KR20000069705A - Enzymatic Resolution of Benzodiazepine-Acetic Acid Esters with a Lipase - Google Patents
Enzymatic Resolution of Benzodiazepine-Acetic Acid Esters with a Lipase Download PDFInfo
- Publication number
- KR20000069705A KR20000069705A KR1019997005777A KR19997005777A KR20000069705A KR 20000069705 A KR20000069705 A KR 20000069705A KR 1019997005777 A KR1019997005777 A KR 1019997005777A KR 19997005777 A KR19997005777 A KR 19997005777A KR 20000069705 A KR20000069705 A KR 20000069705A
- Authority
- KR
- South Korea
- Prior art keywords
- methyl
- benzodiazepine
- oxo
- tetrahydro
- acetic acid
- Prior art date
Links
- 108090001060 Lipase Proteins 0.000 title abstract description 15
- 102000004882 Lipase Human genes 0.000 title abstract description 15
- 239000004367 Lipase Substances 0.000 title abstract description 14
- 235000019421 lipase Nutrition 0.000 title abstract description 14
- UROWRFYCWSNTOI-UHFFFAOYSA-N 2-(1H-1,2-benzodiazepin-3-yl)acetic acid Chemical class OC(=O)CC1=NNc2ccccc2C=C1 UROWRFYCWSNTOI-UHFFFAOYSA-N 0.000 title 1
- 230000002255 enzymatic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 51
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 60
- -1 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid carboxylic acid Chemical class 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 102000004190 Enzymes Human genes 0.000 claims description 21
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- 241000222120 Candida <Saccharomycetales> Species 0.000 claims description 18
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 101710098554 Lipase B Proteins 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
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- 239000005557 antagonist Substances 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
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- 108010049003 Fibrinogen Proteins 0.000 claims description 10
- 229940012952 fibrinogen Drugs 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- CLWDLBDPVUWYEW-JTQLQIEISA-N [(2s)-4-methyl-3-oxo-2,3,4,5-tetrahydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1[C@@H](CC(O)=O)C(=O)N(C)CC2=CC=CC=C21 CLWDLBDPVUWYEW-JTQLQIEISA-N 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- USQCSFAOCPKJQV-JTQLQIEISA-N 2-[(2s)-7-iodo-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1[C@@H](CC(O)=O)C(=O)N(C)CC2=CC(I)=CC=C21 USQCSFAOCPKJQV-JTQLQIEISA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- CLWDLBDPVUWYEW-UHFFFAOYSA-N 2-(4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl)acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC=CC=C21 CLWDLBDPVUWYEW-UHFFFAOYSA-N 0.000 claims description 3
- UKHFOXCPJKIADP-JTQLQIEISA-N 2-[(2s)-7-bromo-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound N1[C@@H](CC(O)=O)C(=O)N(C)CC2=CC(Br)=CC=C21 UKHFOXCPJKIADP-JTQLQIEISA-N 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- PYZOVVQJTLOHDG-FQEVSTJZSA-N 2-[(2s)-4-methyl-3-oxo-7-(4-piperidin-4-ylpiperidine-1-carbonyl)-2,5-dihydro-1h-1,4-benzodiazepin-2-yl]acetic acid Chemical compound O=C([C@H](CC(O)=O)NC1=CC=2)N(C)CC1=CC=2C(=O)N(CC1)CCC1C1CCNCC1 PYZOVVQJTLOHDG-FQEVSTJZSA-N 0.000 claims description 2
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- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003431 cross linking reagent Substances 0.000 claims description 2
- CTNHEPMOYGIJTB-UHFFFAOYSA-N methyl 2-(7-iodo-4-methyl-3-oxo-2,5-dihydro-1h-1,4-benzodiazepin-2-yl)acetate Chemical compound C1N(C)C(=O)C(CC(=O)OC)NC2=CC=C(I)C=C21 CTNHEPMOYGIJTB-UHFFFAOYSA-N 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- UERDEURWAIHIRH-UHFFFAOYSA-N 2-(1,4-dimethyl-3-oxo-2,5-dihydro-1,4-benzodiazepin-2-yl)acetic acid Chemical compound CN1C(CC(O)=O)C(=O)N(C)CC2=CC=CC=C21 UERDEURWAIHIRH-UHFFFAOYSA-N 0.000 claims 1
- IBPYPQBTYONHAX-UHFFFAOYSA-N 2-(1h-1,4-benzodiazepin-2-yl)-2-oxoacetic acid Chemical compound N1C(C(=O)C(=O)O)=CN=CC2=CC=CC=C21 IBPYPQBTYONHAX-UHFFFAOYSA-N 0.000 claims 1
- USQCSFAOCPKJQV-UHFFFAOYSA-N 2-(7-iodo-4-methyl-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl)acetic acid Chemical compound N1C(CC(O)=O)C(=O)N(C)CC2=CC(I)=CC=C21 USQCSFAOCPKJQV-UHFFFAOYSA-N 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 19
- BYTRSUQNZQHUTO-UHFFFAOYSA-N acetic acid 1H-1,2-benzodiazepine Chemical compound C(C)(=O)O.N1N=CC=CC2=C1C=CC=C2 BYTRSUQNZQHUTO-UHFFFAOYSA-N 0.000 abstract 1
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- 235000019439 ethyl acetate Nutrition 0.000 description 12
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- 239000002253 acid Substances 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
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- 238000003786 synthesis reaction Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000006460 hydrolysis reaction Methods 0.000 description 8
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 8
- 229940040461 lipase Drugs 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
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- 229910004013 NO 2 Inorganic materials 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 6
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- 238000004296 chiral HPLC Methods 0.000 description 6
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- 239000000543 intermediate Substances 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
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- 125000001424 substituent group Chemical group 0.000 description 6
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
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- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical compound C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 3
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical compound C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
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- NERBLCVCQKXTEP-UHFFFAOYSA-N tert-butyl 4-piperidin-4-ylpiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C1CCNCC1 NERBLCVCQKXTEP-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/10—Nitrogen as only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/165—Heterorings having nitrogen atoms as the only ring heteroatoms
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
Abstract
본 발명은 거울상 이성질적으로 순수한 벤조디아제핀 아세트산 에스테르, 및 리파제를 이용하여 라세미체 혼합물을 분할함으로써 이 화합물을 제조하는 방법에 관한 것이다.The present invention relates to a process for preparing this compound by dividing the racemic mixture with enantiomerically pure benzodiazepine acetic acid ester, and lipase.
Description
단백질 분해 효소를 사용하여 에스테르를 가수분해하는 것은 잘 알려져 있다. 종종, 기질 에스테르가 1개 이상의 키랄 탄소 원자를 가지는 경우, 단백질 분해 효소는 라세미체 혼합물 중 다른 거울상 이성질체에 비해 어느 한 거울상 이성질체와 훨씬 더 빨리 반응한다. 적절한 기질을 사용할 경우, 이 화학적 선택성은 라세미 혼합물의 분할을 위한 토대로 이용되어 왔다. 이러한 선택적 가수분해 반응의 생성물이 반응성 거울상 이성질체의 경우 카르복실산과 알콜인 반면, 비반응성 거울상 이성질체의 경우는 에스테르로 존속된다. 그러면 에스테르와 산의 분리의 용이함은 카르복실산 또는 알콜 프라그먼트의 입체화학적 정제의 기초가 된다.It is well known to hydrolyze esters using proteolytic enzymes. Often, when the substrate ester has one or more chiral carbon atoms, the proteolytic enzyme reacts much faster with either enantiomer compared to the other enantiomers in the racemic mixture. When using the appropriate substrate, this chemical selectivity has been used as the basis for the partitioning of the racemic mixture. The product of this selective hydrolysis reaction is carboxylic acid and alcohol in the case of reactive enantiomers, while in the case of non-reactive enantiomers it is retained as an ester. The ease of separation of esters and acids is then the basis for stereochemical purification of carboxylic acids or alcohol fragments.
일반적으로 분자 중 카르복실산 프라그먼트에 키랄성과 복잡성이 있는 경우, 에스테라제 또는 프로테아제를 사용하여 대응 키랄산을 제조하고, 알콜 프라그먼트에 복잡성과 키랄성이 있는 경우, 리파제를 사용하여 키랄 알콜을 제조한다. 그럼에도 불구하고, 키랄산을 분할하는 리파제의 일부예가 공지되어 있다.In general, when the carboxylic acid fragment in the molecule has chirality and complexity, the corresponding chiral acid is prepared using an esterase or protease, and if the alcohol fragment has complexity and chirality, the lipase is used to form the chiral alcohol. Manufacture. Nevertheless, some examples of lipases that split chiral acid are known.
공정의 입체화학적 순도는 대개 라세미체의 이성질체 각각의 상대적인 가수분해 속도에 의해 좌우되어 예를 들어 상대 속도차가 클수록 최종 키랄 생성물의 순도는 더 높다. 적절한 효소를 찾을 수 있을 경우, 주어진 화합물을 선택적으로 가수분해하기에 적절한 효소의 선택은 주로 경험에 따른다. 따라서, 유용한 효소는 원하는 화합물을 기질로서 받아들여야 하고, 적절한 거울상 이성질체만을 선택적으로 가수분해하여야 하고, 만족스러운 거울상 이성질체 과잉량 (e.e.)을 생성하여야 한다.The stereochemical purity of the process is usually governed by the relative hydrolysis rates of each of the isomers of the racemate so that, for example, the greater the relative rate difference, the higher the purity of the final chiral product. Where appropriate enzymes can be found, the choice of suitable enzymes to selectively hydrolyze a given compound is largely empirical. Thus, useful enzymes must accept the desired compound as a substrate, selectively hydrolyze only the appropriate enantiomer, and produce a satisfactory enantiomeric excess (e.e.).
제약적 유용성이 있는 특정 벤조디아제핀 화합물들은 국제 특허 공개 제 93/00095호 (PCT/US92/05463), 동 제94/14776호 (PCT/US93/12436), 동 제95/18619호 (PCT/US95/00248) 및 PCT/US96/11108에 개시되어 있다. 이러한 화합물들의 경우 흔히 그런 것처럼 약리 활성은 상기 문헌에 보고된 라세미체 중 하나의 거울상 이성질체에 주로 존재한다. 따라서, 비라세미 화합물의 제조 방법을 보유하는 것이 바람직하다. 상기 문헌에 보고된 방법은 키랄 고성능 액체 크로마토그래피 (HPLC)에 의한 거울상 이성질체의 분할 및 동형 키랄 합성에 따른다. 그러나, HPLC법은 일반적으로 대규모로 행하기가 어렵다는 단점이 있으며, 키랄 합성은 값비싼 키랄 신톤에 의존하고 합성 과정에서 부분적인 라세미화가 발생할 수도 있다. 따라서, 상기 화합물을 제조하기 위한 새로운 입체선택적 방법이 필요하다.Certain benzodiazepine compounds of pharmaceutical utility are disclosed in WO 93/00095 (PCT / US92 / 05463), WO 94/14776 (PCT / US93 / 12436), WO 95/18619 (PCT / US95 / 00248 ) And PCT / US96 / 11108. As is often the case with such compounds, pharmacological activity is mainly present in the enantiomer of one of the racemates reported in the literature. Therefore, it is desirable to have a method for producing a non-racemic compound. The method reported in this document relies on the cleavage of enantiomers and homozygous chiral synthesis by chiral high performance liquid chromatography (HPLC). However, the HPLC method is generally difficult to carry out on a large scale, and chiral synthesis depends on expensive chiral synthons, and partial racemization may occur in the synthesis process. Thus, there is a need for new stereoselective methods for preparing such compounds.
본 발명자들은 국제 특허 공개 제 93/00095호 (PCT/US92/05463), 동 제94/14776호 (PCT/US93/12436) 및 동 제95/18619호 (PCT/US95/00248)에 보고된 화합물 중 일부가 효모인 칸디다 안타크티카 (Candida Antarctica)에서 단리된 리파제를 사용하는 입체선택적 가수분해에 의한 라세미 혼합물의 분할을 포함하는 방법에 의해 비라세미체로 제조될 수 있다는 것을 발견하였다. 이 분할은 간편하고 고도로 선택적이며, 키랄 3-옥소-1,4-벤조디아제핀 아세트산 화학 분야에서 상당히 획기적인 발전이다. 효소적 가수분해를 이용한 라세미체 벤조디아제핀의 분할은 아직 보고된 바 없다.We report the compounds reported in International Patent Publication Nos. 93/00095 (PCT / US92 / 05463), 94/14776 (PCT / US93 / 12436) and 95/18619 (PCT / US95 / 00248). It has been found that some of them can be made into non-racemic bodies by methods involving the cleavage of racemic mixtures by stereoselective hydrolysis using lipases isolated from yeast Candida Antarctica. This cleavage is simple and highly selective and is a significant breakthrough in the field of chiral 3-oxo-1,4-benzodiazepine acetic acid chemistry. The cleavage of racemic benzodiazepines using enzymatic hydrolysis has not been reported yet.
발명의 요약Summary of the Invention
하나의 양태에서, 본 발명은 칸디다 안타크티카로부터의 리파제를 사용하여 키랄 에스테르 중 하나를 선택적으로 가수분해하는, 라세미 상태의 특정 치환된 3-옥소-2,3,4,5-1H-테트라히드로-1,4-벤조디아제핀-2-아세트산 에스테르를 분할하는 방법에 관한 것이다.In one embodiment, the present invention provides certain substituted 3-oxo-2,3,4,5-1H- in the racemic state, wherein the lipase from Candida anthtacica is used to selectively hydrolyze one of the chiral esters. A method for dividing tetrahydro-1,4-benzodiazepine-2-acetic acid ester.
본 발명의 또 다른 양태는 특히 효소적 가수분해 방법에 의해 라세미체 화합물로부터 제조된, 사실상 거울상 이성질적으로 순수한 치환된 3-옥소-2,3,4,5-1H-테트라히드로-1,4-벤조디아제핀-2-아세트산 화합물에 관한 것이다.Another aspect of the invention is in particular enantiomerically pure substituted 3-oxo-2,3,4,5-1H-tetrahydro-1, prepared from racemic compounds, in particular by enzymatic hydrolysis methods It relates to a 4-benzodiazepine-2-acetic acid compound.
본 발명의 또 다른 양태는 3-옥소-2,3,4,5-1H-테트라히드로-1,4-벤조디아제핀-2-아세트산의 에스테르의 입체화학적 순도를 향상시키는 방법에 관한 것이다.Another aspect of the present invention is directed to a method for improving the stereochemical purity of esters of 3-oxo-2,3,4,5-1H-tetrahydro-1,4-benzodiazepine-2-acetic acid.
본 발명의 또 다른 양태는 제약 물질의 합성에 유용한 특정 중간체 화합물에 관한 것이다.Another aspect of the invention relates to certain intermediate compounds useful in the synthesis of pharmaceutical substances.
끝으로, 본 발명은 안정화되고 고정된 칸디다 안타크티카 리파제 B 제제 및 이 제제의 제조 방법에 관한 것이다.Finally, the present invention relates to a stabilized and immobilized Candida anthatic lipase B formulation and a process for preparing the formulation.
본 발명은 화합물의 광학적 이성질체를 분할하는 리파제 효소의 용도에 관한 것이다.The present invention relates to the use of lipase enzymes to cleave the optical isomers of a compound.
본 발명은 하기 화학식 II의 화합물을 칸디다 안타크티카 리파제 B로 처리하고, 생성되는 (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 카르복실산을 대응하는 (R)-에스테르와 분리하는 것을 포함하는, 화학식 I의 화합물의 제조 방법에 관한 것이다.The present invention is prepared by treating a compound of formula II with Candida anthatic lipase B, resulting in (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4- A process for the preparation of the compound of formula (I) comprising separating the benzodiazepine-2-acetic acid carboxylic acid from the corresponding (R) -ester.
상기 식들에서,In the above formulas,
X는 H, 할로겐, CO2R3, OR4, COR5이거나, 피브리노겐 또는 비트로넥틴 길항제 측쇄이고,X is H, halogen, CO 2 R 3 , OR 4 , COR 5 or fibrinogen or vitronectin antagonist side chain,
R1은 경우에 따라서 Ar, NR2또는 NR3 +(여기서, R은 C1-4알킬임)에 의해 치환된 C1-20알킬 또는 C3-20알케닐이고,R 1 is optionally C 1-20 alkyl or C 3-20 alkenyl substituted by Ar, NR 2 or NR 3 + , where R is C 1-4 alkyl,
R2는 경우에 따라서 Ar, Het 또는 C1-6시클로알킬에 의해 치환된 C1-6알킬이고,R 2 is optionally C 1-6 alkyl substituted with Ar, Het or C 1-6 cycloalkyl,
R3은 C1-6알킬 또는 벤질이고,R 3 is C 1-6 alkyl or benzyl,
R4는 C1-6알킬, COR3또는 벤질이고,R 4 is C 1-6 alkyl, COR 3 or benzyl,
R5는 4,4'-비피페리딘-1-일, (1'-벤질옥시카르보닐)-4,4'-비피페리딘-1-일 또는 (1'-t-부톡시카르보닐)-4,4'-비피페리딘-1-일이다.R 5 is 4,4'-bipiperidin-1-yl, (1'-benzyloxycarbonyl) -4,4'-bipiperidin-1-yl or (1'-t-butoxycarbonyl) -4,4'-bipiperidin-1-yl.
화학식 I의 3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀 아세테이트는 제약 물질 또는 제약 물질 제조의 중간체로서 중요하다. 국제 특허 공개 제95/18619호 (PCT/US95/00248)에 보고된 바와 같이, 이들 화합물의 (S)형 입체이성질체는 약리학적 활성의 근원이 된다. 따라서, 동형 키랄 합성, 물리적 분리 또는 화학적 분할을 필요로 한다. 상기 화합물에 대한 물리적 분할과 동형 키랄 합성은 보고되었으나, 화학적 분할에 대한 보고는 없다.3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine acetate of formula I is important as a pharmaceutical substance or as an intermediate in the manufacture of pharmaceutical substances. As reported in WO 95/18619 (PCT / US95 / 00248), the (S) stereoisomers of these compounds are the source of pharmacological activity. Thus, homologous chiral synthesis, physical separation or chemical cleavage is required. Physical cleavage and isomeric chiral synthesis have been reported for these compounds, but no chemical cleavage has been reported.
본 발명자들은 칸디다 안타크티카 리파제 B가 경우에 따라 7-치환된 3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀 아세테이트와 반응하여 높은 입체선택성을 보이면서 (S)-산을 생성한다는 것을 발견하였다. (R)-거울상 이성질체는 실질적으로 이 효소에 대한 가수분해 기질이 아니므로 약 50% 전환시 가수분해가 자발적으로 정지한다. 또한 이 효소는 (S)-기질의 특정 치환에 대해 고도로 민감하다. 예컨대, 1,4-벤조디아제핀의 1-질소가 메틸렌기로 치환되면 활성이 소실된다. 마찬가지로, X 치환기가 CO2R3인 경우에 X 치환기가 7-위치에서 8-위치로 이동하면 가수분해 활성을 잃게 된다. 그럼에도 불구하고, 벤조디아제핀 고리의 7-위치에서는 상당한 다양성이 허용되는 것으로 보인다. 화학식 II는 R1이 경우에 따라서 페닐에 의해 치환된 C1-12알킬 또는 C1-12알케닐인 것이 적합하다. R1이 C1-4알킬 또는 벤질인 것이 더욱 적합하다. R2로는 H, 또는 경우에 따라서 페닐로 치환된 C1-4알킬이 적합하다. 화학식 II는 R1이 메틸이고 R2도 메틸인 것이 바람직하다. X로는 수소, 브로모, 요오도, t-부톡시카르보닐, 벤질옥시카르보닐, 메톡시카르보닐, 히드록시, 메톡시, (4,4'-비피페리딘-1-일)카르보닐 또는 [1'-t-부톡시카르보닐-(4,4'-비피페리딘-1-일)]카르보닐이 적합하다. R3로는 t-부틸이 바람직하다.The inventors have found that Candida anthatic lipase B optionally reacts with 7-substituted 3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine acetate to show high stereoselectivity (S)- It was found to produce acid. Since the (R) -enantiomer is substantially not a hydrolytic substrate for this enzyme, hydrolysis spontaneously stops at about 50% conversion. This enzyme is also highly sensitive to certain substitutions of the (S) -substrate. For example, when 1-nitrogen of 1,4-benzodiazepine is substituted with a methylene group, activity is lost. Likewise, when the X substituent is CO 2 R 3 , if the X substituent moves from the 7-position to the 8-position, the hydrolytic activity is lost. Nevertheless, it appears that considerable diversity is allowed at the 7-position of the benzodiazepine ring. Formula II is suitably in which R 1 is C 1-12 alkyl or C 1-12 alkenyl substituted by phenyl as the case may be. More suitably R 1 is C 1-4 alkyl or benzyl. Suitable R 2 are H, or optionally C 1-4 alkyl substituted with phenyl. In formula (II), it is preferred that R 1 is methyl and R 2 is also methyl. X is hydrogen, bromo, iodo, t-butoxycarbonyl, benzyloxycarbonyl, methoxycarbonyl, hydroxy, methoxy, (4,4'-bipiperidin-1-yl) carbonyl or [1'-t-butoxycarbonyl- (4,4'-bipiperidin-1-yl)] carbonyl is suitable. As R 3, t-butyl is preferable.
상기 효소는 전세포 배양물의 일부, 효소 추출물, 단리된 효소, 또는 마크로-다공질 아크릴 수지와 같은 고상 지지체 상에 부착된 단리된 효소로서 사용될 수 있다. 지지된 칸디다 안타크티카 리파제 B 제제는 덴마크 바드스바엘드 (Badsvaerd)에 소재한 노보 노르디스크 (Novo Nordisk)사의 노보자임 (Novozym) 435와 독일 만하임에 소재한 베링거 만하임 게엠베하 (Boehringer Mannheim Gmbh)의 L-2 리파제란 상품으로 구입할 수 있다. 이 효소는 일반적으로 열안정성이고 고농도의 여러 유기 용매에 대해 내성이 있다. 지지된 효소 제제는 취급이 용이하여 바람직하다.The enzyme can be used as an isolated enzyme attached on a solid support such as a portion of an entire cell culture, an enzyme extract, an isolated enzyme, or a macro-porous acrylic resin. Supported Candida anthatic lipase B formulations are Novozym 435 from Novo Nordisk, Badsvaerd, Denmark, and L-2 of Boehringer Mannheim Gmbh, Mannheim, Germany. Lipase is available as a commodity. This enzyme is generally thermally stable and resistant to high concentrations of various organic solvents. Supported enzyme preparations are preferred because they are easy to handle.
그러나, 지지된 효소 제제를 사용할 경우, 특히 효소가 수지에 비공유결합된 경우, 일부 문제가 발생할 수 있다. 예컨대, 단백질 용출로 인해, 수지 지지된 효소의 재사용 횟수가 다소 제한될 수 있다는 것이 드러났다. 또한, 대규모로 반응을 실시할 경우, 단백질 용출에 의해 에멀젼이 형성될 수도 있다는 것이 밝혀졌다.However, some problems may arise when using supported enzyme preparations, especially if the enzymes are non-covalently bound to the resin. For example, it has been found that due to protein elution, the number of reuse of resin supported enzymes may be somewhat limited. It has also been found that when the reaction is carried out on a large scale, an emulsion may be formed by protein elution.
이러한 문제들은 글루타르알데히드와 같은 가교결합제를 사용하여 수지를 예비처리함으로써 극복될 수 있다는 것이 발견되었다. 디메틸 수베르이미데이트 및 글루타르알데히드 올리고머와 같은 그외의 가교결합제도 유용할 수 있다. 통상 상기 예비처리는 단순히 t-부탄올과 같은 유기 용매와 물의 혼합물에서 수지를 글루타르알데히드로 수시간 동안 처리하는 것으로 이루어진다. 이러한 처리는 수지를 안정화시켜, 매번 사용시 수지로부터 효소의 유실을 크게 줄이므로 수지를 재사용할 수 있는 횟수를 증가시킨다. 또한, 대규모 조작시의 에멀젼 형성에 따른 문제점도 크게 감소된다.It has been found that these problems can be overcome by pretreating the resin with a crosslinking agent such as glutaraldehyde. Other crosslinkers may also be useful, such as dimethyl suverimidate and glutaraldehyde oligomers. Typically the pretreatment simply consists of treating the resin for several hours with glutaraldehyde in a mixture of water and an organic solvent such as t-butanol. This treatment stabilizes the resin, greatly reducing the loss of enzymes from the resin with each use, thus increasing the number of times the resin can be reused. In addition, problems associated with emulsion formation during large scale operation are also greatly reduced.
가수분해는 일반적으로 물-유기 용매 혼합물에서 실행된다. 아세톤, 메틸에틸 케톤, 메틸 이소부틸 케톤, t-부탄올, 벤젠 및 톨루엔 등의 각종 유기 용매가 유용할 수 있고, 용액 또는 이상계 (two-phase system)를 사용하는 것이 적합하다. 그럼에도 불구하고, 기질의 용해도 특성에 맞추기 위해 적절한 용매를 선택할 때 다소의 실험이 필요할 수 있다. 예컨대, 아세톤-물 혼합물을 선택하는 경우, 기질 (R,S)-메틸 7-[(1'-t-부톡시카르보닐-(4,4'-비피페리딘-1-일))카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트는 반응성이 빈약하다. 그러나, t-부탄올/물 혼합물을 사용하면, 반응이 원만하게 진행된다. 케톤과 이급 및 삼급 알콜은 일상계용으로 특히 유용한 유기 용매이다. 때로는 물과 방향족 탄화수소 용매 혼합물 (예, 물과 벤젠, 톨루엔, 크실렌 또는 메시틸렌)과 같은 이상계의 사용으로 반응 속도가 증가할 수 있다. 물/톨루엔이 특히 적합하다.Hydrolysis is generally carried out in a water-organic solvent mixture. Various organic solvents such as acetone, methylethyl ketone, methyl isobutyl ketone, t-butanol, benzene and toluene may be useful and it is suitable to use solutions or two-phase systems. Nevertheless, some experimentation may be necessary when selecting the appropriate solvent to match the solubility characteristics of the substrate. For example, when selecting an acetone-water mixture, substrate (R, S) -methyl 7-[(1'-t-butoxycarbonyl- (4,4'-bipiperidin-1-yl)) carbonyl ] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate is poorly reactive. However, with the t-butanol / water mixture, the reaction proceeds smoothly. Ketones and secondary and tertiary alcohols are particularly useful organic solvents for everyday use. Sometimes the use of an ideal system such as water and aromatic hydrocarbon solvent mixtures (eg water and benzene, toluene, xylene or mesitylene) can increase the reaction rate. Water / toluene is particularly suitable.
반응 혼합물은 염기를 가함으로써 완충되거나 일정한 pH로 작동될 수 있다. 그러나, 일반적으로 pH 6.0 내지 8.0 사이에서는 반응 속도 또는 입체선택성에 거의 변화가 없다.The reaction mixture can be buffered or operated at a constant pH by adding a base. However, generally there is little change in reaction rate or stereoselectivity between pH 6.0 and 8.0.
반응은 적절하게는 20℃를 넘는 온도에서 진행된다. 일반적으로, 반응이 실온을 넘는 온도 (예컨대, 28 내지 45℃)에서 진행될 경우, 용매의 양과 반응 시간이 짧아질 수 있다. 예컨대, 반응이 약 36℃에서 진행되는 경우, 200 부피의 용매가 약 40 부피로 감소될 수 있고, 반응 시간도 4일에서 24시간 이하로 짧아질 수 있다.The reaction proceeds suitably at temperatures above 20 ° C. In general, when the reaction proceeds at a temperature above room temperature (eg, 28 to 45 ° C.), the amount of solvent and the reaction time may be shortened. For example, when the reaction proceeds at about 36 ° C., 200 volumes of solvent can be reduced to about 40 volumes and the reaction time can be shortened from 4 days to 24 hours or less.
통상 반응은 출발 에스테르의 50%가 소모될 때까지 진행된다. 이는 HPLC, 바람직하게는 키랄 HPLC로 관찰할 수 있다. (R)-에스테르가 효소에 대해 아주 열악한 기질이므로, 반응 시간은 결정적이지 않다. 통상 반응은 온도, 용매 및 반응에 사용된 기질에 따라 수시간에서 수일간 진행된다. 10 내지 24시간이 일반적으로 적당하다.Usually the reaction proceeds until 50% of the starting ester is consumed. This can be observed by HPLC, preferably chiral HPLC. Since (R) -ester is a very poor substrate for enzymes, the reaction time is not critical. Typically the reaction proceeds from hours to days depending on the temperature, the solvent and the substrate used in the reaction. 10 to 24 hours are generally suitable.
비록 다수의 리파제가 본 발명의 3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀 화합물에 대한 선택적 작용을 위한 잠재적인 효소로서 시험되었으나, 칸디다 안타크티카 리파제 B만이 이 고리 시스템을 선택적인 가수분해 기질로 받아들였다. 예컨대, 다음의 공급원으로부터의 리파제를 시험한 경우, 반응은 실패하였다. 돼지 췌장 리파제, 칸디다 리포라이티카 (Candida lipolytica), 칸디다 실린드라세아 (Candida Cylindracea), 무코르 자바니쿠스 (Mucor Javanicus), 슈도모나스 플루오레슨스 (Pseudomonas Fluorescens), 아스페르길루스 우사미이 (Aspergillus usamii), 게오트리쿰 칸디둠 (Geotrichum Candidum), 아스페르길루스 니거 (Aspergillus Niger), 후미콜라 라누기노사 (Humicola Lanuginosa), 암마노 (Ammano) SAM2, 리조푸스 아리주스 (Rhizopus Arrhizus), 페니실륨 사이코품 (Penicillium cycopum), 리조푸스 니벤스 (Rhizopus Nivens), 리조푸스 자바누니쿠스 (Rhizopus Javanunicus), 암마노 리파제 (Ammamo Lipase) A, 리조푸스 델레웨어 (Rhizopus Delewar), 페니실리늄 로퀘포르티 (Penicillinium Roqueforti), 베링거 리파제 L-1, L-3, L-4, L-5, L-6 및 L-8. 칸디다 안타크티카에서 얻어진 또 다른 리파제인 리파제 A 역시 비반응성이었다.Although many lipases have been tested as potential enzymes for the selective action of the 3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine compounds of the invention, only Candida anthatic lipase B The ring system was accepted as a selective hydrolysis substrate. For example, when lipases from the following sources were tested, the reaction failed. Porcine pancreatic lipase, Candida lipolytica, Candida Cylindracea, Mucor Javanicus, Pseudomonas Fluorescens, Aspergillus Usami (Aspergillus usi) Geotrichum Candidum, Aspergillus Niger, Humicola Lanuginosa, Ammano SAM2, Rhizopus Arrhizus, Penicillium Psycho Products (Penicillium cycopum), Rhizopus Nivens, Rhizopus Javanunicus, Ammamo Lipase A, Rhizopus Delewar, Penicillium Loquefort Roqueforti), Boehringer Lipase L-1, L-3, L-4, L-5, L-6 and L-8. Lipase A, another lipase obtained from Candida antarctica, was also non-reactive.
칼스버그 서브틸리신 (Carlsberg subtilisin) 및 돼지 간 에스테라제와 같은 그외의 가수분해 효소도 7-비치환된 벤조디아제핀의 메틸 에스테르를 가수분해시키기는 하지만, 입체선택성은 거의 없다.Other hydrolytic enzymes, such as Carlsberg subtilisin and swine liver esterase, also hydrolyze the methyl esters of 7-unsubstituted benzodiazepines, but have little stereoselectivity.
에스테르를 산과 분리하기 위한 통상적인 기술이 카르복실산 생성물을 반응하지 않은 에스테르와 분리하는 데 사용된다. 통상적으로, 반응 혼합물은 염기성 pH (예, > pH 7)와 고농도의 염으로 조정되고 적절한 유기 용매를 사용하여 추출된다. 이는 유기 용매에 용해되는 반응하지 않은 에스테르와 수성층에 존재하는 카르복실산 생성물을 낳는다. 유기 용매를 건조시키고 증발시켜 키랄 에스테르를 수득하는 한편, 수성층을 산성화시키고, 추출하고, 유기층을 건조시키고 증발시켜 원하는 키랄산을 수득하였다. 결정화, 또는 실리카 겔을 기재로 한 지지체 상에서의 크로마토그래피, 또는 이온 교환법 또는 다른 적절한 수지를 사용하는 것과 같은 다른 기술을 사용하여 산을 에스테르와 분리할 수도 있으며, 이 또한 본 발명의 범위에 속한다.Conventional techniques for separating esters from acids are used to separate carboxylic acid products from unreacted esters. Typically, the reaction mixture is adjusted to basic pH (eg> pH 7) and high concentration of salt and extracted using a suitable organic solvent. This results in unreacted esters dissolved in organic solvents and carboxylic acid products present in the aqueous layer. The organic solvent was dried and evaporated to yield chiral esters, while the aqueous layer was acidified, extracted and the organic layer was dried and evaporated to give the desired chiral acid. The acid can also be separated from the ester using crystallization, or chromatography on a support based on silica gel, or other techniques such as using ion exchange or other suitable resin, which is also within the scope of the present invention.
다른 관련 기술을 사용하여 특정 에스테르 기질을 생성되는 카르복실산 생성물과 분리할 수도 있다. 예컨대, 메틸 (R)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산은 물에 고도로 용해성이어서, 염기성 pH인 경우에 조차 수성층으로부터 추출하기가 어렵다. 산과 에스테르의 혼합물인 경우, 반응 생성물은 하나의 기질과 우선적으로 반응하는 반응 시약으로 처리하여 분리를 용이하게 할 수 있다. 예컨대, pH 약 7.0에서 (S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산과 그의 대응 (R)메틸 에스테르 이성질체를 카르보벤질옥시-클로라이드, t-부틸옥시카르보닐-클로라이드 또는 대응 무수물로 처리한 결과, 우선적으로 에스테르의 피페리디닐 고리의 아실화가 일어난다. 일단 피페리딘 고리가 아실화되면, 에스테르가 유기 용매에 용해성이고 이는 추출에 의해 분리될 수 있다.Other related techniques can also be used to separate a particular ester substrate from the resulting carboxylic acid product. For example, methyl (R) -7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1 , 4-Benzodiazepine-2-acetic acid is highly soluble in water, making it difficult to extract from the aqueous layer even at basic pH. In the case of mixtures of acids and esters, the reaction product can be treated with a reaction reagent that preferentially reacts with one substrate to facilitate separation. For example, (S) -7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo- at a pH of about 7.0 Treatment of 1H-1,4-benzodiazepine-2-acetic acid and its corresponding (R) methyl ester isomers with carbenzyloxy-chloride, t-butyloxycarbonyl-chloride or the corresponding anhydride results in preferentially piperidi of esters. Acylation of the Neyl ring occurs. Once the piperidine ring is acylated, the ester is soluble in organic solvents which can be separated by extraction.
본 발명의 방법에 의해 적절하게 제조된 생성물은 거울상 이성질체적으로 거의 순수하다. 통상적으로 이 순도는 80% (e.e.) 이상, 바람직하게는 90% 이상, 더욱 바람직하게는 95% 이상, 가장 바람직하게는 99% 이상일 것이다.The product suitably prepared by the process of the invention is almost enantiomerically pure. Typically this purity will be at least 80% (e.e.), preferably at least 90%, more preferably at least 95% and most preferably at least 99%.
본 발명은 주로 화학식 I에 따른 비라세미체 3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀 생성물의 제조 방법에 관한 것이지만, 또한 본 발명이 (R)-거울상 이성질체가 뚜렷한 양으로 존재하는 화학식 I에 따른 키랄 화합물의 입체화학적 순도를 증가시키기 위한 방법으로도 사용될 수 있다는 것을 인식하여야 한다. 예컨대, 화학적 합성, 또는 크로마토그래피와 같은 물리적 방법이 불만스런 거울상 이성질체 순도로 생성물을 수득한 경우, 본 발명의 방법을 이용하여 생성물의 e.e.을 증가시킬 수 있다.The present invention mainly relates to a process for the preparation of non-racemic 3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine products according to formula (I), but the present invention also relates to the (R) -enantiomer It should be appreciated that it can also be used as a method for increasing the stereochemical purity of chiral compounds according to formula (I) present in distinct amounts. For example, if a physical method such as chemical synthesis or chromatography yields the product with unsatisfactory enantiomeric purity, the method of the invention can be used to increase the e.e. of the product.
구체적인 양태에서, 본 발명은In a specific embodiment, the present invention
(a) 화학식 IV의 화합물을 칸디다 안타크티카 리파제 B로 처리하는 단계 및(a) treating a compound of Formula IV with Candida anthatic lipase B and
(b) 생성되는 (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 카르복실산을 대응하는 (R)-에스테르와 분리하는 단계(b) the corresponding (R) -ester to the resulting (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid carboxylic acid To separate with
를 포함하는 화학식 III의 화합물의 제조 방법에 관한 것이다.It relates to a process for the preparation of a compound of formula III comprising a.
상기 식들에서,In the above formulas,
X'는 H, 할로겐, CO2R3또는 OR4이고,X 'is H, halogen, CO 2 R 3 or OR 4 ,
R1은 경우에 따라서 Ar, NR2또는 NR3 +(여기서, R은 C1-4알킬임)에 의해 치환된 C1-20알킬 또는 C3-20알케닐이고,R 1 is optionally C 1-20 alkyl or C 3-20 alkenyl substituted by Ar, NR 2 or NR 3 + , where R is C 1-4 alkyl,
R2는 경우에 따라서 Ar, Het 또는 C1-6시클로알킬에 의해 치환된 C1-6알킬이고,R 2 is optionally C 1-6 alkyl substituted with Ar, Het or C 1-6 cycloalkyl,
R3은 C1-6알킬 또는 벤질이고,R 3 is C 1-6 alkyl or benzyl,
R4는 C1-6알킬, COR3또는 벤질이다.R 4 is C 1-6 alkyl, COR 3 or benzyl.
바람직한 양태에서, 본 발명은 칸디다 안타크티카로부터의 리파제 B로 (R,S)-메틸 7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트를 처리하여 (S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산을 (R) 메틸 7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트와 분리하는 것을 포함하는, (S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조 방법에 관한 것이다. 이 바람직한 양태의 다른 변형으로는 기질이 (R,S)-메틸 7-[(1'-t-부톡시카르보닐-(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트, 또는 (R,S)-메틸 7-[(1'-t-벤질옥시카르보닐-(4,4'-비피페리딘-1-일))카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트이고, 거울상 이성질체를 분리한 다음 t-부톡시카르보닐 또는 벤질옥시카르보닐기의 제거 단계를 더 포함하는 방법이 있다. 상기 보호기는 일반적으로 산처리 또는 촉매적 수소화와 같은 통상적인 수단에 의해 제거된다.In a preferred embodiment, the invention relates to (R, S) -methyl 7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4, with lipase B from Candida anthracica Treatment of 5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepin-2-acetate to (S) -7-[(4,4'-bipiperidin-1-yl) carbonyl ] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid (R) methyl 7-[(4,4'-bipiperidine- (S) -7, comprising separating with 1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepines-2-acetate -[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid It relates to a method for producing. Another variation of this preferred embodiment is that the substrate is (R, S) -methyl 7-[(1'-t-butoxycarbonyl- (4,4'-bipiperidin-1-yl) carbonyl] -2 , 3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate, or (R, S) -methyl 7-[(1'-t-benzyloxycarr Carbonyl- (4,4'-bipiperidin-1-yl)) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2- Acetate, and the enantiomers are separated and then further comprising the step of removing the t-butoxycarbonyl or benzyloxycarbonyl groups, said protecting groups being generally removed by conventional means such as acid treatment or catalytic hydrogenation. .
또 다른 바람직한 양태에서, 본 발명은 (R,S) 메틸 7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트를 칸디다 안타크티카로부터의 리파제 B로 처리하고, (S) 7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산을 (R) 메틸 7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트와 분리하는 것을 포함하는, (S) 7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조 방법에 관한 것이다.In another preferred embodiment, the invention provides (R, S) methyl 7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate Was treated with lipase B from Candida anthracica and (S) 7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2- (S) comprising separating acetic acid from (R) methyl 7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate, (S ) 7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid.
또 다른 바람직한 양태에서, 본 발명은 (R,S) 메틸 2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트를 칸디다 안타크티카 리파제 B로 처리하고, (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산을 (R)-메틸 2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트와 분리하는 단계를 포함하는 (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조 방법에 관한 것이다.In another preferred embodiment, the present invention relates to (R, S) methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate candida anthetica Treatment with lipase B and (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid (R) -methyl 2,3, (S) -2,3,4,5-tetrahydro-4-, comprising the step of separating with 4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate A method for producing methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid.
또 다른 양태에서, 본 발명은 X가 H, 할로겐, CO2R3또는 OR4인 화학식 I의 화합물을 전환시키는 것을 포함하는, X가 -COR5이거나 피브리노겐 또는 비트로넥틴 길항제 측쇄인 화학식 I에 따른 비라세미체 화합물의 제조 방법에 관한 것이다.In another embodiment, the invention relates to a compound according to formula I, wherein X is -COR 5 or a fibrinogen or vitronectin antagonist side chain, comprising converting a compound of formula I wherein X is H, halogen, CO 2 R 3 or OR 4 A method for producing a non-racemic compound.
화학식 III의 화합물은 X가 -COR5이거나 피브리노겐 또는 비트로넥틴 길항제 측쇄인 화학식 I에 따른 화합물의 제조에서 특히 유용한 중간체이다. X'로 바람직한 것은 H, Br, I, CO2CH3, CO2-t-Bu 및 OH이다. R1으로 바람직한 것은 C1-4알킬 및 벤질이다.Compounds of formula III are particularly useful intermediates in the preparation of compounds according to formula I, wherein X is -COR 5 or a fibrinogen or vitronectin antagonist side chain. Preferred as X 'are H, Br, I, CO 2 CH 3 , CO 2 -t-Bu and OH. Preferred as R 1 are C 1-4 alkyl and benzyl.
본 발명의 방법으로 제조된 특히 유용한 화합물은 (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산, (S)-7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산, (S)-7-브로모-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 또는 (S)-7-t-부톡시카르보닐-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 및 이들의 단순한 에스테르들이다. 전형적인 에스테르는 C1-4알킬, 페닐 또는 벤질 에스테르, 및 이들의 유도체일 것이고, 이들은 대응하는 카르복실산으로부터 통상적인 에스테르 교환반응에 의해 제조될 수 있다.Particularly useful compounds prepared by the process of the invention are (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, (S)- 7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, (S) -7-bromo-2,3,4 , 5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid or (S) -7-t-butoxycarbonyl-2,3,4,5-tetrahydro- 4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and simple esters thereof. Typical esters will be C 1-4 alkyl, phenyl or benzyl esters, and derivatives thereof, which can be prepared by conventional transesterification from the corresponding carboxylic acid.
따라서, 또 다른 양태에서 본 발명은 상기 방법에 의해 화학식 III의 화합물을 제조하는 단계, 및 화학식 III의 화합물을 X가 COR5, 또는 피브리노겐 또는 비트로넥틴 길항제 측쇄인 화학식 I의 화합물로 전환시키는 단계를 포함하는, X가 COR5, 또는 피브리노겐 또는 비트로넥틴 길항제 측쇄인 화학식 I의 화합물의 제조 방법에 관한 것이다. 본 발명의 중간체 화합물을 X가 COR5, 또는 피브리노겐 또는 비트로넥틴 길항제 측쇄인 화학식 I의 화합물로 전환시키는 것은 본 명세서에 참고로 도입한 국제 특허 공개 제93/00095호 (PCT/US92/05463), 동 제94/14776호 (PCT/US93/12436), 동 제95/18619호 (PCT/US95/00248), 동 제96/00730호 (PCT/US95/08306), 동 제96/00574호 (PCT/US95/08146), PCT/US97/18001 및 국제 특허 공개 제97/24336호에 개시된 바와 같은 통상적인 반응 및 방법에 의해 수행될 수 있다.Thus, in another embodiment, the present invention provides a process for preparing a compound of formula III by the above method, and converting the compound of formula III to a compound of formula I wherein X is COR 5 , or a fibrinogen or vitronectin antagonist side chain. X, which comprises COR 5 , or a fibrinogen or vitronectin antagonist side chain. The conversion of intermediate compounds of the present invention to compounds of formula (I) wherein X is COR 5 , or a fibrinogen or vitronectin antagonist side chain, is disclosed in WO 93/00095 (PCT / US92 / 05463), incorporated herein by reference. 94/14776 (PCT / US93 / 12436), 95/18619 (PCT / US95 / 00248), 96/00730 (PCT / US95 / 08306), 96/00574 (PCT) / US95 / 08146), PCT / US97 / 18001 and International Patent Publication No. 97/24336.
보다 구체적인 양태에서, 본 발명은 (S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산, (S)-7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산, (S)-7-브로모-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 또는 (S)-7-t-부톡시카르보닐-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산을 (S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-아세트산으로 전환시키는 것을 포함하는 (S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산과 같은 화학식 I에 따른 화합물의 제조 방법에 관한 것이다.In a more specific embodiment, the invention provides (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, (S) -7-io Figure 2,3,4,5-Tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid, (S) -7-bromo-2,3,4,5- Tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid or (S) -7-t-butoxycarbonyl-2,3,4,5-tetrahydro-4-methyl -3-oxo-1H-1,4-benzodiazepine-2-acetic acid (S) -7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5- (S) -7-[(4,4'-bipiperidin-1-yl) carbonyl] comprising converting to tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-acetic acid A process for the preparation of compounds according to formula (I), such as -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid.
상기 중간체를 화학식 I의 화합물로 전환시키기 위해 사용될 수 있는 예시적인 방법을 반응식 I에 나타내었다.Exemplary methods that can be used to convert the intermediates into compounds of formula I are shown in scheme I.
a) 피리딘·ICl 또는 CBr4/Ph3P, b) CO, Pd(OAc)4, Ph3P 및 (4,4'-비피페리딘 또는 1'-Boc-4,4'-비피페리딘 또는 1'-Cbz-4,4'-비피페리딘)a) pyridine.ICl or CBr 4 / Ph 3 P, b) CO, Pd (OAc) 4 , Ph 3 P and (4,4'-bipiperidine or 1'-Boc-4,4'-bipiperidine Or 1'-Cbz-4,4'-bipiperidine)
그러나, 화학식 I의 화합물을 제조하기 위해 화학식 III의 개별 키랄 중간체를 사용하는 많은 기타 통상의 합성법을 구상할 수 있다.However, many other conventional synthesis methods can be envisioned using the individual chiral intermediates of formula III to prepare compounds of formula I.
본 발명에서 유용한 화합물들을 기재하기 위해 화학 분야에서 통상적으로 사용된 약어와 기호를 본 명세서에 사용하였다. 또한, 특정 용어는 다음의 의미를 나타내고자 함이다.Abbreviations and symbols commonly used in the chemical art to describe the compounds useful in the present invention are used herein. In addition, specific terms are intended to indicate the following meanings.
본 명세서에서 사용된 경우, 피브리노겐 길항제 또는 비트로넥틴 길항제 측쇄란 일반적으로 아래 화학식으로 나타낼 수 있다.As used herein, a fibrinogen antagonist or a vitronectin antagonist side chain can generally be represented by the formula below.
W-(CR'2)q-Z-(CR'R10)r-U-(CR'2)s-V- 또는 W'-(CR'2)q-U-(CR'2)s-W- (CR ' 2 ) q -Z- (CR'R 10 ) r -U- (CR' 2 ) s -V- or W '-(CR' 2 ) q -U- (CR ' 2 ) s-
상기 식들에서,In the above formulas,
R'은 H, C1-6알킬, C3-7시클로알킬-C0-4알킬 또는 Ar-C0-4알킬이고,And R 'is H, C 1-6 alkyl, C 3-7 cycloalkyl, -C 0-4 alkyl, or C 0-4 alkyl-Ar,
R"는 R', -C(O)R' 또는 -C(O)OR'이고,R "is R ', -C (O) R' or -C (O) OR ',
R1은 H, C1-6알킬, C3-7시클로알킬-C0-4알킬 또는 Ar-C0-4알킬이고,And R 1 is H, C 1-6 alkyl, C 3-7 cycloalkyl, -C 0-4 alkyl, or C 0-4 alkyl-Ar,
R5는 H, C1-6알킬, C3-7시클로알킬-C0-4알킬 또는 Ar-C0-4알킬이고,R 5 is H, C 1-6 alkyl, C 3-7 cycloalkyl, -C 0-4 alkyl, or C 0-4 alkyl-Ar,
R7은 H, 할로, OR12, SR12, -CN, -NR'R12, -NO2, -CF3, CF3S(O)r-, -CO2R', -CONR'2, R14-C0-6알킬-, R14-C1-6옥살로알킬-, R14-C2-6알케닐-, R14-C2-6알키닐-, R14-C0-6알킬옥시-, R14-C0-6알킬아미노- 또는 R14-C0-6알킬-S(O)r-이고,R 7 is H, halo, OR 12 , SR 12 , -CN, -NR'R 12 , -NO 2 , -CF 3 , CF 3 S (O) r- , -CO 2 R ', -CONR' 2 , R 14 -C 0-6 alkyl-, R 14 -C 1-6 oxaloalkyl-, R 14 -C 2-6 alkenyl-, R 14 -C 2-6 alkynyl-, R 14 -C 0- 6 alkyloxy-, R 14 -C 0-6 alkylamino- or R 14 -C 0-6 alkyl-S (O) r- ,
R8은 R', C(O)R', CN, NO2, SO2R' 또는 C(O)OR5이고,R 8 is R ′, C (O) R ′, CN, NO 2 , SO 2 R ′ or C (O) OR 5 ,
R9는 R', -CF3, -SR' 또는 -OR'이고,R 9 is R ', -CF 3 , -SR' or -OR ',
R10은 H, C1-4알킬 또는 -NR'R"이고,R 10 is H, C 1-4 alkyl or —NR′R ″,
R12는 R', -C(O)R', -C(O)NR'2, -C(O)OR5, -S(O)mR' 또는 S(O)2NR'2이고,R 12 is R ′, —C (O) R ′, —C (O) NR ′ 2 , —C (O) OR 5 , —S (O) m R ′ or S (O) 2 NR ′ 2 ,
R14는 H, C3-6시클로알킬, Het 또는 Ar이고,R 14 is H, C 3-6 cycloalkyl, Het or Ar,
R15는 H, C1-10알킬, C3-7시클로알킬-C0-8알킬 또는 Ar-C0-8알킬이고,R 15 is H, a C 1-10 alkyl, C 3-7 cycloalkyl, -C 0-8 alkyl or Ar-C 0-8 alkyl,
U 및 V는 존재하지 않거나, CO, CR'2, C(=CR15 2), S(O)n, O, NR15, CR15'OR15, CR'(OR")CR'2, CR'2CR'(OR"), C(O)CR'2, CR15 2C(O), CONR15, NR15CO, OC(O), C(O)O, C(S)O, OC(S), C(S)NR15, NR15C(S), SO2NR15, NR15SO2, N=N, NR15NR15, NR15CR15 2, CR15 2O, OCR15 2, C≡C, CR15=CR15, Het 또는 Ar이되,U and V are absent or CO, CR ' 2 , C (= CR 15 2 ), S (O) n , O, NR 15 , CR 15' OR 15 , CR '(OR ") CR' 2 , CR ' 2 CR' (OR "), C (O) CR ' 2 , CR 15 2 C (O), CONR 15 , NR 15 CO, OC (O), C (O) O, C (S) O, OC (S), C (S) NR 15 , NR 15 C (S), SO 2 NR 15 , NR 15 SO 2 , N = N, NR 15 NR 15 , NR 15 CR 15 2 , CR 15 2 O, OCR 15 2 , C≡C, CR 15 = CR 15 , Het or Ar,
단 U 및 V 중 적어도 하나는 존재하고,Provided that at least one of U and V is present,
W는 R'R"N-, R'R"NR'N-, R'R"NR'NCO-, R'2NR'NC(=NR')-, R'ONR'C(=NR')-,W is R'R "N-, R'R"NR'N-,R'R"NR'NCO-, R ' 2 NR'NC (= NR')-, R'ONR'C (= NR ') -,
또는이고, or ego,
W'은이고,W 'is ego,
Q는 NR', O 또는 S이고,Q is NR ', O or S,
Ra는 H, C1-6알킬, Ar-C0-6알킬, Het-C0-6알킬 또는 C3-6시클로알킬-C0-6알킬, 할로겐, OR1, SR1, COR1, OH, NO2, N(R1)2, CO(NR1)2, CH2N(R1)2이고,R a is H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, OR 1 , SR 1 , COR 1 , OH, NO 2 , N (R 1 ) 2 , CO (NR 1 ) 2 , CH 2 N (R 1 ) 2 ,
Rb및 Rc는 독립적으로 H, C1-6알킬, Ar-C0-6알킬, Het-C0-6알킬 또는 C3-6시클로알킬-C0-6알킬, 할로겐, OR1, SR1, COR1, OH, NO2, N(R1)2, CO(NR1)2, CH2N(R1)2로부터 독립적으로 선택되거나, Rb및 Rc는 함께, 경우에 따라 할로겐, C1-4알킬, OR1, SR1, COR1, OH, NO2, N(R1)2, CO(NR1)2, CH2N(R1)2, CN 또는 R"R'NC(=NR')-에 의해 치환된, 5 또는 6원의 방향족 또는 비방향족 고리를 형성하고,R b and R c are independently H, C 1-6 alkyl, Ar-C 0-6 alkyl, Het-C 0-6 alkyl or C 3-6 cycloalkyl-C 0-6 alkyl, halogen, OR 1 , Independently selected from SR 1 , COR 1 , OH, NO 2 , N (R 1 ) 2 , CO (NR 1 ) 2 , CH 2 N (R 1 ) 2 , or R b and R c together, optionally Halogen, C 1-4 alkyl, OR 1 , SR 1 , COR 1 , OH, NO 2 , N (R 1 ) 2 , CO (NR 1 ) 2 , CH 2 N (R 1 ) 2 , CN or R ″ R Forms a 5 or 6 membered aromatic or non-aromatic ring substituted by 'NC (= NR')-,
X는 N=CR', C(O) 또는 O이고,X is N = CR ', C (O) or O,
Y는 존재하지 않거나 S 또는 O이고,Y is absent or S or O,
Z는 (CH2)t, Het, Ar 또는 C3-7시클로알킬이고,Z is (CH 2 ) t , Het, Ar or C 3-7 cycloalkyl,
m은 1 또는 2이고,m is 1 or 2,
n은 0, 1, 2 또는 3이고,n is 0, 1, 2 or 3,
q는 0, 1, 2 또는 3이고,q is 0, 1, 2 or 3,
r은 0, 1 또는 2이고,r is 0, 1 or 2,
s는 0, 1 또는 2이고,s is 0, 1 or 2,
t는 0, 1 또는 2이고,t is 0, 1 or 2,
v는 0 또는 1이고,v is 0 or 1,
w는 1 또는 1이고 q는 0, 1, 2 또는 3임.w is 1 or 1 and q is 0, 1, 2 or 3.
예컨대, 상기 측쇄는 본 명세서에 참고로 도입된 국제 특허 공개 제93/00095호 (PCT/US92/05463), 동 제94/14776호 (PCT/US93/12436), 동 제95/18619호 (PCT/US95/00248), 동 제96/00730호 (PCT/US95/08306), 동 제96/00574호 (PCT/US95/08146) 및 PCT/US96/11108호에 기재되어 있다. 기 W 또는 W'의 염기성 질소가 본 발명에 따른 방법의 수행에서 선택적으로 보호될 수 있다는 것이 이해될 것이다. 질소 보호기는 당업계에 잘 알려져 있으며, 아세틸, 포르밀, 트리플루오로아세틸, 벤조일, 벤질옥시카르보닐 및 알킬옥시카르보닐기와 같은 기를 포함한다.For example, the side chains are described in International Patent Publication Nos. 93/00095 (PCT / US92 / 05463), 94/14776 (PCT / US93 / 12436), 95/18619 (PCT, which are incorporated herein by reference. / US95 / 00248, 96/00730 (PCT / US95 / 08306), 96/00574 (PCT / US95 / 08146) and PCT / US96 / 11108. It will be appreciated that the basic nitrogen of the group W or W 'may be selectively protected in the performance of the process according to the invention. Nitrogen protecting groups are well known in the art and include groups such as acetyl, formyl, trifluoroacetyl, benzoyl, benzyloxycarbonyl and alkyloxycarbonyl groups.
대표적인 피브리노겐 수용체 및 비트로넥틴 수용체 측쇄는 다음과 같다.Representative fibrinogen receptors and vitronectin receptor side chains are as follows.
. .
본 명세서에서 사용된 C1-4알킬은 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸 및 t-부틸을 포함하는 의미이다. C1-6알킬은 펜틸, n-펜틸, 이소펜틸, 네오펜틸 및 헥실, 및 이들의 간단한 지방족 이성질체들을 추가로 포함한다. C1-20알킬도 마찬가지로 표시된 탄소수의 간단한 지방족 탄화수소를 포함한다. 모든 알킬기는 다른 표시가 없는한 R7에 의해 치환되거나 치환되지 않을 수 있다. C0-4알킬 및 C0-6알킬은 알킬기가 존재할 필요가 없음 (예, 공유결합이 존재)을 추가로 나타낸다.C 1-4 alkyl as used herein is meant to include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. C 1-6 alkyl further comprises pentyl, n-pentyl, isopentyl, neopentyl and hexyl, and simple aliphatic isomers thereof. C 1-20 alkyl likewise includes simple aliphatic hydrocarbons of the indicated carbon number. All alkyl groups may or may not be substituted by R 7 unless otherwise indicated. C 0-4 alkyl and C 0-6 alkyl further indicate that an alkyl group does not need to be present (eg, a covalent bond is present).
본 명세서에서 사용된 C2-6알케닐은 탄소-탄소 단일 결합이 탄소-탄소 이중결합으로 대체된 탄소 원자수 2 내지 6개의 알킬기를 의미한다. C2-6알케닐은 에틸렌, 1-프로펜, 2-프로펜, 1-부텐, 2-부텐, 이소부텐 및 수개의 이성질체 펜텐 및 헥센을 포함한다. C3-20알케닐도 마찬가지로 하나 이상의 탄소-탄소 단일 결합이 탄소-탄소 이중 결합으로 대체된, 표시된 탄소수의 간단한 지방족 탄화수소를 포함한다. 시스 및 트랜스 이성질체 모두가 포함된다. 모든 알케닐기는 다른 표시가 없는한 R7에 의해 치환되거나 치환되지 않을 수 있다.As used herein, C 2-6 alkenyl refers to an alkyl group having 2 to 6 carbon atoms in which a carbon-carbon single bond is replaced with a carbon-carbon double bond. C 2-6 alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and several isomers pentene and hexene. C 3-20 alkenyl likewise includes simple aliphatic hydrocarbons of the indicated carbon number, in which one or more carbon-carbon single bonds are replaced with carbon-carbon double bonds. Both cis and trans isomers are included. All alkenyl groups may or may not be substituted by R 7 unless otherwise indicated.
C2-6알키닐은 하나의 탄소-탄소 단일 결합이 탄소-탄소 삼중 결합으로 대체된 탄소수 2 내지 6개의 알킬기를 의미한다. C2-6알키닐은 아세틸렌, 1-프로핀, 2-프로핀, 1-부틴, 2-부틴, 3-부틴, 및 펜틴 및 헥신의 간단한 이성질체를 포함한다. C2-6알키닐기의 모든 sp3탄소 원자는 R7에 의해 치환되거나 치환되지 않을 수 있다.C 2-6 alkynyl refers to an alkyl group having 2 to 6 carbon atoms in which one carbon-carbon single bond is replaced with a carbon-carbon triple bond. C 2-6 alkynyl includes acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and simple isomers of fentin and hexine. All sp 3 carbon atoms of the C 2-6 alkynyl group may or may not be substituted by R 7 .
C1-4옥소알킬은 CH2기가 C(O) 또는 카르보닐기에 의해 치환된, 4개 이하의 탄소 원자로 된 알킬기를 일컫는다. 치환된 포르밀, 아세틸, 1-프로파날, 2-프로판온, 3-프로파날, 2-부탄온, 3-부탄온, 1- 및 4-부타날 기들이 대표적이다. C1-6옥소알킬은 카르보닐기에 의해 치환된 탄소수 5 및 6개의 고급 동족체 및 이성질체를 추가로 포함한다.C 1-4 oxoalkyl refers to an alkyl group of up to 4 carbon atoms in which the CH 2 group is substituted by a C (O) or carbonyl group. Substituted formyl, acetyl, 1-propanal, 2-propanone, 3-propanal, 2-butanone, 3-butanone, 1- and 4-butanal groups are representative. C 1-6 oxoalkyl further includes 5 and 6 higher homologs and isomers substituted by carbonyl groups.
R7과 같은 C1-6알킬, C2-6알케닐, C2-6알키닐 또는 C1-6옥소알킬기 상의 치환기는 임의의 탄소 원자 상에 존재하여, 안정한 구조를 이룰 수 있으며, 통상적인 합성 기술로 가능하다.Substituents on C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 oxoalkyl groups such as R 7 may be present on any carbon atom to form a stable structure, and Phosphorus synthesis is possible.
할로겐은 불소, 염소, 브롬 또는 요오드를 나타낸다.Halogen represents fluorine, chlorine, bromine or iodine.
본 명세서에서 사용딘 Ar 또는 아릴은 페닐 또는 나프틸, 또는 1 내지 3개의 R7부분에 의해 치환된 페닐 또는 나프틸을 의미한다. 특히, R7은 C1-4알킬, C1-4알콕시, C1-4알킬티오, 트리플루오로알킬, OH, F, Cl, Br 또는 I일 수 있다.As used herein, Ar or aryl means phenyl or naphthyl, or phenyl or naphthyl substituted by one to three R 7 moieties. In particular, R 7 can be C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, trifluoroalkyl, OH, F, Cl, Br or I.
Het 또는 헤테로사이클은 경우에 따라 치환된 5 또는 6원의 모노시클릭 고리이거나, 질소, 산소 및 황으로 구성되는 군으로부터 선택된 1 내지 3개의 이종원자를 함유하는 9 또는 10원의 비시클릭 고리이고, 이들은 안정하며 통상적인 화학적 합성법으로 가능하다. 헤테로사이클의 예는 벤조푸란, 벤즈이미다졸, 벤조피란, 벤조티오펜, 푸란, 이미다졸, 인돌, 인돌린, 모르폴린, 피페리딘, 피페라진, 피롤, 피롤리딘, 테트라히드로피리딘, 피리딘, 티아졸, 티오펜, 퀴놀린, 이소퀴놀린 및 테트라- 및 퍼히드로-퀴놀린 및 이소퀴놀린이 있다. 피페리딘, 피페라진, 테트라히드로피리딘 및 피리딘과 같은 1 또는 2개의 질소를 함유하는 6원 고리 헤테로사이클은 Z부분을 위한 헤테로사이클로 바람직하다. 화학적 합성법에 의해 이용할 수 있고 안정한 Het 고리상에서 R7로부터 선택된 것과 같은 3개 이하의 치환기의 허용되는 모든 조합이 본 발명의 범위에 속한다.Het or heterocycle is a optionally substituted 5 or 6 membered monocyclic ring or a 9 or 10 membered bicyclic ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, They are stable and possible by conventional chemical synthesis. Examples of heterocycles are benzofuran, benzimidazole, benzopyran, benzothiophene, furan, imidazole, indole, indolin, morpholine, piperidine, piperazine, pyrrole, pyrrolidine, tetrahydropyridine, pyridine , Thiazole, thiophene, quinoline, isoquinoline and tetra- and perhydro-quinoline and isoquinoline. Six-membered ring heterocycles containing one or two nitrogens such as piperidine, piperazine, tetrahydropyridine and pyridine are preferred as heterocycles for the Z moiety. All acceptable combinations of up to 3 substituents, such as those selected from R 7 on a stable Het ring, available by chemical synthesis, are within the scope of the present invention.
C3-7시클로알킬은 2개 이하의 불포화 탄소-탄소 결합을 함유할 수 있는 3 내지 7개의 선택적으로 치환된 탄소고리계를 일컫는다. 대표적인 C3-7시클로알킬은 시클로프로필, 시클로부틸, 시클로펜틸, 시클로펜테닐, 시클로헥실, 시클로헥세닐 및 시클로헵틸이다. 통상적인 화학적 합성법에 의해 이용할 수 있고 안정한 시클로알킬 고리 상에서 R7로부터 선택된 것과 같은 3개 이하의 치환기로 된 모든 조합이 본 발명의 범위에 속한다.C 3-7 cycloalkyl refers to 3 to 7 optionally substituted carbon ring systems which may contain up to 2 unsaturated carbon-carbon bonds. Representative C 3-7 cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cycloheptyl. All combinations of up to 3 substituents, such as those selected from R 7 on a stable cycloalkyl ring, available by conventional chemical synthesis, are within the scope of the present invention.
본 명세서에서 사용된 경우,은 3개 이하의 질소 원자를 함유하거나 하나의 질소와 산소 및 황으로부터 선택된 하나의 이종 원자를 함유하는, 포화 또는 불포화된 안정한 5-, 6- 또는 7-원의 모노시클릭 고리, 또는 7- 내지 10-원의 비시클릭 고리일 수 있는 질소 헤테로사이클을 나타내고, 이는 안정한 구조를 이룬 임의의 원자 상에서 치환될 수 있다. 상기 고리에서의 질소 원자는 치환되어 4급 질소를 이룰 수 있다. 질소 헤테로사이클은 R20(예, H, C1-4알콕시, F, Cl, Br, I, NO2, NR'2, OH, CO2R', CONHR', CF3, R14-C0-4알킬, R14-C1-4알킬-S(O)u(여기서, u는 0, 1 또는 2임), 또는 상기 치환기들 중 어느 것에 의해 치환된 C1-4알킬)에 의해 임의의 안정한 위치에서 치환될 수 있다. 대표적인은 피롤린, 피롤리딘, 이미다졸, 이미다졸린, 이미다졸리딘, 피라졸, 피라졸린, 피라졸리딘, 피페리딘, 피페라진, 모르폴린, 피리딘, 피리디늄, 테트라히드로피리딘, 테트라히드로- 및 헥사히드로-아제핀, 퀴누클리딘, 퀴누클리디늄, 퀴놀린, 이소퀴놀린 및 테트라- 및 퍼히드로-퀴놀린 및 이소퀴놀린이다. 특히,은 피리딜, 피롤리디닐, 피페리디닐, 피페라지닐, 아제티디닐, 퀴누클리디닐 또는 테트라히드로피리디닐이다.은 4-피리딜, 4-(2-아미노-피리딜), 4-테트라히드로피리딜, 4-피페리디닐 또는 4-피페라지닐이 바람직하다.As used herein, Is a saturated, unsaturated, stable 5-, 6- or 7-membered monocyclic ring containing 7 or less nitrogen atoms or containing one hetero atom selected from nitrogen and oxygen and sulfur, or 7- Nitrogen heterocycle, which may be from 10 to 10 membered bicyclic rings, which may be substituted on any atom having a stable structure. The nitrogen atom in the ring may be substituted to form quaternary nitrogen. Nitrogen heterocycles are R 20 (e.g., H, C 1-4 alkoxy, F, Cl, Br, I, NO 2 , NR ' 2 , OH, CO 2 R', CONHR ', CF 3 , R 14 -C 0 Optionally by -4 alkyl, R 14 -C 1-4 alkyl-S (O) u , wherein u is 0, 1 or 2, or C 1-4 alkyl substituted by any of the above substituents It may be substituted at a stable position of. representative Silver pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, pyridine, pyridinium, tetrahydropyridine, tetra Hydro- and hexahydro-azepine, quinuclidin, quinuclidinium, quinoline, isoquinoline and tetra- and perhydro-quinoline and isoquinoline. Especially, Is pyridyl, pyrrolidinyl, piperidinyl, piperazinyl, azetidinyl, quinuclidinyl or tetrahydropyridinyl. Silver 4-pyridyl, 4- (2-amino-pyridyl), 4-tetrahydropyridyl, 4-piperidinyl or 4-piperazinyl is preferred.
Rb및 Rc가 함께 결합되어 이들이 부착된 고리에 융합된 5- 또는 6-원의 방향족 또는 비방향족 고리를 형성할 경우, 형성된 고리는 Het로 상기 열거된 것들로부터 선택된 5- 또는 6-원의 헤테로사이클이거나, 페닐, 시클로헥실 또는 시클로펜틸고리일 것이다. 벤즈이미다졸릴, 4-아자벤즈이미다졸릴, 5-아자벤즈이미다졸릴 및 이들의 치환된 유도체들이 W' 부분으로 바람직하다.When R b and R c are joined together to form a 5- or 6-membered aromatic or non-aromatic ring fused to a ring to which they are attached, the ring formed is a 5- or 6-membered selected from those listed above as Het It may be a heterocycle or a phenyl, cyclohexyl or cyclopentyl ring. Benzimidazolyl, 4-azabenzimidazolyl, 5-azabenzimidazolyl and substituted derivatives thereof are preferred as the W 'moiety.
본 발명에서 사용된 화학식 II 및 IV의 에스테르는 참고로 본 명세서에 도입된 국제 특허 공개 제93/00095호 (PCT/US92/05463), 동 제94/14776호 (PCT/US93/12436), 동 제95/18619호 (PCT/US95/00248), 동 제96/00730호 (PCT/US95/08306), 동 제96/00574호 (PCT/US95/08146), 동 제97/24336호 및 PCT/US96/11108에 기재된 방법에 따라 제조된다.Esters of formulas (II) and (IV) used in the present invention are described in WO 93/00095 (PCT / US92 / 05463), 94/14776 (PCT / US93 / 12436), 95/18619 (PCT / US95 / 00248), 96/00730 (PCT / US95 / 08306), 96/00574 (PCT / US95 / 08146), 97/24336 and PCT / It is prepared according to the method described in US96 / 11108.
또한, 본 발명의 방법이 화학식 V의 화합물을 제조하는 데 사용될 수 있다는 것과 이들 화합물들이 R1이 H인 화학식 II의 비라세미체 (R) 카르복실산 이성질체를 얻는 통상적인 방법에 의해 가수분해될 수 있다는 것이 당업계의 숙련자들에게는 명백할 것이다.In addition, the process of the present invention can be used to prepare compounds of formula V and these compounds can be hydrolyzed by conventional methods of obtaining the non-racemic (R) carboxylic acid isomers of formula II wherein R 1 is H. It will be apparent to those skilled in the art.
상기 식에서, R1, R2및 X는 화학식 II에 대해 기재된 것과 같다.Wherein R 1 , R 2 and X are as described for Formula II.
<실시예 1><Example 1>
칸디다 안타크티카 리파제 B를 사용한 가수분해를 위한 일반적인 방법General Method for Hydrolysis Using Candida Antachica Lipase B
메틸-3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀-2-아세테이트 0.5 g 또는 적절하게 치환된 그의 유도체를 아세톤 30 ㎖ 또는 t-부탄올와 완충용액 (70 ㎖, pH 7.0, 0.1 N 인산염)에 용해시켰다. 대공질 아크릴레이트 수지상에 지지된 칸디다 안타크티카 리파제 (200 ㎎/700 PLU/g, 노보자임 435로 시판)를 가하고 반응물을 실온에서 4.0일간 교반하였다. 반응물을 HPLC로 관찰하니, 가수분해가 47% 진행되었을 때 반응이 자발적으로 정지하였다. NaOH 용액을 사용하여 pH를 8.0으로 조정하고 EtOAc 75 ㎖를 가하였다. 혼합물을 여과하여 효소 촉매를 제거하고 EtOAc층을 분리하였다. 수성층을 EtOAc (2 x 75 ㎖)로 재추출하였다. 합한 EtOAc 추출물을 황산나트륨 상에서 건조시키고 EtOAc를 진공에서 증발시켜 (R)-에스테르 0.28 g을 남겼다. 입체화학은 인증된 (R)-에스테르 (e.e. > 99%)와 비교 (키랄 HPLC)하여 지정하였다.0.5 g of methyl-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetate or an appropriately substituted derivative thereof was added with 30 ml of acetone or t-butanol and a buffer solution (70 ml, pH 7.0, 0.1 N phosphate). Candida anthatic lipase (200 mg / 700 PLU / g, sold as Novozyme 435) supported on the porous acrylate resin was added and the reaction was stirred at room temperature for 4.0 days. Observation of the reaction by HPLC showed that the reaction spontaneously stopped when the hydrolysis proceeded 47%. The pH was adjusted to 8.0 using NaOH solution and 75 mL EtOAc was added. The mixture was filtered to remove the enzyme catalyst and the EtOAc layer was separated. The aqueous layer was reextracted with EtOAc (2 x 75 mL). The combined EtOAc extracts were dried over sodium sulphate and EtOAc was evaporated in vacuo leaving 0.28 g of (R) -ester. Stereochemistry was designated by comparison (chiral HPLC) with certified (R) -ester (e.e.> 99%).
진한 HCl을 사용하여 수성층의 pH를 5로 조정하고 EtOAc (5 x 75 ㎖)로 추출하였다. 합한 EtOAc 추출물을 황산나트륨 상에서 건조시키고 증발시켜 (S)-산 0.23 g을 남겼다. e.e.은 99%였다 (키랄 HPLC로 계산).The pH of the aqueous layer was adjusted to 5 with concentrated HCl and extracted with EtOAc (5 × 75 mL). The combined EtOAc extracts were dried over sodium sulfate and evaporated to leave 0.23 g of (S) -acid. e.e. was 99% (calculated by chiral HPLC).
상기 방법을 사용하여 다음의 3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀-2-아세트산을 분할하였다.The following 3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetic acid was partitioned using this method.
<실시예 2><Example 2>
(S)-7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조(S) -7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4- Preparation of benzodiazepine-2-acetic acid
(R,S) 메틸 7-[(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세테이트 (34 g, 0.077 몰)을 물 580 ㎖와 1.0N HCl 34 ㎖에 슬리리시켰다. 이 혼합물에 1.0N HCl을 가하여 pH를 6.2 이하로 유지시키면서 30℃에서 0.5시간 동안 교반하였다. 고정된 리파제 수지 (베링거 L-2 리파제, 8.2 g)를 가하고 반응물에 1.5M NH3용액을 가하여 pH를 6.2로 유지하면서 이를 30℃에서 교반하였다. 적정제를 첨가할 필요가 없을 때, 효소 수지를 여과 제거하고 물 50 ㎖로 세척하였다.(R, S) methyl 7-[(4,4'-bipiperidin-1-yl) carbonyl] -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1, 4-benzodiazepine-2-acetate (34 g, 0.077 mole) was slid in 580 mL of water and 34 mL of 1.0N HCl. 1.0N HCl was added to the mixture and stirred at 30 ° C. for 0.5 hour while maintaining the pH at 6.2 or below. Fixed lipase resin (Boehringer L-2 Lipase, 8.2 g) was added and 1.5M NH 3 solution was added to the reaction and stirred at 30 ° C. while maintaining the pH at 6.2. When no titrant was needed, the enzyme resin was filtered off and washed with 50 ml of water.
여액을 CH2Cl2130 ㎖ 중의 벤질 클로로포르메이트 (7.8 g, 0.046 몰)로 된 용액으로 처리하였다. 이 혼합물에 1.5 몰농도의 NH3용액을 가하여 pH를 7.0으로 유지시키면서 30℃에서 1시간 동안 교반하였다. 상들을 분리하고 수성상을 CH2Cl2130 ㎖로 재추출하였다.The filtrate was treated with a solution of benzyl chloroformate (7.8 g, 0.046 mol) in 130 mL of CH 2 Cl 2 . A 1.5 molar NH 3 solution was added to the mixture and stirred at 30 ° C. for 1 hour while maintaining the pH at 7.0. The phases were separated and the aqueous phase was reextracted with 130 mL CH 2 Cl 2 .
수성상을 pH 6.8로 유지시키면서 55℃ 진공에서 가열하였다. 용액 부피가 150 ㎖ 이하인 경우, 용액을 5℃로 냉각시키고 경우에 따라 pH를 조정하면서 12시간 동안 두었다. 그 다음 고체를 여과 제거하고, 냉수로 세척하고 건조시켜 표제 화합물 (16 g, 80%)을 수득하였다. 키랄 HPLC 분석: (S)-이성질체 99.9%.The aqueous phase was heated in 55 ° C. vacuum while maintaining pH 6.8. If the volume of the solution is 150 ml or less, the solution is cooled to 5 ° C. and optionally left for 12 hours with pH adjustment. The solid was then filtered off, washed with cold water and dried to give the title compound (16 g, 80%). Chiral HPLC analysis: 99.9% of (S) -isomer.
디클로로메탄 추출물을 증발시켜 옅은 노란색 결정질 고체로 된 표제 화합물 (R) 메틸 7-[1'-벤질옥시카르보닐-(4,4'-비피페리딘-1-일)카르보닐]-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 (23 g, 100%)을 수득하였다. 키랄 HPLC 분석: (R)-이성질체 >98%.Dichloromethane extract was evaporated to give the title compound (R) methyl 7- [1'-benzyloxycarbonyl- (4,4'-bipiperidin-1-yl) carbonyl] -2,3 as a pale yellow crystalline solid. , 4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid (23 g, 100%) was obtained. Chiral HPLC analysis: (R) -isomer> 98%.
<실시예 3><Example 3>
(S)-7-[[(N'-벤질옥시카르보닐)-4,4'-비피페리딘]카르보닐]-3-옥소-2,3,4,5-테트라히드로-1H-1,4-벤조디아제핀-2-아세트산의 제조(S) -7-[[(N'-benzyloxycarbonyl) -4,4'-bipiperidine] carbonyl] -3-oxo-2,3,4,5-tetrahydro-1H-1, Preparation of 4-benzodiazepine-2-acetic acid
a) 메틸 7-[[(N'-벤질옥시카르보닐)-4,4'-비피페리디닐]카르보닐]-3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀-2-아세테이트a) Methyl 7-[[(N'-benzyloxycarbonyl) -4,4'-bipiperidinyl] carbonyl] -3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine -2-acetate
메틸 7-요오도-3-옥소-2,3,4,5-테트라히드로-1,4-벤조디아제핀-2-아세테이트 (50 g, 134 mmol), 1'-벤질옥시카르보닐-4,4'-비피페리딘 히드로클로라이드 (52.12 g, 154 mmol), 후닉스 (Hunigs) 염기 (67.9 ㎖, 402 mmol), NMP 200 ㎖, 물 (5.2 ㎖, 289 mmol) 및 팔라듐(II) 클로라이드 비스트리페닐포스핀 (1.88 g, 2.68 mmol)을 8 내지 14 psi의 일산화탄소하에서 95℃의 파르 (Parr) 진탕기에서 진탕시켰다. 4시간 후, 일산화탄소 흡수를 중단하고 반응 혼합물을 실온으로 냉각되게 두었다. 그 다음 디클로로메탄 400 ㎖를 가하고 용액을 여과하고 물로 세척하였다. 유기층을 농축 건조시키고 잔류물을 메탄올 770 ㎖에 슬러리화시켰다. 생성물을 여과하고 메탄올로 세척하고 흡인 건조시켜 표제 화합물 (54 g, 70%)을 생성하였다.Methyl 7-iodo-3-oxo-2,3,4,5-tetrahydro-1,4-benzodiazepine-2-acetate (50 g, 134 mmol), 1'-benzyloxycarbonyl-4,4 ' Bipiperidine hydrochloride (52.12 g, 154 mmol), Hunigs base (67.9 mL, 402 mmol), NMP 200 mL, water (5.2 mL, 289 mmol) and palladium (II) chloride bistriphenylphosphate Fins (1.88 g, 2.68 mmol) were shaken on a Parr shaker at 95 ° C. under carbon monoxide at 8-14 psi. After 4 hours, carbon monoxide absorption was stopped and the reaction mixture was allowed to cool to room temperature. Then 400 ml of dichloromethane were added and the solution was filtered and washed with water. The organic layer was concentrated to dryness and the residue slurried in 770 ml of methanol. The product was filtered off, washed with methanol and dried by aspiration to yield the title compound (54 g, 70%).
b) (S)-7-(4,4'-비피페리디닐)카르보닐-3-옥소-2,3,4,5-테트라히드로-1H-1,4-벤조디아제핀-2-아세트산b) (S) -7- (4,4'-bipiperidinyl) carbonyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetic acid
실시예 3(a)의 화합물을 t-부탄올 및 완충용액 (70 ㎖, pH 7.0, 0.1N 인산염)에 용해시켰다. 대공질 아크릴레이트 수지 상에 지지된 칸디다 안타크티카 리파제 B (200 ㎎, /700 PLU/g, 노보자임 435로 시판)을 가하고, 반응물을 실온에서 4.0일간 교반하였다. NaOH 용액을 사용하여 pH를 8.0으로 조정하고 에탄올 75 ㎖를 가하였다. 혼합물을 여과하고, EtOAc 층을 분리하였다. 수성층을 EtOAc로 재추출하고, 합한 EtOAc 추출물을 황산나트륨 상에서 건조시키고 EtOAc를 진공에서 증발시켜 (R)-에스테르를 수득하였다.The compound of Example 3 (a) was dissolved in t-butanol and buffer (70 mL, pH 7.0, 0.1 N phosphate). Candida Antarctica Lipase B (200 mg, / 700 PLU / g, sold as Novozyme 435) supported on the porous acrylate resin was added and the reaction was stirred at room temperature for 4.0 days. The pH was adjusted to 8.0 using NaOH solution and 75 mL of ethanol was added. The mixture was filtered and the EtOAc layer was separated. The aqueous layer was reextracted with EtOAc, the combined EtOAc extracts were dried over sodium sulfate and EtOAc was evaporated in vacuo to afford (R) -ester.
HCl을 사용하여 수성상의 pH를 5로 조정하고 EtOAc로 추출하였다. 합한 EtOAc 추출물을 황산나트륨 상에서 건조시키고 증발시켜 (S)-산 (99% e.e.)을 남겼다.The pH of the aqueous phase was adjusted to 5 with HCl and extracted with EtOAc. The combined EtOAc extracts were dried over sodium sulphate and evaporated to leave (S) -acid (99% e.e.).
메탄올 40 ㎖ 및 아세트산 8 방울 중의 (S)-산 용액 (0.15 mmol)을 30분간 10% Pd/C 20 ㎎을 사용하여 수소 대기 45 psi에서 진탕시켰다. 이 혼합물을 셀라이트를 통해 여과하고 여액을 진공에서 농축시켜 표제 화합물을 수득하였다.A solution of (S) -acid (0.15 mmol) in 40 ml of methanol and 8 drops of acetic acid was shaken at 45 psi in a hydrogen atmosphere using 20% 10% Pd / C for 30 minutes. This mixture was filtered through celite and the filtrate was concentrated in vacuo to afford the title compound.
<실시예 4><Example 4>
(S)-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조Preparation of (S) -2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid
(R,S)-메틸 2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산 (20 g, 0.081 몰)을 톨루엔 200 ㎖ 중에 슬러리시키고 5분간 환류로 가열하였다. 이 용액을 40℃로 냉각시키고 물 200 ㎖와 노보자임 435 20 g을 가하였다. 1.5M 암모니아 용액을 사용하여 pH를 7.0으로 유지시키면서, 반응물을 40℃에서 교반하였다. 16시간 후, HPLC 분석으로 반응이 완료되었음을 관찰하였다. 효소 수지를 여과 제거하고 온수 45 ㎖와 따뜻한 톨루엔 75 ㎖로 세척하였다.Slurry of (R, S) -methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid (20 g, 0.081 mol) in 200 ml of toluene And heated to reflux for 5 minutes. The solution was cooled to 40 ° C. and 200 ml of water and 20 g of Novozyme 435 were added. The reaction was stirred at 40 ° C. while maintaining the pH at 7.0 using 1.5 M ammonia solution. After 16 hours, the HPLC analysis observed that the reaction was complete. The enzyme resin was filtered off and washed with 45 ml of hot water and 75 ml of warm toluene.
톨루엔층을 분리하고 1.5M 암모니아 용액을 사용하여 pH를 8.0으로 유지시키면서, 수성층을 에틸 아세테이트 (2 x 100 ㎖)로 추출하였다. 합한 유기 추출물 (툴루엔 및 에틸 아세테이트)를 스트리핑하여 건조시키고, 잔류물을 디클로로메탄-헥산으로부터 재결정화시켜 출발 에스테르의 (R)-이성질체 (8 g, 80%)를 수득하였다.The toluene layer was separated and the aqueous layer was extracted with ethyl acetate (2 × 100 mL) while maintaining the pH at 8.0 using 1.5M ammonia solution. The combined organic extracts (toluene and ethyl acetate) were stripped and dried, and the residue was recrystallized from dichloromethane-hexane to give the (R) -isomer (8 g, 80%) of the starting ester.
수성층을 에틸 아세테이트로 층화시키고, 염산을 사용하여 pH 4.0으로 산성화시키고, 스트리핑하여 건조시키고, 재결정화시켜 표제 화합물을 수득하였다.The aqueous layer was layered with ethyl acetate, acidified to pH 4.0 with hydrochloric acid, dried by stripping and recrystallized to afford the title compound.
<실시예 5>Example 5
(S)-7-요오도-2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산의 제조Preparation of (S) -7-iodo-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid
(S) 2,3,4,5-테트라히드로-4-메틸-3-옥소-1H-1,4-벤조디아제핀-2-아세트산을 함유하는 수성상으로부터 (R)-에스테르를 추출하는 시점까지 실시예 3의 방법을 반복하였다. 그 다음 수용액을 pH 7.0으로 조정하고 피리딘 ICl 착화합물 (10.2 g, 0.042 몰)을 가하였다. 1.5M 암모니아 용액을 사용하여 이 혼합물의 pH를 6.0으로 유지시키면서, 1시간 동안 교반하였다. 그 다음 진한 HCl을 사용하여 pH를 4.0으로 조정하고 16시간 동안 교반하였다. 생성물을 여과 제거하고 차가운 pH 4인 완충용액으로 세척하고 건조시켜 표제 화합물 (11.2 g, 84%)을 수득하였다. 키랄 HPLC 분석: 99.82% (S)-이성질체.(S) up to the point of extraction of (R) -ester from an aqueous phase containing 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid The method of Example 3 was repeated. The aqueous solution was then adjusted to pH 7.0 and pyridine ICl complex (10.2 g, 0.042 mol) was added. The mixture was stirred for 1 hour while maintaining the pH of the mixture at 6.0 using a 1.5 M ammonia solution. Then the pH was adjusted to 4.0 with concentrated HCl and stirred for 16 h. The product was filtered off, washed with cold pH 4 buffer and dried to afford the title compound (11.2 g, 84%). Chiral HPLC analysis: 99.82% (S) -isomer.
<실시예 6><Example 6>
안정화되고 지지된 효소의 제조Preparation of Stabilized and Supported Enzymes
노보 노르디스크사로부터의 노보자임 435 3 g을 물 4 ㎖, t-부탄올 45 ㎖ 및 글루타르알데히드 (1 ㎖, 수중의 50% 중량/중량)로 된 혼합물에서 pH를 조정하지 않고 약 3 내지 4시간 동안 실온에서 교반하였다. 수지를 여과하고 물로 세척하여 더 건조시키지 않고 사용하였다.3 g of Novozyme 435 from Novo Nordisk was ca. 3-4 h without adjusting the pH in a mixture of 4 ml of water, 45 ml of t-butanol and glutaraldehyde (1 ml, 50% weight / weight in water). Stirred at room temperature. The resin was filtered, washed with water and used without further drying.
Claims (14)
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| EP1290208B1 (en) * | 2000-06-01 | 2010-10-13 | SK Holdings Co., Ltd. | Method for optically resolving a racemic alpha-substituted heterocyclic carboxylic acid using enzyme |
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| KR100650798B1 (en) * | 2004-07-19 | 2006-11-27 | (주)제이코통상 | Process for preparing chiral substituted carboxylic acid |
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