CN1167711C - 八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]二氮杂�-1-羧酸的衍生物、其制备方法及其用途 - Google Patents
八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]二氮杂�-1-羧酸的衍生物、其制备方法及其用途 Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title claims description 3
- 239000000203 mixture Substances 0.000 claims abstract description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 13
- 150000001412 amines Chemical group 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 11
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
- 125000005544 phthalimido group Chemical group 0.000 claims description 4
- 230000006340 racemization Effects 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
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- 150000003818 basic metals Chemical class 0.000 claims description 2
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- 239000000126 substance Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract 1
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
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- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- IMJLPXIWIIDKHO-UHFFFAOYSA-N ethyl 2,5-dibromopentanoate Chemical compound CCOC(=O)C(Br)CCCBr IMJLPXIWIIDKHO-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000005649 metathesis reaction Methods 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- JDAVNLLRFXIKKD-UHFFFAOYSA-N 2,5-dibromopentanoic acid Chemical compound OC(=O)C(Br)CCCBr JDAVNLLRFXIKKD-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 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
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
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- 239000002253 acid Substances 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical class OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- NCPHGZWGGANCAY-UHFFFAOYSA-N methane;ruthenium Chemical compound C.[Ru] NCPHGZWGGANCAY-UHFFFAOYSA-N 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- 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
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- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及SR构型或SR+SS混合物型的式(I)化合物,其中R代表氢原子、烷基或含有可高达18个碳原子的芳烷基,所述胺官能团处于游离或受保护状态。该化合物可用于制备医用活性物质。
Description
本发明涉及八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]二氮杂-1-羧酸的衍生物、其制备方法以及它们在制备治疗活性化合物中的用途。
US 4512924,WO 93 23403,US 5723602,WO 97 22619,US5,656,627和WO 33751描述了9-氨基-八氢-6,10-二氧代-6H-哒嗪[1,2-a][1,2]二氮杂草-1-羧酸的衍生物作为初始原料用作制备药物,它的胺可任选以具有1S,9S构型的苯二甲酰亚氨基的形式被保护。在环化以前的阶段,通过分离方法尤其是结晶或色谱法获得SS构型的非对映异构体。
本发明的主题是具有SR构型或SR+SS混合物形式的下式(I)化合物:
其中R代表氢原子、含有可高达18碳原子的烷基或芳烷基基团,所述胺官能团可以处于游离或保护状态。
R代表如H、甲基、乙基、丙基、异丙基、n-丁基、异丁基或叔丁基、或苯甲基或萘基基团。保护胺官能团时,可以按照保护胺类的标准方法实施保护。
本发明的一个具体主题是具有SR构型或SR+SS混合物形式的对应于下式(IA)的化合物:
其中R与前面的定义一致,同时或者R1代表具有下式的基团:
Ra、Rb、Rc和Rd代表烷基、含有最多可达18个碳原子的芳基基团或含有一个或多个杂原子的单或多环基团,X代表氢原子、含有最多可达8个碳原子的烷基基团或含有最多可达14个碳原子的芳基基团,而R2代表氢原子,或者R1和R2一起构成包含一个或多个杂原子的单环或多环基团。
例如为了保护胺,可以使用环状化合物,例如具有下式基团:
或具有下式的基团:
本发明更具体的主题是具有式(IA)的化合物,其中R1和R2一起构成包含一个或多个杂原子的多环基团,尤其是相当于下式(1A1)的具有SR构型或SR+SS混合物型化合物:
本发明的又一个具体主题是其中R代表甲基的式(I)化合物,该化合物具有SR构型或为SR+SS混合物形式。
本发明主题之一还涉及制备方法,其特征在于其中alk代表含最多可达8个碳原子的烷基基团,Hal代表卤素原子的下式(II)化合物:
,与其中Aryl代表含最多可达14个碳原子的芳香基团的下式(III)的化合物反应:
获得下式(IV)化合物:
上式(IV)化合物与碱性试剂反应,获得下式(V)化合物:
上式(V)化合物可选择性地与烷化剂反应,获得下式(VI)化合物:
上式(VI)化合物与下式(VII)化合物(其中Hal1代表卤素原子,Ar代表芳基或含最多可达18碳原子的芳烷基基团,R1和R2与前面的定义一致)反应:
获得具有SR构型或SR+SS混合物型的下式(VIII)化合物:
上式(VIII)化合物与氢化剂反应,获得具有SR构型或SR+SS混合
物型的下式(IX)化合物:
上式(IX)化合物与缩合剂反应以获得相应的具有式(IA)的化合物,然后如果需要的话,释放胺官能团以获得其中胺官能团是游离的式(I)化合物。
在优选的实施方案中:
-Hal和Hal1代表氯原子,
-alk代表包含最多可达4个碳原子的烷基基团,
-Aryl代表苯基或萘基基团,
-芳烷基代表苯甲基基团,
-在碱存在下,例如碱性碳酸盐(如碳酸钾)存在下,使式(II)化合物和式(III)化合物发生反应,
-与式(IV)化合物反应的碱性剂为氢氧化钠或氢氧化钾,
-与式(V)化合物反应的烷化剂是醇类如甲醇,
-式(VI)和(VII)化合物之间的缩合反应是在碱存在下进行,所述碱例如吡啶、TEA、二异丙胺,
-氢化剂例如在以下情况下的氢:在披钯炭存在下、在滑石粉存在下的氢氧化钯、在氧化铝存在下的铑、披钌炭或存在阮内镍,
-在SOCl2、PCl5、活化酯或在脱水剂如PTSA的存在下进行环化作用,
-用肼可释放胺。
在所述方法过程中所用的产物(IV)、(VII)、(VIII)和(IX)为新型产物,其本身也是本发明的主题。
本发明的一个更具体的主题是所述产物尤其是所述外消旋混合物,所述产物的制备在下文实验部分中给出。
同样,本发明主题之一为所述用途,该用途的特征在于SS、SR混合物型或者SR型的式(I)化合物与具有6元环携带的不对称碳原子的去消旋剂反应,获得SS型的下式(Iopt)化合物:
其中所述胺官能团为游离的或受保护的,其R的含义与前面一致。
本发明的一个更具体的主题是上述定义的式(IA)化合物的用途,它用于制备SS型的下式(IAopt)化合物:
其中R、R1和R2保持其前面的定义不变。
本发明的一个更具体的主题是所述用途,其特征在于R代表甲基基团,并且其中所述胺官能团以苯二甲酰亚氨基的形式受保护。
本发明的一个更为具体的主题是所述用途,其特征在于去消旋剂为一种碱,尤其为一种强碱,例如碱金属或碱土金属醇化物(如甲醇钠或甲醇钾、叔丁醇钠(terbutylate)或叔丁醇钾)或锂化胺(lithiatedamine)如LDA。
本发明的一个非常具体的主题是在后面实验部分描述的用途用于制备下述化合物:
-(1s-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-3,4,7,8,9,10-六氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯。
例如在专利EP 94095中描述了具有SS构型的式(I)的产物,其中R为叔丁基基团,所述胺是以苯二甲酰亚氨基的形式受到保护,此化合物是在合成具有治疗作用的产物中的中间产物。
式(I)产物通常可以用于合成上述专利指出的药物。
下面的实施例用于说明本发明,但并不局限于此。
实施例1:(1S-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯和甲基(1R-反式)-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯
a)
制备2,5-二溴戊酸
将39ml溴加入到106g 5-溴戊酸与1ml三溴化磷的混合物中。使反应混合物加热到70~80℃16.5小时。再将反应介质加热到100℃15分钟,然后使其冷却到室温。获得147g所需要的产物。
b)
制备2,5-二溴戊酸乙酯
在含有50g上一阶段制备的产物、15滴DMF和300ml二氯甲烷的混合物中加入24.37g草酰氯。在室温下搅拌反应混合物,直到反应完成。然后将反应混合物冷却到10℃,再加入50ml乙醇。在10℃下搅拌反应介质30分钟,取出降至室温,并在室温下搅拌3小时。干燥后获得所需要的产物。
c)
制备双(苯甲基)1,2-肼羧酸酯
1.5升甲醇与25g 80%的一水合肼溶液置于氮气中。将反应介质冷却到0℃,在0℃下加入75g的氯甲酸苯甲酯,然后作为93g碳酸钠的1100ml软化水溶液再加入75g的氯甲酸苯甲酯。将反应混合物在0℃下放置1小时,然后用100ml甲醇与100ml水的混合物通过置换作用分离、洗涤,再在0℃下用500ml水通过置换作用进行洗涤。经过干燥,获得107.6g所需要的产物。
d)
制备(S)3-乙基-1,2-双(苯甲基)-四氢-1,2,3-哒嗪三羧酸酯和(R)3-乙基-1,2-双(苯甲基)-四氢-1,2,3-哒嗪三羧酸酯
在20~25℃下,将12.1g 2,5二溴戊酸乙酯与50ml的二甘醇二甲醚的悬浮液加入到含有10.42g的双(苯甲基)-1,2-肼二羧酸酯、65ml的二甘醇二甲醚和8.26g的碳酸钾的悬浮液中。
将所获得的悬浮液在90℃下加热。搅拌48小时,然后冷却到20℃,将其倒入含有50ml 2N盐酸和150ml的冰水混合物的溶液中,用乙酸乙酯萃取,用水洗涤,干燥,过滤,用乙酸乙酯冲洗并干燥。将所获得产物在二氧化硅上经色谱法(洗脱液庚烷40,AcOEt 20),获得10.71g所需要的产物。
e)
制备(S)1-(苯甲基)-四氢-1,3(2H)-哒嗪二羧酸酯和(R)1-(苯甲基)-四氢-1,3(2H)-哒嗪二羧酸酯
将含有23.25g的上一阶段产物和80ml乙醇的溶液加入到338ml的40g/l氢氧化钠的乙醇溶液中。持续搅拌5.5小时,然后加入57ml 2N苏打。将反应混合持续搅拌30小时。加入141ml 2N盐酸溶液。将260ml反应混合物在80~90毫巴下蒸馏。用二氯甲烷萃取,加入20ml乙醇,然后用普通苏打水溶液(water-normal solution of soda)洗涤。用二氯甲烷萃取水相。合并水相,搅拌,并用135ml 2N盐酸溶液酸化。用二氯甲烷萃取,然后用水洗涤,干燥,过滤,用二氯甲烷洗涤,浓缩并干燥。加入146ml异丙醚,然后在20℃下搅拌1小时,过滤,洗涤,浓缩并干燥。获得11.41g所需要的产物。
f)
制备(S)3-甲基1-(苯甲基)四氢-1,3(2H)-哒嗪二羧酸酯和(R)3-甲 基1-(苯甲基)四氢-1,3(2H)-哒嗪二羧酸酯
将220ml的甲醇和脱水对甲苯磺酸(由一水合PTSA和12ml二氯甲烷制备)加入到11.05g上一阶段制备的产物中。将所获得的悬浮液持续搅拌15小时,然后加热到65℃,再持续搅拌6.5小时。在冷却到5℃后,加入5.5ml 10%的碳酸氢钠溶液,然后减压浓缩,溶解于100ml二氯甲烷与100ml水的混合物中。搅拌之后倾析,洗涤有机相,用二氯甲烷萃取,干燥,过滤并浓缩。获得11.39g所需产物。
g)
制备[3S-[2(R * ),3R * ]]3-甲基1-(苯甲基)2-[2-(1,3-二氢-1,3-二氧代- 2H-异吲哚-2-基)-1,5-二氧代-5-(苯基甲氧基)戊基]四氢-1,3(2H)哒嗪 二羧酸酯和[3R-[2(S * ),3R * ]]3-甲基1-(苯甲基)2-[2-(1,3-二氢-1,3-二 氧代-2H-异吲哚-2-基)-1,5-二氧代-5-(苯基甲氧基)戊基]四氢-1,3(2H) 哒嗪二羧酸酯
在一小时内,将包含11.01g上一阶段所制备产物和50ml二氯甲烷的溶液在4℃下加入到包含19.88g的(S)-γ-(gamma)(氯羰基)-1,3-二氢-1,3-二氧代-2H-异吲哚-2-丁酸苯甲酯和100ml二氯甲烷的溶液中。在4℃下搅拌30分钟,然后在1.5小时里加入4.15ml吡啶的25m二氯甲烷的溶液。搅拌并让反应介质缓慢地降到室温,然后在减压下浓缩,将其溶于200ml乙酸乙酯中,用饱和碳氢酸钠溶液洗涤,再接着搅拌30分钟,倾析,用饱和碳酸氢钠洗涤,搅拌并倾析。将反应介质用含5ml盐酸当量溶液和25ml水的溶液洗涤,然后用饱和氯化钠水溶液洗涤并干燥。用乙酸乙酯萃取,然后浓缩并干燥。获得25.2g所需产物。
h)
制备[6S-[1(R * ),6R * ]]-1,3-二氢-1,3-二氧代-γ-[[6-(甲氧基羰基)-四 氢-1(2H)-哒嗪基]羰基]-2H-异吲哚-2-丁酸和[6R-[1(S * ),6R * ]]-1,3-二氢 -1,3-二氧代-γ-[[6-(甲氧基羰基)-四氢-1(2H)-哒嗪基]羰基]-2H-异吲哚- 2-丁酸
将20.23g上阶段的产物、250ml THF以及3.03g 10%披钯炭加入到氢装置。通入氢气3小时,再加入3.03g的催化剂。持续氢化22小时后,过滤,用THF洗涤并蒸发。加入25ml的异丙醇,然后浓缩,除去THF,加入15ml异丙醇。在所获得的悬浮液中加入100ml的异丙醚,接着在氮氛围中搅拌2小时,分离,用含5%异丙醇的异丙醚洗涤。分离并干燥后,获得9.5g所需产物。
I)
制备(1S-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)八氢- 6,10-二氧代-6H-哒嗪并-[1,2-a][1,2]-二氮杂-1-羧酸酯和(1R-反式)甲 基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)八氢-6,10-二氧代-6H-哒嗪 并-[1,2-a][1,2]-二氮杂-1-羧酸酯
在5℃下,将含有1ml的亚硫酰氯和40ml二氯甲烷的溶液加入含有4.038g上阶段产物、40ml二氯甲烷和0.4ml二甲基甲酰胺的混合物中。搅拌3.5小时。将温度升到20℃,然后再搅拌1.5小时,浓缩。加入含有0.15ml亚硫酰氯和5ml二氯甲烷的溶液。反应混合物在约20℃下搅拌16小时,然后冷却到约5℃,加入27ml的饱和碳酸氢钠溶液。在搅拌30分钟后倾析,用含有10ml碳酸氢钠和40ml软化水的溶液洗涤。搅拌3分钟后倾析,用二氯甲烷萃取含水相,干燥,过滤,用二氯甲烷洗涤,最后在减压下浓缩。获得3.85g所需产物。
(1S-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)八氢-6,10-二
氧代-6H-哒嗪并-[1,2-a][1,2]-二氮杂-1-羧酸酯的应用
在-45℃/-48℃下,1.5小时内将含有0.029g叔丁醇钾和0.3mlDMF的溶液加入到含有0.194g实施例1产物、1.5ml二甲基甲酰胺和0.75ml叔丁醇(terbutanol)的混合物中。将混合物搅拌1小时,然后在冷却到-50℃后加入0.4g氯化铵粉。在-45℃下搅拌10分钟,连续两次加入20%的氯化铵溶液1ml,同时每次加入后搅拌10分钟。再加入2ml的软化水,用乙酸乙酯萃取,用软化水洗涤,倾析,浓缩并干燥。获得0.166g产物。αD=-75.3°(在甲醇中含1%)。
Claims (16)
1.具有SR构型或SR+SS混合物形式的下式化合物:
其中R代表氢原子、烷基或含有最高可达18个碳原子的芳烷基基团,所述胺官能团可以为游离的或受保护的基团。
3.权利要求2中定义的具有SR构型或者SR+SS混合物形式的式(IA)化合物,其中R1和R2一起构成包含一个或多个杂原子的多环基团。
5.权利要求1-4中任意一项所定义的式(I)化合物,其中R代表甲基基团。
6.权利要求1中定义的式(I)化合物的外消旋混合物,其名称如下:
(1S-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯和
(1R-反式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-八氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯。
7.制备权利要求1-6中任何一项所定义的式(I)化合物的方法,其特征在于使其中alk代表含最多可达8个碳原子的烷基基团,Hal代表卤素原子的下式(II)化合物:
,与其中Aryl代表含最多可达14个碳原子的芳香基团的下式(III)化合物反应:
获得下式(IV)化合物:
使上式(IV)化合物与碱性剂反应,获得下式(V)化合物:
使上式(V)化合物任选地与烷化剂反应,获得下式(VI)化合物:
使上式(VI)化合物与下式(VII)化合物反应:
其中Hal1代表卤素原子,Ar代表含最多可达18个碳原子的芳基或芳烷基基团,R1和R2与权利要求2中的定义一致,
获得具有SR构型或SR+SS混合物形式的下式(VIII)化合物:
使上式(VIII)化合物与氢化剂反应,获得具有SR构型或SR+SS混合物形式的下式(IX)化合物:
使上式(IX)化合物与缩合剂反应,获得相应的具有式(IA)的化合物,然后,释放胺官能团以获得其中胺官能团是游离的式(I)化合物。
8.权利要求7所定义的作为化学产品的式(IV)、(VIII)和(IX)化合物。
9.权利要求1-6中任何一项所定义的SS、SR混合物形式或SR构型的式(I)化合物的用途,其特征在于使式(I)化合物与6元环上含有不对称碳原子的去消旋剂反应,获得SS构型的式(Iopt)化合物:
其中胺官能团为游离或受保护状态,R同权利要求1中的定义。
11.依照权利要求9或10的用途,其特征在于R代表甲基基团。
12.依照权利要求9或10的用途,其特征在于所述胺官能团以苯二甲酰亚氨基的形式被保护。
13.依照权利要求9或10的用途,其特征在于所述去消旋剂为一种碱。
14.依照权利要求13的用途,其特征在于所述碱为一种强碱。
15.依照权利要求14的用途,其特征在于所述强碱为碱金属或碱土金属醇化物或锂化胺。
16.依照权利要求9或10的用途,其特征在于原料为依照权利要求6的外消旋混合物,所制备的产物为:
(1s-顺式)甲基-9-(1,3-二氢-1,3-二氧代-2H-异吲哚-2-基)-3,4,7,8,9,10-六氢-6,10-二氧代-6H-哒嗪并[1,2-a][1,2]-二氮杂-1-羧酸酯。
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US6204261B1 (en) * | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
GB2128984B (en) * | 1982-05-12 | 1985-05-22 | Hoffmann La Roche | Diaza-bicyclic compounds |
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ES2138622T3 (es) * | 1992-05-15 | 2000-01-16 | Merrell Pharma Inc | Derivados de mercaptoacetilamido piridazo(1,2-a)(1,2)diazepina utilizados como inhibidores de encefalinasa y eca. |
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US5756466A (en) * | 1994-06-17 | 1998-05-26 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1β converting enzyme |
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US6177565B1 (en) * | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
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1998
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1999
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