公开(公告)号：JPH10251281A

公开(公告)日：1998-09-22

申请号：JP5760298

申请日：1998-03-10

Applicant: HOFFMANN LA ROCHE

Inventor： BURKART WOLFGANG ,  SCALONE MICHELANGELO ,  SCHMID RUDOLF

IPC: B01J31/24 ,  B01J31/18 ,  C07B53/00 ,  C07F9/46 ,  C07F9/655 ,  C07F9/6568 ,  C07F15/00

Abstract: PROBLEM TO BE SOLVED: To obtain the subject novel compound that is a specific phosphorous amide phosphine and is useful as a ligand for a catalyst that can attain high optical yield in reactions such as enantiomer selective hydrogenation reaction, allyl substitution reaction and the like. SOLUTION: This novel compound is represented by formula I (R is a 2-8C alkyl, a 3-8C cycloalkyl; R is a 1-8C alkyl, a 3-8C cycloalkyl, an aryl; R and R in corporate together with a phosphorus atom to form 9-benzophosphoryl, 9-phosphabicyclo[3.3.1] nonyl; * is the chiral center) and is a (R) or (S) chiral novel phosphorous acid amide phosphine, which is useful as a ligand for a catalyst attaining high optical yield in an enantiomer selective reaction. This compound is prepared by reaction of a compound of formula II with a substituted chlorophosphane represented by the formula: R R PCl in a solvent in the presence of a base.

公开(公告)号：JPH1017536A

公开(公告)日：1998-01-20

申请号：JP6588597

申请日：1997-03-19

Applicant: HOFFMANN LA ROCHE

Inventor： BROGER EMIL ALBIN ,  SCHMID RUDOLF

IPC: B01J23/42 ,  B01J23/44 ,  C07B61/00 ,  C07C227/32 ,  C07C249/02 ,  C07C251/08 ,  C07C251/12

Abstract: PROBLEM TO BE SOLVED: To obtain the subject optically active derivative useful for the production of an α-aminocarboxylic acid derivative useful as a synthetic intermediate for a pseudo-peptide for medical treatment. SOLUTION: This α-iminocarboxylic acid derivative is expressed by the formula I (R is OH, NH2 , a lower alkyl-NH or a phenyl-lower alkyl-NH), e.g. (S)-3,3,N-trimethyl-2-(1-phenylethylimino)-butyramide. The derivative of the formula I can be produced e.g. by reacting trimethylpyruvic acid of the formula II with a compound of the formula III. The derivative of the formula I can be converted into an α-aminocarboxylic acid derivative of the formula IV (R is H, etc.) by the catalytic hydrogenation in the presence of a platinum catalyst or a palladium catalyst.

公开(公告)号：JP2001039993A

公开(公告)日：2001-02-13

申请号：JP2000203499

申请日：2000-07-05

Applicant: HOFFMANN LA ROCHE

Inventor： KIENZLE FRANK ,  LALONDE MICHEL ,  SCHMID RUDOLF ,  WANG SHAONING

IPC: C07B55/00 ,  C07F9/50 ,  C07F9/53

Abstract: PROBLEM TO BE SOLVED: To provide a method for utilizing an undesirable enantiomer of an intermediate product for improving the synthetic efficiency of an optically active ligand of a specific compound. SOLUTION: This method for racemizing an atrope isomeric compound of the formula (R1 is a 1-8C alkoxy; R2 is H, a 1-8C alkyl or the like, or R1 and R2 together are ethylenedxoxy or the like, R is H, a 1-8C alkyl or the like; and R4 is phenyl or a substituted phenyl), presenting as (R) or (S) form or a non-racemic mixture of the (R) and (S) forms, is to perform the racemization thermally at 280-380 deg.C.

公开(公告)号：JP2000063355A

公开(公告)日：2000-02-29

申请号：JP22474499

申请日：1999-08-09

Applicant: HOFFMANN LA ROCHE

Inventor： SCHMID RUDOLF ,  LOHRI BRUNO ,  VIEIRA ERIC

IPC: C07D213/89 ,  C07B57/00 ,  C07D211/42 ,  C07D211/52 ,  C07D211/70 ,  C07D211/74

Abstract: PROBLEM TO BE SOLVED: To obtain a new substituted piperidine useful as a chiral-constitutive block in the synthesis of renin inhibitors, esp. disubstituted renin inhibitors. SOLUTION: This new compound (salt) of formula II pref. (3R,4R)-4-(4- benzyloxyphenyl)-1-[(R)-1-phenylethyl] piperidin-3-ol} is obtained by hydroboronizing a compound of formula I [A is an arylene; R1 is C*R3R4R5 (R3 is H; R4 is an aryl; R5 is an alkyl, cycloalkyl, aryl or the like; C* is an asymmetric carbon atom); R2 is O-alkyl, O-cycloalkyl, alkenyl or the like] using pref. NaBH4/BF3.Et2O, BH3-THF or the like followed by, optionally, isolating the desired stereoisomer. Further, the compound of formula I is prepared by reacting a compound of formula III or formula IV with a compound of the formula R1-NH2 or a salt thereof.

公开(公告)号：JP2000063383A

公开(公告)日：2000-02-29

申请号：JP22617399

申请日：1999-08-10

Applicant: HOFFMANN LA ROCHE

Inventor： GUELLER ROLF ,  LOHRI BRUNO ,  SCHMID RUDOLF

IPC: C07D211/52 ,  C07D211/70 ,  C07D211/74 ,  C07D491/04 ,  C07D491/044 ,  C07D491/08

Abstract: PROBLEM TO BE SOLVED: To produce a substituted piperidine epoxide useful for efficiently synthesizing a renin inhibitor by epoxidizing a specific compound. SOLUTION: By epoxidizing a compound of formula I [A is arylene; R1 is CR3R4R5 (R3 is H; R4 is an aryl; R5 is an alkyl, an aryl or the like; C* is asymmetric carbon atom); R2 is an O-alkyl, an O-cycloalkyl, an O-aryl or the like] or its salt a compound of formula II is obtained. The compound of formula I is e.g. (1R,6R)-6-(4-benzyloxy-phenyl)-3-[(R)-1-phenyl-ethyl]-7-oxa-3-aza- bicyclo[4.1.0]heptane or the like. The compound of formula II is a new substance and is e.g. (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5- ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine.

公开(公告)号：JPH11246576A

公开(公告)日：1999-09-14

申请号：JP36404498

申请日：1998-12-22

Applicant: HOFFMANN LA ROCHE

Inventor： FORICHER JOSEPH ,  SCHMID RUDOLF

IPC: B01J31/24 ,  C07B37/04 ,  C07B57/00 ,  C07F9/40 ,  C07F9/53 ,  C07F9/655 ,  C07F9/6553

Abstract: PROBLEM TO BE SOLVED: To obtain the subject intermediate by forming a racemic compound by reacting a specific compound with a specific compound in an organic solvent at a low temperature, then resolving the same. SOLUTION: This method for producing a bisphosphonate consists of reacting, etc., a compound of formula I (R , R are each H, a 1-8C alkyl or the like; R is H, a 1-8C alkyl or the like; R is a 1-8C alkoxy or the like), with 0.5-3 equivalent, preferably 0.9-1.2 equivalent of a compound of formula II (R is a 1-8C alkyl, phenyl or the like; R is a 1-8C alkyl, a 3-6C cycloalkyl), etc., in an organic solvent at a temp. of (-)70-20 deg.C, preferably at a temp. of (-)30-0 deg.C, then adding 0.5-3 equivalent, preferably 1-1.5 equivalent of a metal salt (complex) having oxidizing capacity at a temp. of (-)70-20 deg.C, preferably at a temp. of (-)30-20 deg.C to obtain a racemic compound of formula III, etc., and if desired, performing a resolution of the racemic compound, and converting the obtained bisphosphonate to bisphosphine oxide.

公开(公告)号：WO2006074873A2

公开(公告)日：2006-07-20

申请号：PCT/EP2006000046

申请日：2006-01-05

Applicant: HOFFMANN LA ROCHE ,  SCHMID RUDOLF ,  TRUSSARDI RENE

Inventor： SCHMID RUDOLF ,  TRUSSARDI RENE

CPC classification number: C07K5/0205 ,  C07C213/08 ,  C07C215/52 ,  C07C215/54 ,  C07D207/08

Abstract: The present invention relates to the manufacture of the compounds of formula (I) said compounds of formula (I), or their lithium salts, being valuable intermediates in the manufacture of Dolastatin analogues, which are useful in the treatment of cancer.

Abstract translation: 本发明涉及式（I）化合物的制备，所述式（I）化合物或其锂盐在制备可用于治疗癌症的多拉司他汀类似物中是有价值的中间体。

公开(公告)号：WO2008031750A3

公开(公告)日：2008-06-19

申请号：PCT/EP2007059265

申请日：2007-09-05

Applicant: HOFFMANN LA ROCHE ,  ABRECHT STEFAN ,  SCALONE MICHELANGELO ,  SCHMID RUDOLF

Inventor： ABRECHT STEFAN ,  SCALONE MICHELANGELO ,  SCHMID RUDOLF

IPC: C07D471/04

CPC classification number: C07D455/06 ,  B01J31/2295 ,  B01J2231/641 ,  B01J2531/822 ,  C07D471/04 ,  Y02P20/55

Abstract: The invention relates to a process for the preparation of pyrido[2, 1-a] isoquinoline derivatives of the formula (I), weherein R 2 , R 3 and R 4 are as defined in the specification, comprising the steps of: a) catalytic asymmetric hydrogenation of an enamine of the formula (II), wherein R 1 is lower alkyl, in the presence of a transition metal catalyst containing a chiral diphosphane ligand, b) introduction of an amino protecting group Prot and c) amidation of the ester to form an amide of formula (V), wherein R 2 , R 3 , R 4 and Prot are as defined in the specification.

Abstract translation: 本发明涉及制备式（I）的吡啶并[2,1-a]异喹啉衍生物的方法，其中R 2，R 3，R 3和R 3， SUP 4+如说明书中所定义，包括以下步骤：a）在式（II）的烯胺的催化不对称氢化中，其中R 1是低级烷基，在 存在含有手性二膦配体的过渡金属催化剂，b）引入氨基保护基团Prot和c）酯的酰胺化以形成式（V）的酰胺，其中R 2，R R 4和R 4如说明书中所定义。

公开(公告)号：CA2607927A1

公开(公告)日：2006-11-30

申请号：CA2607927

申请日：2006-05-15

Applicant: HOFFMANN LA ROCHE

Inventor： MOINE GERARD ,  SCHMID RUDOLF ,  ZUTTER ULRICH ,  ADAM JEAN-MICHEL ,  LOHRI BRUNO ,  MATTEI PATRIZIO ,  ABRECHT STEFAN ,  FETTES ALEC ,  FORICHER JOSEPH

IPC: C07D307/32 ,  C07D307/38

Abstract: This invention relates to a process of the preparation of the novel intermediate (S)-4-fluoromethyl-dihydro-furan-2-one of the formula and with its use for the manufacture of pyrido[2,1-a]isoquinoline derivatives of the formula which are useful for the treatment and/or prophylaxis of diseases which are associated with DPP IV.

公开(公告)号：JO2284B

公开(公告)日：2005-09-12

申请号：JO2000111

申请日：2000-07-06

Applicant: HOFFMANN LA ROCHE

Inventor： KIENZLE FRANK ,  LALONDE MICHEL ,  SCHMID RUDOLF ,  WANG SHAONING

IPC: C07B55/00 ,  C07F9/50 ,  C07F9/53

CPC classification number: C07F9/5329 ,  C07F9/5054

Abstract: The present invention is concerned with a novel process for the racemization of atropisomeric bis(phosphine oxide) compounds of formula I in their (S) or (R) or non-racemic form, for the preparation of optical active bisphosphine ligands, which form optical active complexes with transition metals. These complexes are used as catalysts in a number of asymmetric reactions. The racemization is thermal and carried out in high or low boiling solvent, under normal or elevated pressure at 10 to 3.5x10 Pa. The heating is performed in a system which allows heating up to 400 DEG C (reactor, autoclave, aluminum block, round-bottom flask with heating/stirring mantle and the like) or by microwave irradiation or in the melt at a temperature from 260 to 400 DEG C, preferably from 280 to 380 DEG C, batchwise or in a continuous manner