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1. 发明申请

WO2007118682A1 PROCESS FOR THE PREPARATION OF ENANTIOMERI CALLY ENRICHED BETA-AMINO ALCOHOLS STARTING FROM GLYCINE AND AN ALDEHYDE IN THE PRESENCE OF A THREONINE ALDOLASE AND A DECARBOXYLASE 审中-公开
标题翻译：制备在丙二醛和十二烷基硫酸钠存在下从甘氨酸和阿尔德星开始的高效液相色谱法制备精氨酸的氨基酸醇的方法
公开(公告)号：WO2007118682A1
公开(公告)日：2007-10-25
申请号：PCT/EP2007/003274
申请日：2007-04-12
申请人： DSM IP ASSETS B.V. , SCHÜRMANN, Martin , MINK, Daniel , WOLBERG, Michael
发明人： SCHÜRMANN, Martin , MINK, Daniel , WOLBERG, Michael
IPC分类号： C12P13/00 , C12P13/06 , C12P41/00
CPC分类号： C12P13/001
摘要： The invention relates to a process for the preparation of an enantiomerically enriched β-amino alcohol, wherein glycine or a glycine salt and an aldehyde are reacted in the presence of a threonine aldolase and a decarboxylase to form the corresponding enantiomerically enriched β-aminoalcohol, and wherein at least either the threonine aldolase or the decarboxylase is β-selective. In a preferred embodiment of the invention at least either the threonine aldolase or the decarboxylase is enantioselective.
摘要翻译：本发明涉及制备对映体富集的β-氨基醇的方法，其中甘氨酸或甘氨酸盐和醛在苏氨酸醛缩酶和脱羧酶的存在下反应以形成相应的对映体富集的β-氨基醇，以及其中至少苏氨酸醛缩酶或脱羧酶是β选择性的。在本发明的优选实施方案中，苏氨酸醛缩酶或脱羧酶中的至少一种是对映选择性的。

2. 发明申请

WO2007068498A1 PROCESS FOR THE PREPARATION OF DELTA LACTONES 审中-公开
标题翻译：制备三角法的过程
公开(公告)号：WO2007068498A1
公开(公告)日：2007-06-21
申请号：PCT/EP2006/012141
申请日：2006-12-15
申请人： DSM IP ASSETS B.V. , MINK, Daniel , WOLBERG, Michael , SCHÜRMANN, Martin , HILKER, Iris
发明人： MINK, Daniel , WOLBERG, Michael , SCHÜRMANN, Martin , HILKER, Iris
IPC分类号： C12P17/06
CPC分类号： C12P17/06 , C07B53/00 , C07D309/10 , C07D309/30
摘要： The invention relates to a process for the preparation of δ-lactones by reacting acetaldehyde and a substituted acetaldehyde in the presence of an aldolase, preferably a DERA from Escherichia coli, from Bacillus subtilis or from a Geobacillus species, δ-lactones, such as saturated δ-lactones, α, β-unsaturated δ-lactones and 3-hydroxy- δ-lactones can suitably be used as (intermediates in the production of) flavors and/or fragrances and/or pharmaceuticals.
摘要翻译：本发明涉及通过乙醛和取代的乙醛在醛缩酶，优选来自大肠杆菌的DERA，来自枯草芽孢杆菌或地芽孢杆菌属物种，d-内酯如饱和食物的存在下反应来制备D-内酯的方法 D-内酯，α，β-不饱和的D-内酯和3-羟基-D-内酯可以适当地用作香料和/或香料和/或药物的（生产中的中间体）。

3. 发明申请

WO2005118794A2 IMPROVED 2-DEOXY-D-RIBOSE 5-PHOSPHATE ALDOLASES FOR, AND USE IN PRODUCTION OF 2, 4, 6-TRIDEOXYHESOSES AND 6-HALO- OR 6-CYANO-SUBSTITUTED DERIVATIVES THEREOF 审中-公开
标题翻译：改进的2-脱氧-D-呋喃五磷酸酯，用于生产2,4,6-三磷酸和其中6-取代或6-取代的衍生物。
公开(公告)号：WO2005118794A2
公开(公告)日：2005-12-15
申请号：PCT/EP2005/005989
申请日：2005-06-02
申请人： DSM IP ASSETS B.V. , JENNEWEIN, Stefan, Martin , SCHUERMANN, Martin , MOMMERS, Johannes, Helena, Michael , MINK, Daniel , WOLBERG, Michael , WUBBOLTS, Marcel, Gerhardus
发明人： JENNEWEIN, Stefan, Martin , SCHUERMANN, Martin , MOMMERS, Johannes, Helena, Michael , MINK, Daniel , WOLBERG, Michael , WUBBOLTS, Marcel, Gerhardus
IPC分类号： C12N9/00
CPC分类号： C12N9/88 , C12P19/02
摘要： The invention relates to isolated mutants of enzymes from the group of 2-deoxy-D-ribose 5-phosphate aldolase wild-type enzymes having a productivity factor (as determined by a specific test) which is at least 10% higher than the productivity factor for the corresponding wild-type enzyme from which it is a mutant. The mutants have at least one amino acid substitution at one or more of the positions corresponding to K13, T19, Y49, N80, D84, A93, E127, A128, K146, K160,1166, A174, M185, K196, F200, and S239 in Escherichia coli K12 (EC 4.1.2.4) wild-type enzyme sequence, and/or a deletion of at least one amino acid at the positions corresponding to S258 and Y259 therein, optionally combined with, specific, C-terminal extension and/or N terminal extension. The invention also relates to screening processes to find 2-deoxy-D-ribose 5-phosphate aldolase enzymes (either as such or as mutants) having a productivity factor (as determined by said specific test, which forms an essential part of the screening) which is at least 10% higher than the reference value. Moreover, the invention relates to mutant enzymes obtained by the screening process, and to nucleic acids encoding such mutants, and to vectors and host cells comprising, respectively, such nucleic acids or mutants. Finally the invention relates to the use of such (preferably mutant) enzymes, nucleic acids, vectors and host cells in the production of, for instance, 6-chloro-2,4,6-trideoxyD-erythrohexapyranoside.
摘要翻译：本发明涉及分离的2-脱氧-D-核糖5-磷酸醛缩酶野生型酶的突变体，其具有比生产率高至少高10％的生产率因子（通过特异性测试确定）对于其为突变体的相应野生型酶。突变体在对应于K13，T19，Y49，N80，D84，A93，E127，A128，K146，K160,1166，A174，M185，K196，F200和S239的一个或多个位置具有至少一个氨基酸取代在大肠杆菌K12（EC 4.1.2.4）野生型酶序列中，和/或在其对应于S258和Y259的位置上的至少一个氨基酸的缺失，任选地与特异性C末端延伸和/或 N终端扩展。本发明还涉及筛选方法以找到具有生产率因子的2-脱氧-D-核糖-5-磷酸醛缩酶（或者作为突变体）（通过所述具体试验确定，其形成筛选的重要部分）其比参考值高至少10％。此外，本发明涉及通过筛选方法获得的突变酶，以及编码这种突变体的核酸，以及分别含有这些核酸或突变体的载体和宿主细胞。最后，本发明涉及这种（优选突变的）酶，核酸，载体和宿主细胞在生产例如6-氯-2,4,6-三脱氧-D-赤藓糖苷中的用途。

4. 发明申请

WO2004096788A1 PROCESS FOT THE PREPARATION OF (4-HYDROXY-6-OXO-TETRAHYDROPYRAN-2-YL) ACETONITRILE AND DERIVATIVES THEREOF 审中-公开
标题翻译：方法制备（4-羟基-6-氧代 - 四氢吡喃-2-基）乙酸酯及其衍生物
公开(公告)号：WO2004096788A1
公开(公告)日：2004-11-11
申请号：PCT/NL2004/000284
申请日：2004-04-28
申请人： DSM IP ASSETS B.V. , MINK, Daniel , WOLBERG, Michael , BOESTEN, Wilhelmus, Hubertus, Joseph , SEREINIG, Natascha
发明人： MINK, Daniel , WOLBERG, Michael , BOESTEN, Wilhelmus, Hubertus, Joseph , SEREINIG, Natascha
IPC分类号： C07D309/00
CPC分类号： C07D309/30
摘要： The invention relates to a process for the preparation of (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile from 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one, wherein X stands for a leaving group, by reacting 6-X-substituted-methyl-4-hydroxy-tetrahydro-pyran-2-one with a cyanide ion in water and by subsequent lowering of the pH to a pH between 0 and 5. (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable from (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile may suitably be used in the preparation of a pharmaceutical preparation, more in particular in the preparation of statins, more in particular in the preparation of Atorvastatine or a salt thereof, for instance its calcium salt. The invention also relates to (4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)-acetonitrile and other compounds obtainable therefrom.
摘要翻译：本发明涉及从6-X取代的甲基-4-羟基 - 四氢 - 吡喃-2-酮制备（4-羟基-6-氧代 - 四氢 - 吡喃-2-基） - 乙腈的方法，其中X代表离去基团，通过使6-X取代的甲基-4-羟基 - 四氢 - 吡喃-2-酮与氰化物离子在水中反应，随后将pH降低至0至5之间的pH。（4-羟基-6-氧代 - 四氢 - 吡喃-2-基） - 乙腈和从（4-羟基-6-氧代 - 四氢 - 吡喃-2-基） - 乙腈获得的其它化合物可适当地用于制备药物制剂，更特别是制备他汀类药物，更特别是制备阿托伐他汀或其盐，例如其钙盐。本发明还涉及（4-羟基-6-氧代 - 四氢 - 吡喃-2-基） - 乙腈及其可得的其它化合物。

5. 发明申请

WO2010041943A2 METHOD FOR PREPARING ε-CAPROLACTAM FROM N-ACYL-6-AMINOCAPROIC ACID 审中-公开
标题翻译：从N-亚氨基-6-氨基己酸制备电子捕获物的方法
公开(公告)号：WO2010041943A2
公开(公告)日：2010-04-15
申请号：PCT/NL2009/050610
申请日：2009-10-09
申请人： DSM IP ASSETS B.V. , MINK, Daniel , GUIT, Rudolf Philippus Maria , MÜLLER, Monika , RAEMAKERS-FRANKEN, Petronella Catharina
发明人： MINK, Daniel , GUIT, Rudolf Philippus Maria , MÜLLER, Monika , RAEMAKERS-FRANKEN, Petronella Catharina
IPC分类号： C07D201/08 , C07D223/10 , C12P17/10
CPC分类号： C07D201/08 , C07D223/10 , C12P17/10
摘要： The invention relates to a method for preparing ε-caprolactam comprising deacylating N-acyl-6-aminocaproic acid and forming ε-caprolactam. The deacylation may be carried out chemically or biocatalytically. The invention further relates to a host cell, 5 comprising a recombinant vector comprising a nucleic acid sequence encoding an enzyme capable of catalysing the formation of 6-aminocaproic acid from N-acyl-6- aminocaproic acid.
摘要翻译：本发明涉及一种制备ε-己内酰胺的方法，其包括使N-酰基-6-氨基己酸脱酰并形成ε-己内酰胺。脱酰基化可以化学或生物催化进行。本发明还涉及宿主细胞，其包含重组载体，其包含编码能够从N-酰基-6-氨基己酸催化形成6-氨基己酸的酶的核酸序列。

6. 发明申请

WO2006128590A1 HYDROLASES, NUCLEIC ACIDS ENCODING THEM AND METHODS FOR MAKING AND USING THEM 审中-公开
标题翻译：水解物，核酸编码方法及其使用方法
公开(公告)号：WO2006128590A1
公开(公告)日：2006-12-07
申请号：PCT/EP2006/004736
申请日：2006-05-18
申请人： DSM IP ASSETS B.V. , MINK, Daniel , KIERKELS, Joannes, Gerardus, Theodorus , DESANTIS, Grace , FARWELL, Robert , WHIPPLE, Lawrence , BURK, Mark
发明人： MINK, Daniel , KIERKELS, Joannes, Gerardus, Theodorus , DESANTIS, Grace , FARWELL, Robert , WHIPPLE, Lawrence , BURK, Mark
IPC分类号： C12P41/00
CPC分类号： C12P7/62 , C12N9/16 , C12P17/06 , C12P41/005
摘要： The invention provides hydrolases, polynucleotides encoding them, and methods of making and using these polynucleotides and polypeptides. In one aspect, the invention is directed to polypeptides, e.g., enzymes, having a hydrolase activity, e.g., an esterase, acylase, lipase, phospholipase (e.g., phospholipase A, B, C and/or D activity, patatin activity, lipid acyl hydrolase (LAH) activity) or protease activity, including thermostable and thermotolerant hydrolase activity, and polynucleotides encoding these enzymes, and making and using these polynucleotides and polypeptides. The hydrolase activities of the polypeptides and peptides of the invention include esterase activity, lipase activity (hydrolysis of lipids), acidolysis reactions (to replace an esterified fatty acid with a free fatty acid), transesterification reactions (exchange of fatty acids between triglycerides), ester synthesis, ester interchange reactions, phospholipase activity and protease activity (hydrolysis of peptide bonds). The polypeptides of the invention can be used in a variety of pharmaceutical, agricultural and industrial contexts, including the manufacture of cosmetics and nutraceuticals. In another aspect, the polypeptides of the invention are used to synthesize enantiomerically pure chiral products.
摘要翻译：本发明提供水解酶，编码它们的多核苷酸，以及制备和使用这些多核苷酸和多肽的方法。一方面，本发明涉及具有水解酶活性的多肽，例如酯酶，酰基转移酶，脂肪酶，磷脂酶（例如，磷脂酶A，B，C和/或D活性，patatin活性，脂质酰基水解酶（LAH）活性）或蛋白酶活性，包括热稳定和耐热水解酶活性，以及编码这些酶的多核苷酸，以及制备和使用这些多核苷酸和多肽。本发明的多肽和肽的水解酶活性包括酯酶活性，脂肪酶活性（脂质水解），酸解反应（用游离脂肪酸代替酯化脂肪酸），酯交换反应（甘油三酸酯之间的脂肪酸交换），酯合成，酯交换反应，磷脂酶活性和蛋白酶活性（肽键的水解）。本发明的多肽可用于各种药物，农业和工业环境中，包括制造化妆品和营养品。另一方面，本发明的多肽用于合成对映体纯的手性产物。

7. 发明申请

WO2006069799A1 PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED INDOLINE-2-CARBOXYLIC ACID 审中-公开
标题翻译：制备完全富含的吲哚-2-羧酸的方法
公开(公告)号：WO2006069799A1
公开(公告)日：2006-07-06
申请号：PCT/EP2005/014171
申请日：2005-12-22
申请人： DSM IP ASSETS B.V. , DE VRIES, Andreas, Hendrikus, Maria , DE VRIES, Johannes, Gerardus , VAN ASSEMA, Friso, Bernard, Jan , DE LANGE, Ben , MINK, Daniel , HYETT, David, John , MAAS, Peter, Johannes, Dominicus
发明人： DE VRIES, Andreas, Hendrikus, Maria , DE VRIES, Johannes, Gerardus , VAN ASSEMA, Friso, Bernard, Jan , DE LANGE, Ben , MINK, Daniel , HYETT, David, John , MAAS, Peter, Johannes, Dominicus
IPC分类号： C07D209/42
CPC分类号： C07D209/42
摘要： The present invention relates to a process for the preparation of an enantiomerically enriched optionally substituted indoline-2-carboxylic acid or a salt thereof, wherein an enantiomerically enriched chiral ortho-X-substituted phenylalanine compound, wherein X is a leaving group, is subjected to cyclisation, preferably at a temperature of below about 140°C, upon formation of the enantiomerically enriched indoline-2-carboxylic acid compound.
摘要翻译：本发明涉及一种制备对映异构体富集的任选取代的二氢吲哚-2-羧酸或其盐的方法，其中将对映异构体富集的手性邻位取代的苯丙氨酸化合物（其中X为离去基团）在形成对映体富集的二氢吲哚-2-羧酸化合物时，优选在低于约140℃的温度下进行环化。

8. 发明申请

WO2007128469A1 PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY ENRICHED NITRILES 审中-公开
标题翻译：制备充分增强的硝酸盐的方法
公开(公告)号：WO2007128469A1
公开(公告)日：2007-11-15
申请号：PCT/EP2007/003852
申请日：2007-05-02
申请人： DSM IP ASSETS B.V. , MINK, Daniel , LUTJE SPELBERG, Jeffrey, Harald , VRIES,DE, Erik Jan
发明人： MINK, Daniel , LUTJE SPELBERG, Jeffrey, Harald , VRIES,DE, Erik Jan
IPC分类号： C12P13/00 , C12P41/00 , C12P17/02 , C12P17/10 , C12P17/12
CPC分类号： C12P13/002 , C12P17/02 , C12P17/10 , C12P17/12 , C12P41/001 , C12P41/006
摘要： The invention relates to a process for the preparation of an enantiomerically enriched nitrile by reacting an epihalohydrin (derivative) with Br - and CN - in the presence of an enantioselective haloalcohol dehalogenase. The process of the invention leads to enantiomerically enriched nitriles in a high yield and in a high enantiomeric excess. Preferably the haloalcohol dehalogenase used is HheC, more preferably HheC from Agrobacterium radiobacter AD1, most preferably the W249F mutant from HheC from Agrobacterium radiobacter AD1. In one preferred embodiment of the invention the epihalohydrin (derivative) is epichlorohydrin. The enantiomerically enriched nitriles obtained by the process of the invention are especially suitable as intermediates in the preparation of statins, in particular of atorvastatin or rosuvastatin.
摘要翻译：本发明涉及一种通过在对映选择性卤代醇脱卤酶存在下使表卤代醇（衍生物）与Br - 和/或SUP反应来制备对映体富集的腈的方法。本发明的方法以高产率和高对映体过量导致对映体富集的腈。优选使用的卤代醇脱卤酶是HheC，更优选来自放射性土壤杆菌AD1的HheC，最优选来自放射性土壤杆菌AD1的来自HheC的W249F突变体。在本发明的一个优选实施方案中，表卤代醇（衍生物）是表氯醇。通过本发明方法获得的对映异构体富集的腈特别适合作为他汀类药物，特别是阿托伐他汀或罗苏伐他汀制剂的中间体。

9. 发明申请

WO2004078702A1 PROCESS FOR THE PREPARATION OF AN α-AMINO CARBONYL COMPOUND 审中-公开
标题翻译：制备α-氨基羰基化合物的方法
公开(公告)号：WO2004078702A1
公开(公告)日：2004-09-16
申请号：PCT/NL2004/000162
申请日：2004-03-04
申请人： DSM IP ASSETS B.V. , HYETT, David, John , MINK, Daniel , BROXTERMAN, Quirinus, Bernardus , KAPTEIN, Bernardus , ZEEGERS, Hubertus, Josephus, Marie
发明人： HYETT, David, John , MINK, Daniel , BROXTERMAN, Quirinus, Bernardus , KAPTEIN, Bernardus , ZEEGERS, Hubertus, Josephus, Marie
IPC分类号： C07C249/02
CPC分类号： C07C231/02 , C07C249/02 , C07C253/30 , C07C237/16 , C07C251/08 , C07C251/24 , C07C255/28 , C07C255/61
摘要： The invention relates to a process for the preparation of an α-amino carbonyl compound by reacting an imine starting material with a suitable electrophile in the presence of a base. This process has the advantage that the imine starting materials can be prepared from glyoxylic acid esters or glyoxylic acid ester derivatives and α-hydrogen containing primary amines, which are usually cheap and readily available. These imine starting materials can usually be prepared with a high yield and/or almost without the formation of any side products.
摘要翻译：本发明涉及通过在碱存在下使亚胺起始原料与合适的亲电子试剂反应来制备α-氨基羰基化合物的方法。该方法的优点在于，亚胺原料可以由乙醛酸酯或乙醛酸酯衍生物和含α-伯氢的伯胺制备，通常便宜且易于获得。这些亚胺原料通常可以以高产率和/或几乎不形成任何副产物来制备。

10. 发明申请

WO2007137816A1 PROCESS FOR THE PREPARATION OF EPOXIDE INTERMEDIATES FOR PHARMACEUTICAL COMPOUNDS SUCH AS STATINS 审中-公开
标题翻译：用于制备化学药物的环氧化物中间体的方法如统计
公开(公告)号：WO2007137816A1
公开(公告)日：2007-12-06
申请号：PCT/EP2007/004743
申请日：2007-05-29
申请人： DSM IP ASSETS B.V. , MINK, Daniel , LUTJE SPELBERG, Jeffrey, Harald , DE VRIES, Erik, Jan
发明人： MINK, Daniel , LUTJE SPELBERG, Jeffrey, Harald , DE VRIES, Erik, Jan
IPC分类号： C12P17/02 , C12P13/00 , C12P17/06
CPC分类号： C12P13/004 , C12P17/02 , C12P17/06
摘要： The invention relates to a process for the preparation of intermediates, which can suitably be used in the preparation of active pharmaceutical ingredients, in particular in the preparation of HMG-CoA reductase inhibitors, more in particular in the preparation of statines, for example lovastatin, cerivastatin, rosuvastatin, simvastatin, pravastatin, atorvastatin or fluvastatin, most in particular of atorvastatin. The intermediates are prepared according to the process of the invention by reaction of (enantiomerically enriched) 6-chloromethyl-4-hydroxy-tetrahydro-pyran- 2-one or the ring opened formed thereof with cyanide in the presence of a haloalcohol dehalogenase, preferably HheA from Arthrobacter sp. strain AD2.
摘要翻译：本发明涉及一种制备中间体的方法，其可适用于制备活性药物成分，特别是制备HMG-CoA还原酶抑制剂，特别是在制备他汀类药物中，例如洛伐他汀，西立伐他汀，瑞舒伐他汀，辛伐他汀，普伐他汀，阿托伐他汀或氟伐他汀，最特别是阿托伐他汀。根据本发明的方法，通过（对映体富集的）6-氯甲基-4-羟基 - 四氢 - 吡喃-2-酮或其形成的环与氰化物在卤代醇脱卤素酶的存在下反应制备中间体，优选来自节节杆菌的HheA 菌株AD2。

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