JP2011157326A - Maxacalcitol intermediate and process for producing the same - Google Patents
Maxacalcitol intermediate and process for producing the same Download PDFInfo
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- DTXXSJZBSTYZKE-ZDQKKZTESA-N Maxacalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](OCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C DTXXSJZBSTYZKE-ZDQKKZTESA-N 0.000 title claims abstract description 18
- 229950006319 maxacalcitol Drugs 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- SYTBZMRGLBWNTM-SNVBAGLBSA-N (R)-flurbiprofen Chemical compound FC1=CC([C@H](C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-SNVBAGLBSA-N 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 238000003786 synthesis reaction Methods 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical group CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 125000005103 alkyl silyl group Chemical group 0.000 claims description 4
- 229910000000 metal hydroxide Inorganic materials 0.000 claims description 4
- 150000004692 metal hydroxides Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052987 metal hydride Inorganic materials 0.000 claims description 2
- 150000004681 metal hydrides Chemical class 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- -1 lithium aluminum hydride Chemical compound 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 229930003316 Vitamin D Natural products 0.000 description 6
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000011710 vitamin D Substances 0.000 description 6
- 235000019166 vitamin D Nutrition 0.000 description 6
- 150000003710 vitamin D derivatives Chemical class 0.000 description 6
- 229940046008 vitamin d Drugs 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 0 CC([C@@](CC1)[C@@](C)(CCC2)C1C2=CC=C(C[C@@](*)CC1)C1=C)O Chemical compound CC([C@@](CC1)[C@@](C)(CCC2)C1C2=CC=C(C[C@@](*)CC1)C1=C)O 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- 102000009310 vitamin D receptors Human genes 0.000 description 3
- 108050000156 vitamin D receptors Proteins 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- MECHNRXZTMCUDQ-UHFFFAOYSA-N Vitamin D2 Natural products C1CCC2(C)C(C(C)C=CC(C)C(C)C)CCC2C1=CC=C1CC(O)CCC1=C MECHNRXZTMCUDQ-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
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- 230000004069 differentiation Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960002061 ergocalciferol Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 239000011653 vitamin D2 Substances 0.000 description 2
- 235000001892 vitamin D2 Nutrition 0.000 description 2
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 description 2
- AEXCZQSITJAZRN-UHFFFAOYSA-N 9-hexadecylanthracene Chemical compound CCCCCCCCCCCCCCCCc1c2ccccc2cc2ccccc12 AEXCZQSITJAZRN-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 208000001126 Keratosis Diseases 0.000 description 1
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 208000005770 Secondary Hyperparathyroidism Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 230000000125 calcaemic effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
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- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
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- XPYGGHVSFMUHLH-UUSULHAXSA-N falecalcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(O)(C(F)(F)F)C(F)(F)F)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C XPYGGHVSFMUHLH-UUSULHAXSA-N 0.000 description 1
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- 230000000148 hypercalcaemia Effects 0.000 description 1
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- 210000000936 intestine Anatomy 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 229960000987 paricalcitol Drugs 0.000 description 1
- BPKAHTKRCLCHEA-UBFJEZKGSA-N paricalcitol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](\C=C\[C@H](C)C(C)(C)O)C)=C\C=C1C[C@@H](O)C[C@H](O)C1 BPKAHTKRCLCHEA-UBFJEZKGSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本発明は、ビタミンＤ類似体、マキサカルシトール、中間体、およびこれらの製造方法に関する。 The present invention relates to vitamin D analogs, maxacalcitol, intermediates, and methods for their production.
ビタミンＤは、筋肉、免疫系、生殖系、ならびに細胞の増殖および分化に深く影響を及ぼす。実際に、ビタミンＤ受容体（ＶＤＲ）を有する細胞は、身体の多くの部分（腸、腎臓、前立腺、骨、骨髄、副甲状腺、皮膚、肝臓、筋肉、およびリンパ系組織などを含む）に見られる。ＶＤＲが広範に存在しているため、ビタミンＤおよびその類似体は、癌、皮膚、並びに骨の疾患および自己免疫疾患などを含むさまざまな疾患の治療のための化合物として興味が持たれている。 Vitamin D has a profound effect on muscle, immune system, reproductive system, and cell growth and differentiation. In fact, cells with vitamin D receptor (VDR) are found in many parts of the body, including intestine, kidney, prostate, bone, bone marrow, parathyroid, skin, liver, muscle, and lymphoid tissue. It is done. Because of the widespread presence of VDR, vitamin D and its analogs are of interest as compounds for the treatment of various diseases including cancer, skin, and bone diseases and autoimmune diseases.
何らかの構造的類似性を有するビタミンＤ類似体類が、これまでに開示されている。例えば、国際出願第87/00834号には、下記式の化合物類：
ビタミンＤおよびその類似体類は、既にＳＨＰＴ（二次性副甲状腺機能亢進症）の治療に用いられている。パリカルシトール（19-ノル-1,15-ジヒドロキシ-ビタミンD2）およびドキセルカルシフェロール（1α-ヒドロキシ-ビタミンD2）は、米国でｓ−ＨＰＴの治療に推奨されており、22-オキサカルシトール（22-オキサ-1、25(OH)2D3、マキサカルシトール）およびヘキサフルオロ-カルシトリオール（ファレカルシトリオール）は、日本で推奨されている。 Vitamin D and its analogs are already used for the treatment of SHPT (secondary hyperparathyroidism). Paricalcitol (19-nor-1,15-dihydroxy-vitamin D 2 ) and doxel calciferol (1α-hydroxy-vitamin D 2 ) are recommended for the treatment of s-HPT in the United States, and 22-oxa Calcitol (22-oxa-1, 25 (OH) 2 D 3 , maxacalcitol) and hexafluoro-calcitriol (farecalcitriol) are recommended in Japan.
マキサカルシトールは、いわゆる「非カルセミック」ビタミンＤ類似体であり、顕著な分化誘導性／抗増殖性を有し、高カルシウム血症を引き起こす能力が低下している。マキサカルシトールは、ＰＴＨの強力な抑制剤として開発された。日本では、その使用により慢性透析患者のＳＨＰＴの改善が認められた。加えて、尋常性乾癬を含む角化症を有する患者に広く使用され、著しくその症状を改善している。 Maxacalcitol is a so-called “non-calcemic” vitamin D analog that has significant differentiation-inducing / antiproliferative properties and reduced ability to cause hypercalcemia. Maxacalcitol was developed as a potent inhibitor of PTH. In Japan, its use has been shown to improve SHPT in chronic dialysis patients. In addition, it is widely used in patients with keratosis, including psoriasis vulgaris, and significantly improves its symptoms.
本発明は、式(I)：
本発明は、さらに、式(II)：
The present invention further provides formula (II):
本発明は、さらに、式(3)：
式(2)：
Formula (2):
本発明の方法の記述において、以下の用語は、特に指定しない限り、以下の意味を有する。 In the description of the method of the present invention, the following terms have the following meanings unless otherwise specified.
用語「アルキル」は、直鎖状または分枝状の一価の飽和炭化水素基を意味する。特に指定しない限り、このようなアルキル基は、典型的には１個〜６個の炭素原子を有する。代表的なアルキル基には、例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、sec-ブチル、イソブチル、tert-ブチル、n-ペンチル、n-ヘキシルなどが含まれる。 The term “alkyl” means a linear or branched monovalent saturated hydrocarbon group. Unless otherwise specified, such alkyl groups typically have from 1 to 6 carbon atoms. Representative alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, and the like.
用語「アルコキシ」は、式：(アルキル)-O-（式中、アルキルは、本明細書で定義したとおりである）の一価の基を意味する。代表的なアルキル基には、例えば、メトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、sec-ブトキシ、イソブトキシ、tert-ブトキシなどが含まれる。 The term “alkoxy” refers to a monovalent group of the formula: (alkyl) -O—, wherein alkyl is as defined herein. Representative alkyl groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.
本発明は、式(I)：
のキラル化合物を提供する。
The present invention relates to a compound of formula (I):
The chiral compound is provided.
本発明はまた、式(II)：
のC-20位がR-形またはS-形であるキラル化合物を提供する。
The present invention also provides a compound of formula (II):
A chiral compound is provided wherein the C-20 position of is in the R-form or S-form.
用語「キラル」は手を意味するギリシャ語の単語「kheir」に由来し、ここで、手は最もよく知られているキラルな物体であり、左／右対称体が存在することを意味する。例えば、左手と右手は同じではなく、互いに鏡像体であり、したがって「キラル」である。 The term “chiral” comes from the Greek word “kheir” meaning hand, where the hand is the best known chiral object, meaning that there is a left / right symmetric. For example, the left hand and the right hand are not the same, but are mirror images of each other and are therefore “chiral”.
ヒトの手に左と右があるのと同様に、分子にも左と右がある。キラル分子は、その鏡像体と重ね合わせることができない分子である。キラル化合物と、その鏡像体とは、エナンチオマーと呼ばれる。天然のほとんど全てのキラル分子は、単独のエナンチオマーとして存在する。分子を工業的な合成によって製造すると、通常、ラセミ体、すなわち２つのエナンチオマーの50/50組成物の形態で存在する。 Just as a human hand has a left and a right, a molecule has a left and a right. A chiral molecule is a molecule that cannot be superposed on its mirror image. Chiral compounds and their enantiomers are called enantiomers. Almost all natural chiral molecules exist as a single enantiomer. When a molecule is produced by industrial synthesis, it usually exists in the form of a racemate, ie a 50/50 composition of two enantiomers.
キラル分子は、光学活性を有し、したがって、エナンチオマーは、時には光学異性体と呼ばれる。各エナンチオマーが偏光面を逆方向に回転させるため、光学活性体と呼ばれる。光を時計方向に回転させるエナンチオマーは、右旋性すなわち（＋）であり、逆のエナンチオマーは、左旋性すなわち（−）である。ラセミ混合物は、光学活性を示さない。 Chiral molecules have optical activity and therefore enantiomers are sometimes referred to as optical isomers. Since each enantiomer rotates the plane of polarization in the opposite direction, it is called an optically active substance. Enantiomers that rotate light in a clockwise direction are dextrorotatory or (+), and the opposite enantiomers are levorotatory or (−). Racemic mixtures do not exhibit optical activity.
１９４８年に、２６歳のLouis Pasteurは、ピンセットを用いて、酒石酸塩の右手型および左手型を顕微鏡下で分離した。これらの結晶は、異なる形状を有していた。Pasteurがこれらの結晶を水に溶解すると、一方の結晶は偏光を右に回転させ、他方の結晶は偏光を左に回転させた。したがって、酒石酸塩は、右手型および左手型が分離された最初の分子であり、右手型および左手型は、現在、化学者らによってR（右を意味するラテン語のrectusから）およびS（左を意味するラテン語のsinisterから）と呼ばれている。この実験は、化学者がこの語を使用し始めるおよそ１００年前の実験であるが、分子のキラリティーの発見として引き合いに出されることが多い。 In 1948, 26-year-old Louis Pasteur used tweezers to separate the right-handed and left-handed forms of tartrate under a microscope. These crystals had different shapes. When Pasteur dissolved these crystals in water, one crystal rotated the polarization to the right and the other crystal rotated the polarization to the left. Thus, tartrate is the first molecule in which the right-handed and left-handed forms were separated, and the right-handed and left-handed forms are now chemisted by chemists from R (from the Latin rectus meaning right) and S (left From the Latin sinister meaning). This experiment is about 100 years ago, when chemists began to use the term, but is often cited as a discovery of molecular chirality.
RおよびSは、分子の絶対配置を表すための記号であり、キラル中心の周りに原子がどのように配置されているかを、優先規則にしたがって示す。 R and S are symbols for representing the absolute configuration of the molecule and indicate how the atoms are arranged around the chiral center according to the priority rules.
本発明の第一の実施態様では、Rは、ヒドロキシル、O-アシル、またはO-tert-ブチルジメチルシリルである。 In a first embodiment of the invention, R is hydroxyl, O-acyl, or O-tert-butyldimethylsilyl.
本発明では、これらの化合物を、マキサカルシトールの合成に用いる。 In the present invention, these compounds are used for the synthesis of maxacalcitol.
本発明は、さらに、化合物(3)：
化合物(2)：
Compound (2):
本発明の方法では、化合物(2)は、化合物(1)：
本発明の方法では、金属水酸化物は、限定されないが、水酸化カリウムであり、前記有機溶媒は、限定されないが、tert-ブタノールである。 In the method of the present invention, the metal hydroxide is, but not limited to, potassium hydroxide, and the organic solvent is, but not limited to, tert-butanol.
以下の実施例は、非限定的なものであり、本発明のさまざまな態様および特徴の単なる代表例である。 The following examples are non-limiting and are merely representative of various aspects and features of the present invention.
［合成例１］：化合物(1)の合成
3(R)-(tert-ブチルメチルシリルオキシ)-20(S)-ホルミル-9,20-セコプレグナ- 5(E), 7(E), 10(19)-トリエン
3 (R)-(tert-butylmethylsilyloxy) -20 (S) -formyl-9,20-secopregna-5 (E), 7 (E), 10 (19) -triene
［合成例２］：化合物(2)の合成
（実施例１）:
3(R)-(tert-ブチルメチルシリルオキシ)-20(S)-ホルミル-9,20-セコプレグナ-5(E),7(E),10(19)-トリエン（化合物 (1) ）(800 g, 1.8 mol)のtert-ブタノール(16L)溶液に、攪拌下、KOH (155 g, 2.76 mol)を添加した。次いで、この溶液に、良好な撹拌下、40℃にて4時間酸素ガスをバブルさせた。
反応が完結した後、tert-ブタノールを蒸発させて除去し、残渣を酢酸エチル(8L)に溶解させ、水で抽出した(8L x 2回)。得られた有機相をMgSO4で無水にした後、濾過した。濾液を、減圧下で濃縮して乾燥させると、オイル状の残渣が得られ、これをカラムカラムクロマトグラフィーで精製（シリカゲル、溶離液はヘキサン中の5％酢酸エチル）して、所望の生成物である化合物(2)を523 g得た（収率67％）。
図２に、化合物(2)の1H NMRの結果を示す。
図３に、化合物(2)の13C NMRの結果を示す。
[Synthesis Example 2]: Synthesis of Compound (2) (Example 1):
3 (R)-(tert-butylmethylsilyloxy) -20 (S) -formyl-9,20-secopregna-5 (E), 7 (E), 10 (19) -triene (compound (1)) ( To a solution of 800 g, 1.8 mol) in tert-butanol (16 L) was added KOH (155 g, 2.76 mol) with stirring. The solution was then bubbled with oxygen gas for 4 hours at 40 ° C. with good stirring.
After the reaction was complete, tert-butanol was removed by evaporation and the residue was dissolved in ethyl acetate (8 L) and extracted with water (2 × 8 L). The resulting organic phase was dried over MgSO4 and filtered. The filtrate is concentrated to dryness under reduced pressure to give an oily residue which is purified by column column chromatography (silica gel, eluent is 5% ethyl acetate in hexane) to give the desired product. 523 g of the compound (2) was obtained (yield 67%).
FIG. 2 shows the 1 H NMR result of the compound (2).
FIG. 3 shows the result of 13 C NMR of the compound (2).
（実施例２）：
フラスコに、3(R)-(tert-ブチルメチルシリルオキシ)-20(S)-ホルミル-9,20-セコプレグナ-5(E),7(E),10(19)-トリエン （化合物 (1)）(3 g, 6.78 mmol)、N,N-ジメチルホルムアミド(150 ml)、1,4-ジアザビシクロ[2.2.2]オクタン(678 mg, 6 mmol), 酢酸銅一水和物(101 mg, 0.5 mmol)、および2,2’-ビピリジル(82 mg,0.51 mmol)を加えた。この混合物を、40℃にて6日間、良好な撹拌下で空気をバブルさせた。
この反応混合物を酢酸エチル(200 ml)で希釈し、水で抽出し(100 mL x 2)、MgSO4で無水にした。酢酸エチルを蒸発により除去し、オイル状の残渣をカラムクロマトグラフィーで精製（シリカゲル、溶離液はヘキサン中の10％酢酸エチル）して、所望の生成物である化合物(2)を得た。
(Example 2):
Into the flask, 3 (R)-(tert-butylmethylsilyloxy) -20 (S) -formyl-9,20-secopregna-5 (E), 7 (E), 10 (19) -triene (compound (1 )) (3 g, 6.78 mmol), N, N-dimethylformamide (150 ml), 1,4-diazabicyclo [2.2.2] octane (678 mg, 6 mmol), copper acetate monohydrate (101 mg, 0.5 mmol), and 2,2′-bipyridyl (82 mg, 0.51 mmol) were added. The mixture was bubbled with air at 40 ° C. for 6 days with good stirring.
The reaction mixture was diluted with ethyl acetate (200 ml), extracted with water (100 mL x 2) and dried over MgSO4. Ethyl acetate was removed by evaporation and the oily residue was purified by column chromatography (silica gel, eluent 10% ethyl acetate in hexane) to give the desired product, compound (2).
［合成例３］：化合物(3)およびその20R-異性体の合成
（実施例１）：
化合物(2)（3 g、7.0 mmol）を、テトラヒドロフラン（140 ml）に溶解し、水素化ホウ素ナトリウム（0.13 g、3.4 mmol）を添加した。次いで、メタノールを、15分かけて滴下により添加した。この反応混合物を、20分間撹拌した後、酢酸エチル（560 ml）で希釈した。この溶液を水（150 mL x 5）および飽和塩化ナトリウム水溶液（150 mL）で抽出し、MgSO4で無水にし、蒸発させて、無色のオイルを得た。このオイル状の残渣をカラムクロマトグラフィーで精製した（シリカゲル、溶離液はヘキサン中の10％酢酸エチル）。最初に留出したものが、化合物(3)の20R-異性体（固体）であった。
図４に、化合物(3)の20R-異性体の1H NMRの結果を示す。
図５に、化合物(3)の20R-異性体の13C NMRの結果を示す。
[Synthesis Example 3]: Synthesis of Compound (3) and its 20R-isomer (Example 1):
Compound (2) (3 g, 7.0 mmol) was dissolved in tetrahydrofuran (140 ml), and sodium borohydride (0.13 g, 3.4 mmol) was added. Methanol was then added dropwise over 15 minutes. The reaction mixture was stirred for 20 minutes and then diluted with ethyl acetate (560 ml). The solution was extracted with water (150 mL x 5) and saturated aqueous sodium chloride solution (150 mL), dried over MgSO4 and evaporated to give a colorless oil. The oily residue was purified by column chromatography (silica gel, eluent 10% ethyl acetate in hexane). The first distillate was the 20R-isomer (solid) of compound (3).
FIG. 4 shows the 1 H NMR result of the 20R-isomer of compound (3).
FIG. 5 shows the result of 13 C NMR of the 20R-isomer of compound (3).
より極性の異性体（化合物(3)）を含有するフラクションを蒸発させて、無色のオイル状付加体を得た。
図７に、化合物(3)の13C NMRの結果を示す。
The fraction containing the more polar isomer (compound (3)) was evaporated to give a colorless oily adduct.
FIG. 7 shows the 13 C NMR result of the compound (3).
（実施例２）：
化合物(2)（500 g、1.16 mol）をキシレン（10 L）に溶解させ、この反応混合物を100〜130℃に加熱した後、ＬＡＨ（リチウムアルミニウムハイドライド）（88.5 g、2.33 mol）を添加した。反応を、撹拌下、20分間行い、室温に冷却した。この反応混合物に、飽和硫酸ナトリウム溶液（100 mL）を加えて30分間撹拌した。反応混合物を濾過し、濾液を蒸発させてオイル状の残渣を得た。R/S比は65:35であった。オイル状残渣をカラムクロマトグラフィーで精製（シリカゲル、溶離液はヘキサン中の5％酢酸エチル）して、最初の留出物が化合物(3)の20R-異性体（白色結晶）350 gであり、収率は63.6％であった。
(Example 2):
Compound (2) (500 g, 1.16 mol) was dissolved in xylene (10 L), the reaction mixture was heated to 100-130 ° C., and LAH (lithium aluminum hydride) (88.5 g, 2.33 mol) was added. . The reaction was carried out with stirring for 20 minutes and cooled to room temperature. To this reaction mixture, saturated sodium sulfate solution (100 mL) was added and stirred for 30 minutes. The reaction mixture was filtered and the filtrate was evaporated to give an oily residue. The R / S ratio was 65:35. The oily residue was purified by column chromatography (silica gel,
より極性の異性体（化合物(3)）を含有するフラクションを蒸発させて、無色のオイル状の付加体を得た（123 g、収率24％）。 The fraction containing the more polar isomer (compound (3)) was evaporated to give a colorless oily adduct (123 g, 24% yield).
［合成例４］：化合物(4)の合成
［合成例５］：化合物(5)の合成
1H NMR (400 MHz, CDCl3): δ6.43 (1H, d, J=11.6), 5.83 (1H, d, J=11.6), 4.89 (1H, s), 4.61 (1H, s), 3.81 (1H, m), 3.62 (1H, m), 3.46 (1H, m), 3.23 (1H, m), 2.82 (1H, dd, J=3.6, 13.6), 2.62 (1H, dd, J=3.6, 13.6), 2.44 (1H, m), 2.23 (1H, m), 2.13 (1H, m), 1.96 (2H, m), 1.83 (4H, m), 1.71 (6H, m), 1.55 (6H, m), 1.21 (6H, m), 1.16 (5H, m), 0.85 (9H, s), 0.51 (3H, s), 0.04 (6H, s).
13C NMR(CDCl3): δ149.9, 142.7, 136.5, 119.8, 116.4, 107.5, 78.9, 70.4, 69.3, 65.5, 57.1, 56.2, 44.7, 41.5, 39.6, 37.5, 35.1, 31.1, 29.3, 29.0, 25.8, 23.1, 22.1, 18.8, 18.1, 12.6.
[Synthesis Example 5]: Synthesis of Compound (5)
1 H NMR (400 MHz, CDCl 3 ): δ6.43 (1H, d, J = 11.6), 5.83 (1H, d, J = 11.6), 4.89 (1H, s), 4.61 (1H, s), 3.81 (1H, m), 3.62 (1H, m), 3.46 (1H, m), 3.23 (1H, m), 2.82 (1H, dd, J = 3.6, 13.6), 2.62 (1H, dd, J = 3.6, 13.6), 2.44 (1H, m), 2.23 (1H, m), 2.13 (1H, m), 1.96 (2H, m), 1.83 (4H, m), 1.71 (6H, m), 1.55 (6H, m ), 1.21 (6H, m), 1.16 (5H, m), 0.85 (9H, s), 0.51 (3H, s), 0.04 (6H, s).
13 C NMR (CDCl 3 ): δ 149.9, 142.7, 136.5, 119.8, 116.4, 107.5, 78.9, 70.4, 69.3, 65.5, 57.1, 56.2, 44.7, 41.5, 39.6, 37.5, 35.1, 31.1, 29.3, 29.0, 25.8, 23.1, 22.1, 18.8, 18.1, 12.6.
［合成例６］：化合物(6)の合成
1H NMR (400 MHz, CDCl3): δ6.46 (1H, d, J=11.6), 5.83 (1H, d, J=11.6), 5.03 (1H, s), 4.91 (1H, s), 4.45 (1H, m), 4.16 (1H, m), 3.80 (1H, m), 3.45 (1H, m), 3.22 (1H, m), 2.82 (1H, dd, J=3.6, 13.6), 2.49 (1H, dd, J=3.6, 13.6), 2.37 (1H, m), 1.83 (5H, m), 1.70 (5H, m), 1.53 (3H, m), 1.29 (2H, m), 1.20 (10H, m), 1.16 (4H, m), 0.84 (9H, s), 0.50 (3H, s), 0.04 (6H, s).
13C NMR(CDCl3): δ153.0, 143.3, 134.5, 122.2, 116.5, 107.6, 78.9, 70.4, 66.7, 65.5, 57.0, 56.1, 44.7, 42.8, 41.4, 39.5, 36.9, 29.3, 29.0, 28.8, 25.7, 23.1, 22.1, 18.8, 18.0, 12.5.
[Synthesis Example 6]: Synthesis of Compound (6)
1 H NMR (400 MHz, CDCl 3 ): δ6.46 (1H, d, J = 11.6), 5.83 (1H, d, J = 11.6), 5.03 (1H, s), 4.91 (1H, s), 4.45 (1H, m), 4.16 (1H, m), 3.80 (1H, m), 3.45 (1H, m), 3.22 (1H, m), 2.82 (1H, dd, J = 3.6, 13.6), 2.49 (1H , dd, J = 3.6, 13.6), 2.37 (1H, m), 1.83 (5H, m), 1.70 (5H, m), 1.53 (3H, m), 1.29 (2H, m), 1.20 (10H, m ), 1.16 (4H, m), 0.84 (9H, s), 0.50 (3H, s), 0.04 (6H, s).
13 C NMR (CDCl 3 ): δ 153.0, 143.3, 134.5, 122.2, 116.5, 107.6, 78.9, 70.4, 66.7, 65.5, 57.0, 56.1, 44.7, 42.8, 41.4, 39.5, 36.9, 29.3, 29.0, 28.8, 25.7, 23.1, 22.1, 18.8, 18.0, 12.5.
［合成例７］：化合物(7)の合成
［合成例８］：マキサカルシトールの合成
［合成例９］：マキサカルシトールの結晶化
粗マキサカルシトール(9.7g, 23.2mmol)を、ジエチルエーテル(200mL)に溶解させた。この溶液を冷却し、5〜10℃にて24時間保った。形成された結晶を濾過し、減圧下、室温で乾燥させて、最終生成物であるマキサカルシトールを得た（1.5 g、純度99.8%、収率15.4%、[α]D20 D=+44°）。
[Synthesis Example 9]: Crystallization of maxacalcitol Crude maxacalcitol (9.7 g, 23.2 mmol) was dissolved in diethyl ether (200 mL). The solution was cooled and kept at 5-10 ° C. for 24 hours. The formed crystals were filtered and dried at room temperature under reduced pressure to give the final product maxacalcitol (1.5 g, purity 99.8%, yield 15.4%, [α] D 20 D = + 44 °).
Claims (8)
を有するキラル化合物。 Formula (I):
A chiral compound having
のC-20位がR-形またはS-形であるキラル化合物。 Formula (II):
A chiral compound wherein the C-20 position of is in the R-form or S-form.
下記構造の化合物(2)：
Compound (2) having the following structure:
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| CN103508999A (en) * | 2013-10-12 | 2014-01-15 | 浙江海正药业股份有限公司 | Maxacalcitol synthesizing intermediate and preparation method and application thereof |
| CN103588689A (en) * | 2012-08-17 | 2014-02-19 | 台耀化学股份有限公司 | Crystalline form of maxacalcitol |
| CN103910666A (en) * | 2014-04-15 | 2014-07-09 | 湖南华腾制药有限公司 | Method for preparing maxacalcitol |
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