発原料とし、安価な原料を用いて簡便かつ収率よく工業的に適した方法でヒドロキシプロリン誘導体を得られる。本発明により得られたヒドロキシプロリン誘導体は、医薬や農薬の原料として有用である。 Using hydroxyproline as a starting material, a hydroxyproline derivative can be obtained by an industrially suitable method in a simple and high yield using an inexpensive raw material. The hydroxyproline derivative obtained by the present invention is useful as a raw material for pharmaceuticals and agricultural chemicals.
本発明の方法により、溶媒費用の大幅削減と工程数の削減が可能であり、さらに従来の方法より高い収率でヒドロキシプロリン誘導体を得ることができる。 By the method of the present invention, the solvent cost can be greatly reduced and the number of steps can be reduced, and a hydroxyproline derivative can be obtained at a higher yield than the conventional method.
本発明の原料であるヒドロキシプロリンはトランス体、シス体、またＤ体、Ｌ体のいずれであっても同様に使用することができ、得られる化合物についても原料と同じ立体関係は保持される。例えば、トランス−（２Ｓ，４Ｒ）−ヒドロキシプロリンから得られる、ヒドロキシプロリン誘導体の立体配置は必ず（２Ｓ，４Ｒ）である。 Hydroxyproline, which is a raw material of the present invention, can be used in the same manner regardless of whether it is in a trans form, a cis form, a D form, or an L form. For example, the configuration of a hydroxyproline derivative obtained from trans- (2S, 4R) -hydroxyproline is always (2S, 4R).
本発明は、カルボキシル基をエステル化するエステル化工程、アミノ基を誘導化するＮ−アシル化の工程から構成される。収率よくヒドロキシプロリン誘導体を得るには、ヒドロキシプロリンをエステル化し、次いでＮ−アシル化する。 The present invention comprises an esterification step for esterifying a carboxyl group and an N-acylation step for derivatizing an amino group. In order to obtain a hydroxyproline derivative with high yield, the hydroxyproline is esterified and then N-acylated.
以下、エステル化、Ｎ−アシル化の各工程の詳細について説明する。 Hereinafter, the detail of each process of esterification and N-acylation is demonstrated.
＜エステル化＞
本発明では、ヒドロキシプロリンをエステル化する。
<Esterification>
In the present invention, hydroxyproline is esterified.
エステル化は、好ましくは、ヒドロキシプロリンをアルコール中で塩化チオニルを用いて反応させる。この際、エステル化に用いるアルコールとしては、炭素数が１〜６のアルキルアルコール、アリールアルコール、アラルキルアルコールのいずれかを用いる。エステル化に用いるアルコールは、好ましくは、炭素数が１〜６のアルキルアルコールを用いる。具体的にはメタノール、エタノール、ｎ−プロパノール、イソプロパノール、ｎ−ブタノール、ｎ−ペンタノール、ｎ−ヘキサノールなどが好ましい。またこの時、反応に関与しない脂肪族炭化水素、芳香族炭化水素などの他の有機溶媒が混在していても問題ない。 For esterification, preferably hydroxyproline is reacted in alcohol with thionyl chloride. Under the present circumstances, as alcohol used for esterification, C1-C6 alkyl alcohol, aryl alcohol, and aralkyl alcohol are used. The alcohol used for esterification is preferably an alkyl alcohol having 1 to 6 carbon atoms. Specifically, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, n-hexanol and the like are preferable. At this time, there is no problem even if other organic solvents such as aliphatic hydrocarbons and aromatic hydrocarbons not involved in the reaction are mixed.
エステル化反応において、使用するアルコールの量は、好ましくは、１〜３０モル倍量であり、より好ましくは５〜２５モル倍量、さらにより好ましくは１０〜２０モル倍量である。 In the esterification reaction, the amount of alcohol to be used is preferably 1 to 30 mole times, more preferably 5 to 25 mole times, and even more preferably 10 to 20 mole times.
好ましく使用する塩化チオニルの量は、０．２〜２．０モル倍量が好ましく、より好ましくは０．５〜１．０モル倍量である。また塩化チオニルの滴下温度は０〜５０℃、好ましくは２０〜３０℃である。添加後は温度を３０〜８０℃、好ましくは５０〜６０℃に昇温して熟成する。熟成時間は反応温度によって異なるため一概に言えないが、通常１〜１０時間、好ましくは３〜５時間である。 The amount of thionyl chloride preferably used is preferably 0.2 to 2.0 mole times, more preferably 0.5 to 1.0 mole times. The dropping temperature of thionyl chloride is 0 to 50 ° C, preferably 20 to 30 ° C. After the addition, the temperature is raised to 30 to 80 ° C, preferably 50 to 60 ° C, and ripened. The aging time varies depending on the reaction temperature and cannot be generally described, but is usually 1 to 10 hours, preferably 3 to 5 hours.
本発明では、ヒドロキシプロリンをエステル化して一般式（１） In the present invention, hydroxyproline is esterified to form the general formula (1)
に示される化合物を得る。Ｒ１は、炭素数１〜６のアルキル基、アリール基、アラルキル基のいずれかであり、好ましくは、炭素数１〜６のアルキル基である。具体的には、Ｒ１は、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ペンチル基、ヘキシル基であり、より好ましくはメチル基、エチル基、ｎ−プロピル基、イソプロピル基であり、特に好ましくはメチル基である。 The compound shown in is obtained. R 1 is any one of an alkyl group having 1 to 6 carbon atoms, an aryl group, and an aralkyl group, and preferably an alkyl group having 1 to 6 carbon atoms. Specifically, R 1 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a pentyl group, or a hexyl group, more preferably a methyl group, an ethyl group, an n-propyl group, An isopropyl group, particularly preferably a methyl group.
エステル反応の終了は高速液体クロマトグラフィー（以下ＨＰＬＣと略す）等の分析により、原料であるヒドロキシプロリンの消失を確認することが好ましい。 Completion of the ester reaction is preferably confirmed by disappearance of the raw material hydroxyproline by analysis such as high performance liquid chromatography (hereinafter abbreviated as HPLC).
エステル反応の終了後は減圧下で未反応のアルコールを留去させて系内の液量を、使用したヒドロキシプロリンに対して２〜３重量倍に濃縮することが好ましい。このときアルコールが過剰に残らないようにすると、後の抽出工程での効率が良い。 After completion of the ester reaction, unreacted alcohol is preferably distilled off under reduced pressure, and the amount of liquid in the system is preferably concentrated to 2 to 3 times the amount of hydroxyproline used. At this time, if the alcohol does not remain excessively, the efficiency in the subsequent extraction step is good.
＜Ｎ−アシル化＞
本発明では、エステル反応に次いでＮ−アシル化反応を行う
Ｎ−アシル化は、好ましくは、塩基共存下でアシルハライド、もしくは二炭酸ジアルキルエステル等のアシル化試薬と反応させるが、原料を仕込む順番としては、エステル化した粗体に塩基、水の順で加え、次いでアシル化試薬を加えることが好ましい。
<N-acylation>
In the present invention, an N-acylation reaction is carried out after the ester reaction. The N-acylation is preferably performed in the presence of a base with an acylating reagent such as an acyl halide or dialkyl dicarbonate, but the raw materials are charged in the order. For example, it is preferable to add a base and water in this order to the esterified crude product, and then add an acylating reagent.
本発明では、好ましくは、まずエステル化で得られた粗体中に塩基と水を加えて中和する。このとき反応に影響しない有機溶媒、例えばメタノール、エタノール等のアルコール、ＴＨＦ、ＣＰＭＥ等のエーテル、トルエン、キシレン等の芳香族炭化水素などを加えてもよい。またこの時、温度が高いとエステル部分が加水分解を受けるため、好ましくは、−１０〜３０℃、より好ましくは０〜１０℃の範囲で中和を行うことが好ましい。 In the present invention, preferably, the base and water are first neutralized in the crude product obtained by esterification. At this time, an organic solvent that does not affect the reaction, for example, an alcohol such as methanol or ethanol, an ether such as THF or CPME, an aromatic hydrocarbon such as toluene or xylene may be added. At this time, since the ester portion undergoes hydrolysis when the temperature is high, neutralization is preferably performed in the range of −10 to 30 ° C., more preferably 0 to 10 ° C.
本発明では、アルカリ金属炭酸塩、アルカリ土類金属炭酸塩、アルカリ金属炭酸水素塩、アルカリ土類金属炭酸水素塩から選ばれる、少なくとも１種類以上の塩基共存下においてＮ−アシル化を行う。水酸化ナトリウム、水酸化カリウム、水酸化リチウム等のアルカリ金属水酸化物はエステル部分の加水分解を引き起こすため適さない。 In the present invention, N-acylation is performed in the presence of at least one base selected from alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates, and alkaline earth metal hydrogen carbonates. Alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, and lithium hydroxide are not suitable because they cause hydrolysis of the ester moiety.
塩基は、炭酸ナトリウム、炭酸カリウム、炭酸リチウム等のアルカリ金属炭酸塩、炭酸水素ナトリウム、炭酸水素カリウム、炭酸水素リチウム等のアルカリ金属炭酸水素塩が好ましい。より好ましくは、炭酸ナトリウム、炭酸水素ナトリウムであり、特に好ましくは炭酸ナトリウムである。塩基は水溶液や固体のままでも反応に使用することができる。また塩基の使用量としてはヒドロキシプロリンに対して１〜３モル倍量用いることが好ましく、より好ましくは１．２〜２．０モル倍量である。 The base is preferably an alkali metal carbonate such as sodium carbonate, potassium carbonate or lithium carbonate, or an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate or lithium hydrogen carbonate. More preferred are sodium carbonate and sodium hydrogen carbonate, and particularly preferred is sodium carbonate. The base can be used in the reaction even in the form of an aqueous solution or solid. Moreover, it is preferable to use 1-3 mol times as a usage-amount of a base with respect to hydroxyproline, More preferably, it is 1.2-2.0 mol times.
Ｎ−アシル化する時のアシル化試薬の使用量は、好ましくは、０．９〜１．５モル倍量、より好ましくは１．０〜１．２モル倍量、さらにより好ましくは１．０５〜１．１０モル倍量であり、アシル化試薬の添加時の温度は、好ましくは、−１０〜３０℃、より好ましくは０〜１０℃である。 The amount of the acylating reagent used when N-acylating is preferably 0.9 to 1.5 mol times, more preferably 1.0 to 1.2 mol times, and even more preferably 1.05. The temperature at the time of addition of the acylating reagent is preferably −10 to 30 ° C., more preferably 0 to 10 ° C.
また系内の温度を保つため、アシル化試薬の添加方法は滴下による方法が好ましい。滴下終了後は、好ましくは、温度１０〜４０℃、より好ましくは２０〜３０℃に昇温して熟成する。熟成時間は、通常１〜１０時間、好ましくは３〜５時間である。 In order to maintain the temperature in the system, the addition method of the acylating reagent is preferably a dropping method. After completion of the dropping, the temperature is preferably increased to 10 to 40 ° C, more preferably 20 to 30 ° C, and aging is performed. The aging time is usually 1 to 10 hours, preferably 3 to 5 hours.
使用するアシル化試薬としては、アルキルカルボニルクロリド、アルコキシカルボニルクロリド、アリールカルボニルクロリド、アラルキルオキシカルボニルクロリド、アリールオキシカルボニルクロリド、二炭酸ジアルキルエステル等を用いることができる。アシル化試薬は、好ましくは、アセチルクロリド、ベンゾイルクロリド、ベンジルオキシカルボニルクロリド、二炭酸ジｔｅｒｔ−ブチルエステルであり、特に好ましくは、ベンジルオキシカルボニルクロリドを用いることができる。 As the acylating reagent to be used, alkylcarbonyl chloride, alkoxycarbonyl chloride, arylcarbonyl chloride, aralkyloxycarbonyl chloride, aryloxycarbonyl chloride, dialkyl dicarbonate, etc. can be used. The acylating reagent is preferably acetyl chloride, benzoyl chloride, benzyloxycarbonyl chloride or ditert-butyl dicarbonate, and benzyloxycarbonyl chloride can be used particularly preferably.
本発明では、Ｎ−アシル化反応の終了はＨＰＬＣ等の分析により、原料であるヒドロキシプロリンエステルの消失を確認することが好ましい。 In the present invention, completion of the N-acylation reaction is preferably confirmed by disappearance of the raw material hydroxyproline ester by analysis such as HPLC.
本発明では、ヒドロキシプロリンをエステル化した後、Ｎ−アシル化して一般式（２） In the present invention, hydroxyproline is esterified and then N-acylated to give the general formula (2)
（式中、Ｒ１は炭素数１〜６のアルキル基、アリール基、アラルキル基のいずれかを示し、Ｒ２は炭素数が１〜６のアルキルカルボニル基、アリールカルボニル基、アルコキシカルボニル基、アリールオキシカルボニル基、アラルキルオキシカルボニル基のいずれかを示す）で表されるヒドロキシプロリン誘導体を製造する。Ｒ２は、好ましくはアセチル基、ｔｅｒｔ−ブトキシカルボニル基、ベンゾイル基、ベンジルオキシカルボニル基、特に好ましくはベンジルオキシカルボニル基である。 (In the formula, R 1 represents any of an alkyl group having 1 to 6 carbon atoms, an aryl group, and an aralkyl group, and R 2 represents an alkylcarbonyl group having 1 to 6 carbon atoms, an arylcarbonyl group, an alkoxycarbonyl group, and an aryl group. A hydroxyproline derivative represented by an oxycarbonyl group or an aralkyloxycarbonyl group is produced. R 2 is preferably an acetyl group, a tert-butoxycarbonyl group, a benzoyl group, a benzyloxycarbonyl group, particularly preferably a benzyloxycarbonyl group.
ヒドロキシプロリン誘導体は、既知の方法を組み合わせることで分離することができるが、好ましくは、以下に有機溶媒を用いた抽出により分離する。 The hydroxyproline derivative can be separated by a combination of known methods, but is preferably separated by extraction using an organic solvent below.
有機溶媒としてはジエチルエーテル、ＴＨＦ、ＣＰＭＥ等のエーテル、トルエン、キシレン等の芳香族炭化水素の使用が好ましいが、抽出効率や経済性を考慮するとＴＨＦ、トルエンがより好ましく、特に好ましくはトルエンである。これらの溶媒は通常単独で用いるが、２種類以上の混合物であってもよい。得られたヒドロキシプロリン誘導体の溶液は必要に応じて、濃縮や蒸留、もしくは晶析を行うことによって、より純度の高い製品を得ることができる。 The organic solvent is preferably an ether such as diethyl ether, THF, or CPME, or an aromatic hydrocarbon such as toluene or xylene. However, THF and toluene are more preferable in consideration of extraction efficiency and economy, and toluene is particularly preferable. . These solvents are usually used alone, but may be a mixture of two or more. The resulting solution of the hydroxyproline derivative can be concentrated, distilled or crystallized as necessary to obtain a product with higher purity.
以下実施例により本発明を説明する。なお実施例において、反応液の組成分析はＨＰＬＣで分析した。分析条件は対象物によって異なるため一律には記載できないが、代表例としてトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンの分析条件を記載する。 The following examples illustrate the invention. In the examples, the composition analysis of the reaction solution was analyzed by HPLC. Although the analysis conditions differ depending on the object, they cannot be described uniformly, but the analysis conditions for trans-benzyloxycarbonyl-4-hydroxy-L-proline are described as typical examples.
＜ＨＰＬＣ分析条件＞
カラム：ＣＡＰＣＥＬＬ ＰＡＫ Ｃ１８（ＳＧ１２０），５μｍ １５０ｍｍ＊４．６ｍｍφ（資生堂）
移動層Ａ：５ｍＭドデシル硫酸ナトリウム＋２０ｍＭリン酸緩衝液（ｐＨ２．８調整）
移動層B：アセトニトリル
Ａ／Ｂ＝８０／２０（１０分）−１０分→４５／５５（２５分）
流速：１．０ｍｌ／ｍｉｎ
温度：４０℃
検出器：ＵＶ ２１０ｎｍ
保持時間 １．８分：トランス−４−ヒドロキシ−Ｌ−プロリン
４．１分：トランス−４−ヒドロキシ−Ｌ−プロリンメチルエステル
８．７分：トランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステル
また、実施例で使用した試薬は、特に注記のない限り市販の試薬１級グレード品を使用した。
<HPLC analysis conditions>
Column: CAPCELL PAK C18 (SG120), 5 μm 150 mm * 4.6 mmφ (Shiseido)
Moving layer A: 5 mM sodium dodecyl sulfate + 20 mM phosphate buffer (pH 2.8 adjustment)
Moving bed B: Acetonitrile A / B = 80/20 (10 minutes) −10 minutes → 45/55 (25 minutes)
Flow rate: 1.0 ml / min
Temperature: 40 ° C
Detector: UV 210nm
Retention time 1.8 minutes: trans-4-hydroxy-L-proline
4.1 min: trans-4-hydroxy-L-proline methyl ester
8.7 min: trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester The reagents used in the examples were commercially available reagent grade 1 grades unless otherwise noted.
実施例１
温度計、ジムロート、攪拌機を備えた３０００ｍｌの４つ口フラスコにメタノール１７７１ｇ、トランス−Ｌ−ヒドロキシプロリン３５４ｇ（２．７０モル）を加えた。１５℃に冷却し、攪拌しながら滴下ロートを用いて塩化チオニル１９３ｇを１時間かけて滴下した。滴下終了後６０℃に昇温して５時間熟成した。次いで温度を保ちながら１３ｋＰａで減圧濃縮でメタノールを留出させ、スラリーを得た。スラリー中のトランス−４−ヒドロキシ−Ｌ−プロリンメチルエステルの含量は２．５８モル（収率９５．７％）であった。
Example 1
To a 3000 ml four-necked flask equipped with a thermometer, a Dimroth, and a stirrer, 1771 g of methanol and 354 g (2.70 mol) of trans-L-hydroxyproline were added. The mixture was cooled to 15 ° C., and 193 g of thionyl chloride was added dropwise over 1 hour using a dropping funnel while stirring. After completion of dropping, the temperature was raised to 60 ° C. and aged for 5 hours. Next, methanol was distilled off under reduced pressure at 13 kPa while maintaining the temperature to obtain a slurry. The content of trans-4-hydroxy-L-proline methyl ester in the slurry was 2.58 mol (yield 95.7%).
スラリー全量に水３５４ｇと炭酸ナトリウム３５８ｇを添加した。温度を１０℃に保ちながら滴下ロートを用いてベンジルオキシカルボニルクロリド４８４ｇを３時間かけて滴下添加した。滴下終了後は２０℃で２時間反応熟成した後、トルエン５３１ｇを加え分液してトランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルを抽出した。分液した水層側からはさらにトルエン１７７ｇを加えることで水層中のトランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルを抽出・回収した。分液した２種類のトルエン層は混合した後、６０℃で８ｋＰａの減圧下で濃縮し、トランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルの粗体７９９ｇを得た。 To the total amount of the slurry, 354 g of water and 358 g of sodium carbonate were added. While maintaining the temperature at 10 ° C., 484 g of benzyloxycarbonyl chloride was added dropwise over 3 hours using a dropping funnel. After completion of the dropwise addition, the reaction was aged at 20 ° C. for 2 hours, 531 g of toluene was added and the mixture was separated to extract trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester. From the separated aqueous layer side, 177 g of toluene was further added to extract and collect trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester in the aqueous layer. The two separated toluene layers were mixed and then concentrated at 60 ° C. under reduced pressure of 8 kPa to obtain 799 g of a crude product of trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester.
粗体中のトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルの含量は２．４１モル（収率９１．６％）であった。また副生したベンジルアルコールと目的物の比率は０．００３（ａｒｅａ／ａｒｅａ）であった。トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は８８％であった。 The content of trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester in the crude product was 2.41 mol (yield 91.6%). The ratio of by-produced benzyl alcohol to the target product was 0.003 (area / area). The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 88%.
実施例２
実施例１と同様の操作で得た、トランス−４−ヒドロキシ−Ｌ−プロリンメチルエステル０．１８ｇ（１．０ｍｍｏｌ）に水２．０ｇを加え、炭酸水素ナトリウム０．１７ｇ（２．１ｍｍｏｌ）を加えた。さらに氷冷下でベンジルオキシカルボニルクロリド０．１５ｇを加え、２５℃で２時間熟成した。
Example 2
2.0 g of water was added to 0.18 g (1.0 mmol) of trans-4-hydroxy-L-proline methyl ester obtained in the same manner as in Example 1, and 0.17 g (2.1 mmol) of sodium bicarbonate was added. added. Further, 0.15 g of benzyloxycarbonyl chloride was added under ice cooling, and the mixture was aged at 25 ° C. for 2 hours.
反応後のサンプルを分析したところ、トランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルの収率は８７％、副生したベンジルアルコールと目的物の比率は、０．００５（ａｒｅａ／ａｒｅａ）であった。トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は８３％であった。 When the sample after the reaction was analyzed, the yield of trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester was 87%, and the ratio of by-produced benzyl alcohol to the target product was 0.005 (area / area). there were. The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 83%.
比較例１
実施例１と同様の操作で得た、トランス−４−ヒドロキシ−Ｌ−プロリンメチルエステル０．３６ｇ（２．０ｍｍｏｌ）に水２．０ｇを加え、２５％水酸化ナトリウム水溶液０．３ｇ（４．１ｍｍｏｌ）を加えた。さらに氷冷下でベンジルオキシカルボニルクロリド０．３ｇを加え、２５℃で２時間熟成した。
Comparative Example 1
2.0 g of water was added to 0.36 g (2.0 mmol) of trans-4-hydroxy-L-proline methyl ester obtained in the same manner as in Example 1, and 0.3 g of 25% aqueous sodium hydroxide solution (4. 1 mmol) was added. Further, 0.3 g of benzyloxycarbonyl chloride was added under ice cooling, and the mixture was aged at 25 ° C. for 2 hours.
反応後のサンプルを分析したところ、トランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルの収率は５７％、副生したベンジルアルコールと目的物の比率は、０．２１１（ａｒｅａ／ａｒｅａ）であった。トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は５４％であった。 When the sample after the reaction was analyzed, the yield of trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester was 57%, and the ratio of by-produced benzyl alcohol to the target product was 0.211 (area / area). there were. The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 54%.
比較例２
実施例１と同様の操作で得た、トランス−４−ヒドロキシ−Ｌ−プロリンメチルエステル０．３６ｇ（２．０ｍｍｏｌ）にトルエン２．０ｇを加え、トリエチルアミン０．２ｇ（４．１ｍｍｏｌ）を加えた。さらに氷冷下でベンジルオキシカルボニルクロリド０．３ｇを加え、２５℃で２時間熟成した。
Comparative Example 2
2.0 g of toluene was added to 0.36 g (2.0 mmol) of trans-4-hydroxy-L-proline methyl ester obtained by the same operation as in Example 1, and 0.2 g (4.1 mmol) of triethylamine was added. . Further, 0.3 g of benzyloxycarbonyl chloride was added under ice cooling, and the mixture was aged at 25 ° C. for 2 hours.
反応後のサンプルを分析したところトランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルの収率は２６％、副生したベンジルアルコールと目的物の比率は０．１７５（ａｒｅａ／ａｒｅａ）であった。トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は２５％であった。 When the sample after the reaction was analyzed, the yield of trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester was 26%, and the ratio of by-produced benzyl alcohol to the target product was 0.175 (area / area). . The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 25%.
比較例３
実施例１と同様の操作で得た、トランス−４−ヒドロキシ−Ｌ−プロリンメチルエステル０．３６ｇ（２．０ｍｍｏｌ）にメタノール２．０ｇを加え、トリエチルアミン０．２ｇ（４．１ｍｍｏｌ）を加えた。さらに氷冷下でベンジルオキシカルボニルクロリド０．３ｇを加え、２５℃で２時間熟成した。
Comparative Example 3
2.0 g of methanol was added to 0.36 g (2.0 mmol) of trans-4-hydroxy-L-proline methyl ester obtained by the same operation as in Example 1, and 0.2 g (4.1 mmol) of triethylamine was added. . Further, 0.3 g of benzyloxycarbonyl chloride was added under ice cooling, and the mixture was aged at 25 ° C. for 2 hours.
反応後のサンプルを分析したところトランス−ベンジルオキシカルボニル−ヒドロキシ−Ｌ−プロリンメチルエステルの収率は６８％、副生したベンジルアルコールと目的物の比率は０．０８８（ａｒｅａ／ａｒｅａ）であった。トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は６５％であった。 When the sample after the reaction was analyzed, the yield of trans-benzyloxycarbonyl-hydroxy-L-proline methyl ester was 68%, and the ratio of by-produced benzyl alcohol to the target product was 0.088 (area / area). . The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 65%.
比較例４
特許文献１記載の方法を追試し、収率を確認した。
Comparative Example 4
The method described in Patent Document 1 was further tested to confirm the yield.
攪拌機、滴下ロート、ジムロート、温度計、ｐＨメーターを装着した２０００ ｍｌの４口フラスコに、Ｌ−ヒドロキシプロリン１３２．０ ｇ（１．０モル）、４８％水酸化ナトリウム水溶液８６ｇ（１．０３モル）、水６５５ｇを仕込み、室温にて撹拌した。ｐＨを１１．５〜１２．０に保ちながら、ベンジルオキシカルボニルクロリド１７９ｇ（１．０５モル）と４８％水酸化ナトリウム水溶液８４ｇを交互に滴下した。滴下終了後１．５時間撹拌したのちトルエン３００ｇを加え、分液してトルエン層を除去した。水層にＣＰＭＥ６００ｇを加え、撹拌しながら９５％硫酸６３．８ｇを加えた。撹拌を停止し、分液して水層を除去したのち、４０ｋＰａで減圧濃縮を行った。留出液の水層を分液除去し、上層をフラスコに戻して再度減圧濃縮を行い、トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンを含むＣＰＭＥ溶液８８８ｇを得た（トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンとして２６重量％、２２９．６ｇ（０．８７モル，収率８６．６％）含有）。本工程の収率は８６．６％であった。 L-hydroxyproline 132.0 g (1.0 mol), 48% aqueous sodium hydroxide solution 86 g (1.03 mol) were added to a 2000 ml four-necked flask equipped with a stirrer, dropping funnel, Dimroth, thermometer and pH meter. ) And 655 g of water were charged and stirred at room temperature. While maintaining the pH at 11.5 to 12.0, 179 g (1.05 mol) of benzyloxycarbonyl chloride and 84 g of 48% aqueous sodium hydroxide solution were alternately added dropwise. After stirring for 1.5 hours after completion of the dropwise addition, 300 g of toluene was added, followed by liquid separation to remove the toluene layer. To the aqueous layer, 600 g of CPME was added, and 63.8 g of 95% sulfuric acid was added with stirring. Stirring was stopped, liquid separation was performed, and the aqueous layer was removed, followed by concentration under reduced pressure at 40 kPa. The aqueous layer of the distillate was removed, and the upper layer was returned to the flask and concentrated again under reduced pressure to obtain 888 g of CPME solution containing trans-benzyloxycarbonyl-4-hydroxyproline (trans-benzyloxycarbonyl-4 -Containing 26% by weight as hydroxyproline, 229.6 g (0.87 mol, yield 86.6%). The yield of this step was 86.6%.
トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンのＣＰＭＥ溶液８８８ｇ（トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンとして２６重量％、２２９．６ｇ含有）にメタノール３２０ｇ（１０モル）、９５％硫酸１０．３ｇ（０．１モル）を加えた。４５〜５０℃に昇温して５時間撹拌したのち、炭酸ナトリウム１５．９ｇ（０．１５モル）を加え０．５時間撹拌したのち、４０ｋＰａで減圧濃縮して過剰のメタノールを除去した。この濃縮液にＣＰＭＥ４００ｇ、水２００ｇを加え撹拌し、水層を分液除去したのち、ＣＰＭＥ層を２４ｋＰａで減圧濃縮した。留出液の水層を分液除去し、上層をフラスコに戻して再度減圧濃縮を行い、トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンメチルエステルを含むＣＰＭＥ溶液６２２ｇを得た（トランス−ベンジルオキシカルボニル−４−ヒドロキシプロリンメチルエステルとして３５重量％、２１８．７ｇ（０．７８モル，収率９０．４％）含有）。 888 g of CPME solution of trans-benzyloxycarbonyl-4-hydroxyproline (containing 26 wt% and 229.6 g as trans-benzyloxycarbonyl-4-hydroxyproline) 320 g (10 mol) of methanol, 10.3 g of 95% sulfuric acid ( 0.1 mol) was added. After raising the temperature to 45-50 ° C. and stirring for 5 hours, 15.9 g (0.15 mol) of sodium carbonate was added and stirred for 0.5 hour, and then concentrated under reduced pressure at 40 kPa to remove excess methanol. To this concentrated liquid, 400 g of CPME and 200 g of water were added and stirred. After the aqueous layer was separated and removed, the CPME layer was concentrated under reduced pressure at 24 kPa. The aqueous layer of the distillate was removed, and the upper layer was returned to the flask and concentrated again under reduced pressure to obtain 622 g of CPME solution containing trans-benzyloxycarbonyl-4-hydroxyproline methyl ester (trans-benzyloxycarbonyl). 35 wt% as 21-hydroxyproline methyl ester, 218.7 g (0.78 mol, yield 90.4%)).
トランス−４−ヒドロキシ−Ｌ−プロリンからトランス−ベンジルオキシカルボニル−４−ヒドロキシ−Ｌ−プロリンメチルエステルまでの収率は７８％であった。 The yield from trans-4-hydroxy-L-proline to trans-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester was 78%.
以上の実施例と比較例の結果を表１に示す。本発明の方法により、溶媒費用の大幅削減と工程数の削減が可能であり、さらに従来の方法より高い収率でヒドロキシプロリン誘導体を得ることができる。 Table 1 shows the results of the above examples and comparative examples. By the method of the present invention, the solvent cost can be greatly reduced and the number of steps can be reduced, and a hydroxyproline derivative can be obtained at a higher yield than the conventional method.
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| CN104030958A (en) * | 2014-06-06 | 2014-09-10 | 河北科技大学 | Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile |
| CN114778743A (en) * | 2022-05-19 | 2022-07-22 | 常州制药厂有限公司 | Method for detecting trace chiral isomer D-proline in L-proline |
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