JPS6245230B2 - - Google Patents
Info
- Publication number
- JPS6245230B2 JPS6245230B2 JP58048769A JP4876983A JPS6245230B2 JP S6245230 B2 JPS6245230 B2 JP S6245230B2 JP 58048769 A JP58048769 A JP 58048769A JP 4876983 A JP4876983 A JP 4876983A JP S6245230 B2 JPS6245230 B2 JP S6245230B2
- Authority
- JP
- Japan
- Prior art keywords
- dimethyl
- dimethylthiazolidine
- benzoyl
- group
- reaction
- 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
Links
- 238000004519 manufacturing process Methods 0.000 claims description 8
- CJVKUCKSANIOEH-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidin-5-ol Chemical class CC1(SC(CN1)O)C CJVKUCKSANIOEH-UHFFFAOYSA-N 0.000 claims description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
- 239000001301 oxygen Substances 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 239000003504 photosensitizing agent Substances 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000000034 method Methods 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- -1 β-lactam compound Chemical class 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- OCQICQZUUHJWGZ-UHFFFAOYSA-N 2,2-Dimethylthiazolidine-4-Carboxylic Acid Chemical compound CC1(C)NC(C(O)=O)CS1 OCQICQZUUHJWGZ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- HOKIDJSKDBPKTQ-GLXFQSAKSA-N cephalosporin C Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(O)=O)[C@@H]12 HOKIDJSKDBPKTQ-GLXFQSAKSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 229960000907 methylthioninium chloride Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 125000001984 thiazolidinyl group Chemical group 0.000 description 3
- SNPQRYOQWLOTFA-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidine Chemical class CC1(C)NCCS1 SNPQRYOQWLOTFA-UHFFFAOYSA-N 0.000 description 2
- ZTNRUDZRCMWXPD-UHFFFAOYSA-N 3-benzoyl-2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid Chemical compound CC1(C)SCC(C(O)=O)N1C(=O)C1=CC=CC=C1 ZTNRUDZRCMWXPD-UHFFFAOYSA-N 0.000 description 2
- IICCLYANAQEHCI-UHFFFAOYSA-N 4,5,6,7-tetrachloro-3',6'-dihydroxy-2',4',5',7'-tetraiodospiro[2-benzofuran-3,9'-xanthene]-1-one Chemical compound O1C(=O)C(C(=C(Cl)C(Cl)=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 IICCLYANAQEHCI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000000862 absorption spectrum Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000921 elemental analysis Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- JEHCHYAKAXDFKV-UHFFFAOYSA-J lead tetraacetate Chemical compound CC(=O)O[Pb](OC(C)=O)(OC(C)=O)OC(C)=O JEHCHYAKAXDFKV-UHFFFAOYSA-J 0.000 description 2
- KFYOQUXLXDGFPE-UHFFFAOYSA-N methyl 3-benzoyl-2,2-dimethyl-1,3-thiazolidine-4-carboxylate Chemical compound COC(=O)C1CSC(C)(C)N1C(=O)C1=CC=CC=C1 KFYOQUXLXDGFPE-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229930187593 rose bengal Natural products 0.000 description 2
- 229940081623 rose bengal Drugs 0.000 description 2
- STRXNPAVPKGJQR-UHFFFAOYSA-N rose bengal A Natural products O1C(=O)C(C(=CC=C2Cl)Cl)=C2C21C1=CC(I)=C(O)C(I)=C1OC1=C(I)C(O)=C(I)C=C21 STRXNPAVPKGJQR-UHFFFAOYSA-N 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- HQMDAVFIGRLKQG-UHFFFAOYSA-N 2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid;hydrochloride Chemical compound Cl.CC1(C)NC(C(O)=O)CS1 HQMDAVFIGRLKQG-UHFFFAOYSA-N 0.000 description 1
- MYZNHPUWNUGYOV-UHFFFAOYSA-N 2,2-dimethyl-3-[(2-methylpropan-2-yl)oxycarbonyl]-1,3-thiazolidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C(C(O)=O)CSC1(C)C MYZNHPUWNUGYOV-UHFFFAOYSA-N 0.000 description 1
- 229910000761 Aluminium amalgam Inorganic materials 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 206010034972 Photosensitivity reaction 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
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000004837 alkyl aryl thioethers Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 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
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000001983 dialkylethers Chemical group 0.000 description 1
- NCBFTYFOPLPRBX-UHFFFAOYSA-N dimethyl azodicarboxylate Substances COC(=O)N=NC(=O)OC NCBFTYFOPLPRBX-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- NCBFTYFOPLPRBX-AATRIKPKSA-N methyl (ne)-n-methoxycarbonyliminocarbamate Chemical compound COC(=O)\N=N\C(=O)OC NCBFTYFOPLPRBX-AATRIKPKSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 208000017983 photosensitivity disease Diseases 0.000 description 1
- 231100000434 photosensitization Toxicity 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 239000010937 tungsten Substances 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Thiazole And Isothizaole Compounds (AREA)
Description
【発明の詳細な説明】
本発明は２・２−ジメチル−５−ヒドロキシチ
アゾリジン誘導体の新規合成方法に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for the synthesis of 2,2-dimethyl-5-hydroxythiazolidine derivatives.
２・２−ジメチル−５−ヒドロキシチアゾリジ
ンはβ−ラクタム系抗生物質であるセフアロスポ
リン合成の際の中間体として有用な化合物であ
る。セフアロスポリンはペニシリンと共に現在広
範に用いられている有用な薬剤であり、一般に発
酵法および化学合成法の併用により製造されてい
る。一方、純化学的合成法によりセフアロスポリ
ンを合成する方法も報告されている。 2,2-dimethyl-5-hydroxythiazolidine is a compound useful as an intermediate in the synthesis of cephalosporin, a β-lactam antibiotic. Cephalosporin is a useful drug that is currently widely used along with penicillin, and is generally produced by a combination of fermentation and chemical synthesis methods. On the other hand, a method for synthesizing cephalosporin using a pure chemical synthesis method has also been reported.
例えば、J.Am.Chem.Soc.88、852頁にはWood
−ward氏等のセフアロスポリンＣの全合成につ
いて記載されており、セフアロスポリンＣ、およ
びペニシリンに共通の基本構造要素として、次式
で示される重要な中間体のβ−ラクタム化合物(H)
を経由して製造される。 For example, in J.Am.Chem.Soc. 88 , p. 852, Wood
The total synthesis of cephalosporin C by Mr. Ward et al. is described, and as a basic structural element common to cephalosporin C and penicillin, an important intermediate β-lactam compound (H) shown by the following formula is used.
Manufactured via.
通常、このβ−ラクタム化合物は先づシステイ
ン(A)とアセトンとの縮合でチアゾリジン環を形成
させて２・２−ジメチルチアゾリジン−４−カル
ボン酸(B)をえ、アミノ基を低級アシル基、ベンゾ
イル基、ベンジルオキシカルボニル基、ｔ−ブチ
ルオキシカルボニル基などのアミノ保護基で保護
し、所望により低級アルキルエステル(C)として、
後続工程に供される。 Usually, this β-lactam compound is first formed by condensing cysteine (A) with acetone to form a thiazolidine ring to obtain 2,2-dimethylthiazolidine-4-carboxylic acid (B), and the amino group is replaced with a lower acyl group. Protected with an amino protecting group such as a benzoyl group, benzyloxycarbonyl group, t-butyloxycarbonyl group, and optionally as a lower alkyl ester (C),
Provided for subsequent processes.
上記文献の記載からこれを要約すると次式の通
りである。 This can be summarized from the description in the above literature as follows.
備 考
(a) アセトンとの縮合によるチアゾリジン環の形
成、
(b) ｔ−ブチルオキシカルボニルクロライドによ
るアミノ基保護と、ジアゾメタンによるメチル
エステル化、
(c) ジメチルアゾジカルボキシレートを用いるヒ
ドラゾジエステル化、
(d) 四酢酸鉛によるヒドロキシエステル化、
(e) 水性ナトリウムアジドによるアジドエステル
化、
(f) アルミニウムアマルガムによる還元。 Notes (a) Formation of a thiazolidine ring by condensation with acetone, (b) Amino group protection with t-butyloxycarbonyl chloride and methyl esterification with diazomethane, (c) Hydrazodiesterization with dimethylazodicarboxylate , (d) hydroxyesterification with lead tetraacetate, (e) azideesterification with aqueous sodium azide, (f) reduction with aluminum amalgam.
本発明者は上記β−ラクタム製造工程におい
て、特に(c)工程および(d)工程を行なう５−ヒドロ
キシ誘導体(E)の製造に関し、該工程がアゾジカル
ボン酸エステルを反応させ、このエステルに毒性
の強い四酢酸鉛を作用させるなど工業的実用性に
乏しい点に着目した。チアゾリジン環の５−位に
ヒドロキシ基を導入する他の技術として、J.Am.
Chem.Soc.、97、5957頁（1975）でBaldwin氏等
は過酸化ベンゾイルを用いてベンゾエートとし、
これを加水分解する方法が教示されているが、こ
の反応も低収率であるため実用性はない。 In the above-mentioned β-lactam production process, the present inventor has found that, in particular, regarding the production of the 5-hydroxy derivative (E) in which steps (c) and (d) are carried out, the process reacts with an azodicarboxylic acid ester, and this ester is toxic. We focused on the lack of industrial practicality, such as the use of strong lead tetraacetate. Another technique for introducing a hydroxy group at the 5-position of the thiazolidine ring is described by J.Am.
Chem.Soc., 97, p. 5957 (1975), Baldwin et al. used benzoyl peroxide to form the benzoate,
Although a method of hydrolyzing this is taught, this reaction also has a low yield and is therefore impractical.
したがつて、本発明の目的は上記２・２−ジメ
チル−５−ヒドロキシチアゾリジン誘導体の新規
合成方法に関し、従来技術に対して一工程をもつ
て極めて簡単、容易に実施することができ、しか
も好収率で５−ヒドロキシ誘導体を製造する方法
を提供することにある。 Therefore, the object of the present invention is to provide a novel method for synthesizing the above-mentioned 2,2-dimethyl-5-hydroxythiazolidine derivatives, which can be carried out in one step, extremely simply and easily, and which is preferable. The object of the present invention is to provide a method for producing 5-hydroxy derivatives with high yield.
本発明によれば、一般式
（但し、式中のR1は水素または低級アルキル基で
あり、R2はアミノ保護基である）で表わされる
２・２−ジメチルチアゾリジン化合物を光増感剤
の存在で酸素酸化することによつて、一般式
（式中のR1およびR2は前記意味を有する）で表わ
される２・２−ジメチル−５−ヒドロキシ−チア
ゾリジン誘導体を製造する方法である。 According to the invention, the general formula (However, R 1 in the formula is hydrogen or a lower alkyl group, and R 2 is an amino protecting group) is oxidized with oxygen in the presence of a photosensitizer. So, general formula This is a method for producing a 2,2-dimethyl-5-hydroxy-thiazolidine derivative represented by the formula (in which R 1 and R 2 have the above meanings).
本発明の出発化合物である（）式化合物は上
表の教示に従つて、システインとアセトンの縮合
によつて製造される前記のWoodward氏の教示に
よると、遊離システイン１ｇを250c.c.のアセトン
中で1.25時間還流して完全な溶液とし、冷却後、
微量の不溶物を別する。液を飽和点まで濃縮
し、過後放置すると目的の２・２−ジメチルチ
アゾリジン−４−カルボン酸が63〜71％の収率で
得られる。このものは水に容易に溶解し、融点
134〜134.5℃を有する。 The starting compound of the present invention, a compound of formula Reflux for 1.25 hours in a solution to make a complete solution, and after cooling,
Separate trace amounts of insoluble matter. When the liquid is concentrated to the saturation point and left to stand after filtration, the desired 2,2-dimethylthiazolidine-4-carboxylic acid is obtained in a yield of 63 to 71%. This substance dissolves easily in water and has a melting point of
It has a temperature of 134-134.5℃.
２・２−ジメチルチアゾリジン−４−カルボン
酸のアミノ保護基は前述した任意の適当なカルボ
ニル誘導基が選ばれるが、前記文献に教示された
ｔ−ブチルオキシカルボニル基の場合は２・２−
ジメチルチアゾリジン−４−カルボン酸をｔ−ブ
チルアルコール、ホスゲンおよびピリジンからメ
チレンクロライド中でその場で生成させたｔ−ブ
チルオキシカルボニルクロライドで処理して得て
いる。相当する３−ｔ−ブチルオキシカルボニル
−２・２−ジメチルチアゾリジン−４−カルボン
酸は融点114〜114.5℃、〔α〕２０ Ｄ−85゜である。 As the amino protecting group of 2,2-dimethylthiazolidine-4-carboxylic acid, any suitable carbonyl derivative group mentioned above can be selected, but in the case of the t-butyloxycarbonyl group taught in the above literature, 2,2-
Dimethylthiazolidine-4-carboxylic acid is obtained by treatment with t-butyloxycarbonyl chloride generated in situ in methylene chloride from t-butyl alcohol, phosgene and pyridine. The corresponding 3-tert-butyloxycarbonyl-2,2-dimethylthiazolidine-4-carboxylic acid has a melting point of 114-114.5°C, [α] 20 D -85°.
本発明の方法に使用できる光増感剤は公知の光
増感酸化反応に通常使用されているものであり、
ローズベンガル、メチレンブルー、テトラフエニ
ルポルフイリン等である。反応にはメタノール、
エタノール、アセトニトリルなどの極性溶媒が好
ましく使用される。また、DMSOを添加すること
によつて反応を円滑に進行させることができる。
したがつて、光増感剤としてはこれらの極性溶媒
に溶解性のよいローズベンガル、メチレンブルー
の使用が好ましい。光照射用ランプはハロゲン
−、タングステン−、ナトリウム−ランプおよび
水銀灯を使用する。 The photosensitizers that can be used in the method of the present invention are those commonly used in known photosensitization oxidation reactions,
These include rose bengal, methylene blue, and tetraphenylporphyrin. For the reaction, methanol,
Polar solvents such as ethanol and acetonitrile are preferably used. Furthermore, by adding DMSO, the reaction can proceed smoothly.
Therefore, as the photosensitizer, it is preferable to use rose bengal and methylene blue, which have good solubility in these polar solvents. For light irradiation lamps, halogen, tungsten, sodium lamps and mercury lamps are used.
本発明は具体的には次の要領で実施する。 Specifically, the present invention is carried out in the following manner.
２・２−ジメチルチアゾリジン誘導体（）を
10〜20倍容のメタノール、エタノール、あるいは
アセトニトリルに溶解させ、さらに原料化合物
（）に対し10倍モル程度のDMSOを添加する
と、良好な結果が得られる。添加する光増感剤の
量は原料化合物に対し0.5〜１重量％程度であ
る。この反応液に細管を通して酸素を導入しなが
ら光照射を行なう。反応温度、時間については厳
密な規定はないが、20〜30℃で２〜３時間で反応
は終結する。反応終了後、溶媒を減圧下に留去
し、生成物をシリカゲル カラム クロマトにか
けることによつて目的の２・２−ジメチル−５−
ヒドロキシチアゾリジン誘導体（）を60〜70％
の収率で得ることができる。この反応で消費され
るものは少量の光増感剤と酸素と光源のみであ
り、しかも従来技術による毒性試薬の使用あるい
は低収率の方法に較べて単一工程で、しかも高収
率で目的化合物の製造を可能とするので、工業的
利用価値は非常に高いものと云える。 2,2-dimethylthiazolidine derivative ()
Good results can be obtained by dissolving the compound in 10 to 20 times the volume of methanol, ethanol, or acetonitrile, and then adding DMSO in an amount of about 10 times the molar amount of the starting compound (). The amount of photosensitizer added is about 0.5 to 1% by weight based on the raw material compound. Light irradiation is performed while introducing oxygen into this reaction solution through a thin tube. Although there are no strict regulations regarding reaction temperature and time, the reaction is completed in 2 to 3 hours at 20 to 30°C. After the reaction is complete, the solvent is distilled off under reduced pressure and the product is subjected to silica gel column chromatography to obtain the desired 2,2-dimethyl-5-
Hydroxythiazolidine derivative () 60-70%
can be obtained with a yield of . The reaction consumes only a small amount of photosensitizer, oxygen, and light source, and is a single step and provides high yields compared to prior art methods that use toxic reagents or produce low yields. Since it enables the production of compounds, it can be said to have very high industrial utility value.
因みに、チオエーテル化合物に対し光増感剤、
酸素の存在下で光照射する方法自体は公知であ
る。例えば、Angew.Chem.74、510（1962）には
ジアルキル−およびアルキル−アリールチオエー
テルはこれらの条件で相当するスルホキシドを定
量的に与えることが教示されている。これに反し
て、本発明の場合は前記チアゾリジン誘導体
（）にこの反応系を適用することによつて期待
されるスルホキシドの生成は僅少であつて、反つ
て基質の特異性から全く新しいタイプの反応生成
物である２・２−ジメチル−５−ヒドロキシチア
ゾリジンを高収率で生成させることができた。こ
の事実は従来技術の教示から全く予想されない結
果であつて、この光増感酸素酸化反応系が本発明
の出発化合物のみならず他の同族化合物のヒドロ
キシル化への応用の可能性をも示唆するものであ
る。 Incidentally, for thioether compounds, photosensitizers,
The method of irradiating light in the presence of oxygen is known per se. For example, Angew. Chem. 74, 510 (1962) teaches that dialkyl- and alkyl-arylthioethers give quantitative amounts of the corresponding sulfoxides under these conditions. On the other hand, in the case of the present invention, the expected formation of sulfoxide by applying this reaction system to the thiazolidine derivative () is minimal, and on the contrary, due to the specificity of the substrate, a completely new type of reaction is required. The product 2,2-dimethyl-5-hydroxythiazolidine could be produced in high yield. This fact is a completely unexpected result based on the teachings of the prior art, and suggests the possibility of application of this photosensitized oxygen oxidation reaction system not only to the starting compounds of the present invention but also to the hydroxylation of other homologous compounds. It is something.
以下に参考例および実施例をもつて本発明の具
体的実施を説明する。 The specific implementation of the present invention will be explained below using reference examples and examples.
参考例
(1) ３−ベンゾイル−２・２−ジメチル−４−カ
ルボキシチアゾリジンの製造
２・２−ジメチル−４−カルボキシチアゾリ
ジン塩酸塩（20ｍmol）のピリジン溶液に当量
のベンゾイルクロライドを滴下し、混合物を室
温で８時間撹拌する。ピリジンの留出残渣をジ
クロロメタンに溶解し、溶液を水で洗浄する。
生成有機層を無水硫酸ナトリウムで乾燥し溶媒
を蒸発させて半結晶塊をえ、クロロホルム／ヘ
キサンから針状結晶で３−ベンゾイル−２・２
−ジメチル−４−カルボキシチアゾリジンを回
収する。収率74％。融点180〜182℃。〔α〕２４ Ｄ−
154゜（C0.83、CHCl2）。Reference Example (1) Production of 3-benzoyl-2,2-dimethyl-4-carboxythiazolidine An equivalent amount of benzoyl chloride was added dropwise to a pyridine solution of 2,2-dimethyl-4-carboxythiazolidine hydrochloride (20 mmol), and the mixture was Stir at room temperature for 8 hours. The pyridine distillation residue is dissolved in dichloromethane and the solution is washed with water.
The resulting organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated to give a semi-crystalline mass, and 3-benzoyl-2.2 was crystallized as needles from chloroform/hexane.
-Dimethyl-4-carboxythiazolidine is recovered. Yield 74%. Melting point 180-182℃. [α] 24 D −
154° (C0.83, CHCl 2 ).
(2) ３−ベンゾイル−４−メトキシカルボニル−
２・２−ジメチルチアゾリジンの製造
３−ベンゾイル−２・２−ジメチル−４−カ
ルボキシチアゾリジン（４ｍmol）のメタノー
ル（20ml）溶液に０℃でやや過剰のジアゾメタ
ンのエーテル溶液を加え、12時間撹拌し、溶媒
を除去して白色の結晶生成物を得た。エーテ
ル／ヘキサンで再結晶すると、白色柱状結晶の
３−ベンゾイル−４−メトキシカルボニル−
２・２−ジメチルチアゾリジンが83％の収率で
得られる。融点105〜106.5℃。〔α〕２３ Ｄ−180゜
（C0.92、CHCl3）。(2) 3-benzoyl-4-methoxycarbonyl-
Production of 2,2-dimethylthiazolidine A slightly excess ethereal solution of diazomethane was added to a solution of 3-benzoyl-2,2-dimethyl-4-carboxythiazolidine (4 mmol) in methanol (20 ml) at 0°C, and the mixture was stirred for 12 hours. Removal of the solvent gave a white crystalline product. Recrystallization from ether/hexane gives white columnar crystals of 3-benzoyl-4-methoxycarbonyl-
2,2-dimethylthiazolidine is obtained with a yield of 83%. Melting point 105-106.5℃. [α] 23 D −180° (C0.92, CHCl 3 ).
実施例
参考例(2)で得られた３−ベンゾイル−４−メト
キシカルボニル−２・２−ジメチルチアゾリジン
2.0ｇをアセトニトリル40mlに溶解させ、これに
DMSO5.0ｇを加える。さらにメチレンブルー20
mgを加え、酸素を細管より導入しつつ300Wハロ
ゲンランプを用いて室温で1.5時間光照射を行な
つた。溶媒を減圧下に留去した後、シリカゲルク
ロマト（ベンゼン：酢酸エチル＝４：１）を行な
い、主生成物を分離する。クロロホルム−ヘキサ
ンから再結晶を行なうと、融点170〜171℃（分
解）の結晶1.3ｇ（収率62％）を得た。このもの
は元素分析、NMRスペクトルおよび赤外線吸収
スペクトル（添付図面）分析の結果から、３−ベ
ンゾイル−５−ヒドロキシ−４−メトキシカルボ
ニル−２・２−ジメチルチアゾリジンであること
を確認した。Example 3-benzoyl-4-methoxycarbonyl-2,2-dimethylthiazolidine obtained in Reference Example (2)
Dissolve 2.0g in 40ml of acetonitrile and add
Add 5.0g of DMSO. Plus methylene blue 20
mg was added and irradiated with light for 1.5 hours at room temperature using a 300W halogen lamp while introducing oxygen through a capillary. After distilling off the solvent under reduced pressure, silica gel chromatography (benzene:ethyl acetate=4:1) is performed to separate the main product. Recrystallization from chloroform-hexane gave 1.3 g (62% yield) of crystals with a melting point of 170-171°C (decomposition). This product was confirmed to be 3-benzoyl-5-hydroxy-4-methoxycarbonyl-2,2-dimethylthiazolidine from the results of elemental analysis, NMR spectrum, and infrared absorption spectrum (attached drawing) analysis.
元素分析値 Ｃ：56.92 Ｈ：5.80 Ｎ：4.69 計算値 Ｃ：56.93 Ｈ：5.80 Ｎ：4.74 （C14H17NO4） 〔α〕２６ Ｄ−75.3°（C1.26、CHCl3）Elemental analysis value C: 56.92 H: 5.80 N: 4.69 Calculated value C: 56.93 H: 5.80 N: 4.74 (C 14 H 17 NO 4 ) [α] 26 D -75.3° (C1.26, CHCl 3 )
第１図は実施例で得られた３−ベンゾイル−５
−ヒドロキシ−４−メトキシカルボニル−２・２
−ジメチルチアゾリジンの重クロロホルム中の
NMRスペクトル、第２図は赤外線吸収スペクト
ルである。
Figure 1 shows 3-benzoyl-5 obtained in Example.
-Hydroxy-4-methoxycarbonyl-2.2
-dimethylthiazolidine in deuterated chloroform
The NMR spectrum and Figure 2 are infrared absorption spectra.
Claims (1)
あり、R2はアミノ保護基である）で表わされる
２・２−ジメチルチアゾリジン誘導体を光増感剤
の存在で酸素酸化することを特徴とする 一般式 （但し、式中のR1及びR2は前記の意味を有する）
で表わされる２・２−ジメチル−５−ヒドロキシ
チアゾリジン誘導体の製造方法。[Claims] 1. General formula (However, R 1 in the formula is hydrogen or a lower alkyl group, and R 2 is an amino protecting group) is oxidized with oxygen in the presence of a photosensitizer. General formula (However, R 1 and R 2 in the formula have the above meanings.)
A method for producing a 2,2-dimethyl-5-hydroxythiazolidine derivative represented by:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58048769A JPS59175478A (en) | 1983-03-25 | 1983-03-25 | Preparation of 2,2-dimethyl-5-hydroxythiazolidine derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58048769A JPS59175478A (en) | 1983-03-25 | 1983-03-25 | Preparation of 2,2-dimethyl-5-hydroxythiazolidine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS59175478A JPS59175478A (en) | 1984-10-04 |
| JPS6245230B2 true JPS6245230B2 (en) | 1987-09-25 |
Family
ID=12812481
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58048769A Granted JPS59175478A (en) | 1983-03-25 | 1983-03-25 | Preparation of 2,2-dimethyl-5-hydroxythiazolidine derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS59175478A (en) |
-
1983
- 1983-03-25 JP JP58048769A patent/JPS59175478A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS59175478A (en) | 1984-10-04 |
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