DE102007049039A1 - Process for the preparation of 8-hydrazino-8-aryl-octanoyl derivatives and their use - Google Patents

Process for the preparation of 8-hydrazino-8-aryl-octanoyl derivatives and their use

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DE102007049039A1
DE102007049039A1 DE102007049039A DE102007049039A DE102007049039A1 DE 102007049039 A1 DE102007049039 A1 DE 102007049039A1 DE 102007049039 A DE102007049039 A DE 102007049039A DE 102007049039 A DE102007049039 A DE 102007049039A DE 102007049039 A1 DE102007049039 A1 DE 102007049039A1
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branched
arylalkyl
hydrogen
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alkyl
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Victor Dr. Meier
Karl Dr. Reuter
Florian Dr. Stolz
Tobias Dr. Wedel
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Reuter Chemischer Apparatebau KG
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    • C07C243/12Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
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    • C07C281/14Compounds containing any of the groups, e.g. semicarbazides the other nitrogen atom being further doubly-bound to a carbon atom, e.g. semicarbazones the carbon atom being further bound to a carbon atom of a six-membered aromatic ring
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    • C07D295/22Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2.] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D307/26Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D307/30Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/04Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to a process for the preparation of 8-aryl-octanoyl derivatives, in particular chiral 8-hydrazino-8-aryl-octanoylamides, and to novel intermediates which are used in the process for the preparation of said octanoyl derivatives, and to their use.

Description

  • The Invention relates to a process for the preparation of 8-aryl-octanoyl derivatives, in particular chiral 8-hydrazine-8-aryl-octanoyl derivatives, as well as new intermediates used in the process for preparing the mentioned Octanoylderivate be used and their use.
  • Chiral 8-aryl-octanoyl derivatives of the general formula (X)
    Figure 00010001
    in particular the amides have valuable, in particular pharmacological properties, such as the renin inhibitor with the name "aliskiren" (CAN: 173334-57-1) from Novartis.
  • In the documents WO 02/02508 . WO 02/08172 and WO 01/09083 describe complex, multistage preparation processes for compounds of the general formula (X) via a chiral phenyl-substituted octenoic acid derivative, so-called "Synthon AB", which is composed of two chiral blocks. These blocks are on the one hand a chiral 3-phenyl-2-isopropyl-propyl halide "synthon A" (known from WO 02/02487 and WO 02/02500 and, on the other hand, a chiral 5-halo-2-isopropyl-pent-4-enoic acid "Synthon B" (described in US Pat WO 01/09079 and WO 02/092828 ). The synthon AB, as the free acid or its derivative, z. B. as N, N-dimethylamide, is reacted in several stages to the chiral 8-aryl-octanoyl derivative of the general formula (X).
  • The WO 2006/024501 describes alternative multi-step processes for the preparation of chiral 8-aryl-octanoylamides of the formula (X) starting from 5-hydroxymethyl-3-isopropylpyrrolidone which is protected at N and O position.
  • The EP 0678503 discloses the preparation of compounds 8-aryl-octanoylamides of formula (X), e.g. As aliskiren, in particular, the starting materials are in turn obtained via complex multi-step process.
  • adversely in the known method is mainly the high procedural Effort for the specific configuration of stereochemical centers, which only with high technical and cost feasible is.
  • The Object of the present invention was therefore in the provision a simplified production process for 8-aryl-octanoyl derivatives the general formula (X).
  • The stated object is achieved by a process for the preparation of 8-aryl-octanoyl derivatives of the general formula (X) or salts thereof
    Figure 00020001
    wherein
    R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl;
    and
    X is hydrogen, halogen, O - , OR 12 , in which R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal,
    or
    is NR 8 R 9 , wherein R 8 and R 9 are independently hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl , Alkyl-NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ;
    or their stereoisomers or mixtures thereof, wherein at least one of the following process steps is carried out
    • A) Reaction of a compound of the formula (IV)
      Figure 00030001
      wherein R 1 and R 2 are as defined above and E is a group of the following formulas
      Figure 00030002
      in formula a A is N, and B is NR 4 R 5 , in which R 4 and R 5 independently of one another represent hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched, optionally halogen-substituted alkyl, arylalkyl, preferably benzyl; or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system; and in formula b b1) the single-dotted line represents a single bond; and A is NR 3 wherein R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, and B is NR 4 wherein R 4 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or b2) the single-dotted line represents no bond; and A is the group NR 3 -NR 4 R 5 wherein R 3 , R 4 and R 5 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system; and B is a nitrogen functionality such as azide, NR 6 R 7 or NH-NR 6 R 7 , wherein R 6 and R 7 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl or trialkylsilyl, or R 6 and R 7 together with the nitrogen atom form a heterocyclic ring system, such as phthalimide, or their stereoisomers or mixtures thereof or their delactonized derivatives in one or more steps with a suitable reducing agent with removal of the nitrogen functionality in the C8 position and with formation of an amine group in the C5 position directly to a compound of the formula (X) or to a compound of the formula (IX)
      Figure 00050001
    • B) opening of the lactone ring in a compound of formula (IV) or (IX),
    • C) optionally, converting a compound of the formula (X) or a delactonated derivative of a compound of the formula (IV) into another suitable derivative, preferably one of the meanings of X given above.
  • The The sequence of process steps A), B) and C) can vary depending on the Process conditions are selected, wherein step C) is preferably optional and following step A) and / or step B) is performed.
  • In a preferred variant of the invention Process are compounds of formula (IV) first according to process step A) reductive to a compound of the formula (IX) and then a Lactonringöffnung subjected to process step B), wherein subsequently optional according to process step C) is derivatized.
  • In a further preferred variant of the invention Process are compounds of formula (IV) first according to process step B) of a lactone ring opening subjected, optionally subsequently according to method step C) is derivatized, and the resulting delactonated derivatives subsequently according to the method step A) reductively converted to a compound of formula (X), wherein subsequently optional according to process step C) is derivatized.
  • The reduction step A) can be carried out in one or more steps by methods known per se to the person skilled in the art, as described, for example, in US Pat J. March, Advanced Organic Chemistry, John Wiley & Sons, 1992 or W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd edition, 1986 and the further references cited therein. The aim of the reduction step A) is the removal of the nitrogen function at the C8 position in the group E of the compound of the formula (IV) with simultaneous or subsequent formation of an amine function in the C5 position.
  • Of the Reduction step A) may be preferred with hydrogen in the presence a conventional homogeneous (eg Wilkinson catalyst) or heterogeneous catalyst. Prefers are metal catalysts such as Pt or Pd or Raney-Ni, Ru, Rh or Ir optionally on a support or complexed used with an N, O, P-containing ligands. The reaction can under normal pressure or overpressure up to 100 bar, preferably up to 50 bar, at temperatures from -20 to 150 ° C, preferably 10 ° C to 150 ° C, are performed. Advantageously, the reaction is carried out in a solvent. As a solvent, polar protic or aprotic solvents and apolar solvents such as alcohols or AcOH, THF, DMF, methylene chloride, ether or aliphatic or aromatic hydrocarbons such as. As toluene, hexane or Heptane, etc. are used.
  • Of the Reduction step can also be done in several steps, so that For example, first the oxygen function A in C8 position reductively removed and then the nitrogen function B is converted into an amino group in C5 position. A reverse one Reaction process is also possible.
  • For the cleavage of the NN bond can in particular also, according to known methods (s. Newbold, BT in Patai The Chemistry of the Hydrazo, Azo and Azoxy Groups, pt. 1, Wiley: NY, 1975, 2-629 .), Na 2 S 2 O 4 , Zn / HCl or BH 3 and other borane derivatives can be used as a reducing agent.
  • Especially in the case of several reduction steps, the respective Steps with different reducing agents and in several Steps are performed.
  • As further possible reducing agents, metal hydrides, preferably LiAlH 4 , Redal, NaBH 4 or DIBAH, etc., or metals such as alkali metals, alkaline earth metals or Al, Fe, Zn, etc. may each advantageously be used as usual in protic or aprotic solvents such as. As alcohols, liquid ammonia, lower carboxylic acids such as AcOH, etc. can be used. The conditions known as Birch reduction with various metals in liquid ammonia or amines can also be used (see, for example, US Pat. W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd edition, 1986, pages 440-450 ).
  • In Cases a) and b1), in which the group E is a nitrogen-containing Represents heterocycle, takes place in the reduction step A) a ring opening, preferably selectively at the C8-A bond, possibly with breakage of the bond FROM. Depending on the chosen conditions is also a reverse Reaction process possible, initially the A-B Binding split and then the A-function in position C8 reductive Will get removed.
  • In Dependence on the chosen reaction route is obtained either A or B at C5 position and in an amino function transformed.
  • As described above, the order of reduction (cleavage the A-B bond and reductive removal of the A function in the C8 position and the formation of the amino function in the C5 position) of the reducing agents used and the conditions chosen. If z. B. carried out the reduction step with hydrogen Preferably, the A-B bond is initially cleaved under simultaneous or subsequent formation of the amino function in the Position C5 and subsequent reductive removal of the A function from position C8.
  • The Lactonöffnung according to step B) is also carried out in a known per se in one or more steps by reaction z. B. with water, an alcohol or amines in the corresponding carboxylic acid, ester or amide (see, eg. HP Latscha, HA Klein "Organic Chemistry", 4th edition, Springer-Verlag, Berlin, 1997 or EP 0678 503 ). For example, if the lactone is converted to the corresponding carboxylic acid with water, the resulting acid may be directly or via an activated form such. As the acid chloride, etc., are converted into the corresponding amide derivative.
  • The Lactone opening can occur during both the reduction step A) and after the reduction. If z. B. as a solvent Alcohol used for the reduction step, the opening takes place of the lactone with simultaneous formation of a corresponding ester.
  • As mentioned above, the order of steps A), B) and C) can be changed. Thus, before the reduction step A), the lactone can first be opened with water and / or alcohol or directly with an amine with concomitant formation of the carboxylic acid, the ester or the amide (step B and, if appropriate, C) followed by a reduction step A) a corresponding delactonated derivative of the carboxylic acid. So z. B. the lactone are first converted with an amine into an amide, under conditions such. B. in the EP 0678 503 described, and the reduction step A) such. Cat. Hydrogenation in the presence of a heterogeneous catalyst preferably Pt, Pd or Raney Ni can be carried out in protic solvents such as alcohol under the conditions given above. Particularly preferred is the cleavage of the C8 nitrogen bond under Birch conditions, for. B. lithium in ammonia, as z. B. also in the WO 2006/131304 to be discribed.
  • Prefers For example, the lactone opening may be simultaneously with the reduction step A).
  • The optionally. Additional derivatization, z. B. of the delactonated derivative, according to process step C) is again carried out according to methods known in the art (see, eg. EP 0 678 503 and references cited therein).
  • For example, the carboxylic acid amide can be obtained from a carboxylic acid ester by reaction with amines in the presence of trialkylaluminum or dialkylaluminum halide or a Lewis acid or base (see, for example, US Pat. S. Weinreb, Org. Synthesis, VI, p. 49, 1988 ).
  • The acid halide is reacted in a known manner by reacting the free acid or acid salt with a halogenating agent, e.g. B. thionyl chloride, if desired, solvent-free or in an inert solvent, for. As a hydrocarbon such as toluene or hexane if necessary. In the presence of a catalyst sators, z. As zinc chloride or dimethylformamide at temperatures preferably between 20 and 120 ° C (see, eg. EP 0 258 183 ).
  • One Carboxylic acid ester or a carboxylic acid amide can For example, converted by alkaline saponification in the free acid become.
  • Derivatization C) in the context of the present invention also means the conversion of a compound obtained with at least one salt-forming group into its salt, the conversion of a salt into the free compound or into another salt, as described, for example, in US Pat. B. in the EP 0 678 503 and EP 0 258 183 is described.
  • According to the invention, the starting compounds of the formula (IV) can be obtained in accordance with the following synthesis routes, with the individual reaction steps being carried out in a manner known per se to one skilled in the art. Different reaction sequences can be carried out. The choice of R 3 , R 4 and R 5 and the stereochemistry at the C 8 position can be used to control the diastereomer selectivity of the cyclizations. Depending on the reaction procedure and on the nature of the radicals R 3 , R 4 , R 5 and X, starting from compounds of the general formula (II), it is possible initially to form a lactone of the general formula (III) or a nitrogen heterocycle (compounds Va, Vb) , The corresponding compounds Va and Vb can only be formed if the cyclus-forming nitrogen atom has a free proton, ie R 3 is hydrogen and / or R 4 or R 5 are hydrogen.
  • A preferred variant of the process according to the invention, as indicated in Scheme 2, is based on compounds of the formula (IVa) or (IVb)
    Figure 00090001
    wherein
    R 1 , R 2 have the abovementioned meaning,
    A and B have the meaning given above under a) and b1),
    or their stereoisomers or mixtures thereof,
    which are obtained by reacting a compound of the formula (II)
    Figure 00100001
    wherein
    R 1 , R 2 , R 3 , R 4 and R 5 and X have the abovementioned meaning, where R 3 , R 4 and R 5 are preferably not hydrogen,
    or their stereoisomers or mixtures thereof
    with a halogenating agent, such as. For example, chlorine, bromine, NCS, NBS, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate, an oxidizing agent such as osmium tetroxide, hydrogen peroxide or meta-chloroperbenzoic acid, if necessary, with the addition of chiral auxiliaries, or a mercury compound, such as Hg (OAc) 2 or Hg (O 2 CCF 3 ) 2 , or a selenium compound, such as PhSeCl or ArSeOTf, and optionally subsequent treatment with a base, such as LiOH in water, and, if appropriate, introduction of a protective group, such as Mesylate, tosylate or triflate, with lactonization to give a compound of the formula (III)
    Figure 00100002
    wherein
    R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and Y is bromine, chlorine, iodine, OH or OR 18 , in which OR 18 is a leaving group, such as mesylate, tosylate or triflate,
    or their stereoisomers or mixtures thereof,
    and
    subsequent conversion of the compound of the formula (III) by intramolecular cyclization into the target compound of the formula (IVa) and / or (IVb).
  • The cyclization to the halo-lactone (compound III, where Y = Br, Cl; I) is carried out according to known methods, such as in EP 0 258 183 described, for. B. with N-bromosuccinimide (NBS), NIS, NCS, bromine, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate appropriate in a solvent such as dimethylformamide, tetrahydrofuran, acetonitrile or water or mixtures this solvent at temperatures between -80 and 50 ° C, preferably between 0 and 30 ° C.
  • Optionally, the halogen compound in the connection according to known methods, for. B .: with a base such. For example: LiOH in water, such as in US 6,730,798 B2 described inversion of the configuration at the C5 atom, into the corresponding hydroxy compound (compound III with Y = OH) are transferred. This can then, also according to known methods, in a leaving group, such as. B .: mesylate or tosylate. The compounds of the general formula (III) obtained (where Y = OR 18 ) can then be used analogously to the halogen compounds of the general formula (III) (where Y = Br, I, Cl) for the subsequent reactions.
  • Alternatively, compounds of the general formula (II) can also be converted by epoxidation, in a manner known per se, to the corresponding compounds of the general formula III (where Y = OH). As epoxidizing z. B. peracid, peroxide, if necessary. In the presence of a conventional catalyst, for example. Based on transition metals, such as. As Ti alkoxides, V, Mo, W, their salts or complexes with inorganic or organic ligands, eg. B. under conditions described as "Sharpless epoxidation" (see W. Carruthers, Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd edition, 1986, pages 374-377 ). Preferably, the epoxidation is carried out enantioselectively. For this purpose, z. B. in a conventional manner ( Shi et al. J. Am. Chem. Soc. 1997, 199, 11224-11235 ) Fructosederivate as chiral Auxiliare set. Alternatively, the chiral dihydroxylation is used. It is in a known manner ( Sharpless et al. Chem. Rev. 1994, 94, 2483-2547 ) AD-mix-α or AD-mix-β used as a chiral auxiliary.
  • Before the formation of the second cycle to give compounds of general formula (IVa) and / or (IVb) are starting from compounds of general formula (III) wherein R 3 , R 4 , R 5 all ≠ H, first one or more the nitrogen protecting groups removed. In the case of compounds of the general formula (III), where R 3 , R 4 and / or R 5 = H, it is optionally possible to remove further protective groups. For this purpose, the methods known per se for the removal of nitrogen protective groups are used, as they are known for. B .: in standard works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenary Press, London and New York 1973 , in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 , in "The Peptides"; Volume 3 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , as in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974 , to be discribed. Preferably z. B. a CBZ protecting group (benzyl carbamate) removed by means of catalytic hydrogenation.
  • If desired, the intramolecular cyclization and the formation of the products IVa and IVb can be carried out in polar protic or aprotic as well as apolar solvents. Preference is given to using solvents such as acetonitrile, DMF, water, N-methylpyrrolidone (NMP), etc., in particular DMF, NMP, acetonitrile or toluene, which are usually used for SN 2 substitution. The reaction can also with bases such. As alkali metal hydroxides, alcoholates or metal hydrides or amine bases such as alkylamines, such as. As organic trialkylamines, preferably triethylamine are catalysed. Also acids, especially Lewis acids can be used. The reaction temperature is preferably between -20 ° C and the boiling point of the respective solvent.
  • In a further preferred variant of the process according to the invention, as indicated in Scheme 2, the compounds of the formula (IVa) or (IVb) are obtained by reacting a compound of the formula (II), where at least one of the radicals R 3 , R 4 and R 5 represents hydrogen, or their stereoisomers or mixtures thereof with a halogenating agent such as chlorine, bromine, NCS, NBS, bromine, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate, an oxidizing agent such as osmium tetroxide , Hydrogen peroxide or meta-chloroperbenzoic acid, optionally with addition of chiral auxiliaries, or a mercury compound such as Hg (OAc) 2 or Hg (O 2 CCF 3 ) 2 , or a selenium compound such as PhSeCl or ArSeOTf to a compound of formula
    Figure 00130001
    wherein
    R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and
    Y is bromine, chlorine, iodine, OH or OR 18 , wherein OR 18 is a leaving group such as mesylate, tosylate or triflate,
    subsequent conversion of the resulting compound of the formula (Va) or (Vb) by lactonization into the target compound of the formula (IVa) and / or (IVb). The lactone of the general formula (IVa) or (IVb) is formed depending on the definition of the radicals X and Y with acidic or basic activation; according to methods known per se (see, for example: Acct. Chem. Res. 14, 95 (1981); J. Org Chem. 55, 5867 (1990) ).
  • For acidic activation, Lewis acids or Bronsted acids, preferably acetic acid, trifluoroacetic acid, p-toluenesulfonic acid are advantageously used in polar protic or aprotic solvents. The reaction can also be carried out with bases such. As alkali metal hydroxides, alkali metal carbonates, alcoholates or metal hydrides or amine bases such as alkylamines, preferably triethylamine, are catalyzed. The preferred reaction temperature is between -20 ° C and the boiling point of the respective solvent. It is preferable to use solvents such as acetonitrile, DMF, water, N-methylpyrrolidone (NMP), etc., which are commonly used for SN 2 substitution.
  • In a further preferred process variant, both cycles are formed without isolation of the monocycles. For this purpose, compounds of the formula (II) are preferably reacted with reagents which lead directly to doubly cyclized compounds of the general formulas (IVa) and (IVb), for. Hypervalent iodine compounds such as PhI (OAc) 2 , PhI (O 2 CCF 3 ) 2 , or (hydroxy (tosyloxy) iodo) benzene ( Koser's reagent; see Koser, GF, Aldrichimica Acta, Vol. 34, No.3 (2001) . p.91; Moriarty et al., Synlett 1990, 365 ; such as Zhdankin, VV et al., Chem. Rev. 2002, 102, 2523-84 ).
  • In a further preferred process variant, the process of compounds of the formula (IVc)
    Figure 00140001
    wherein
    R 1 , R 2 have the abovementioned meaning,
    A and B have the meaning given above under b2),
    or their stereoisomers or mixtures thereof,
    which are obtained from a compound of the formula (III)
    Figure 00140002
    wherein
    R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and
    Y is bromine, chlorine, iodine, OH or OR 18 , wherein OR 18 is a leaving group such as mesylate, tosylate or triflate,
    or their stereoisomers or mixtures thereof,
    by reaction with a nitrogen nucleophile in the target compound (IVc). In this case, a nucleophilic substitution of the leaving group Y by the nitrogen nucleophiles, such as. Azide, amines, ammonia, cyanamides, etc. For this purpose, the compounds of the formula (III) are reacted with a nitrogen-containing reagent, such as ammonia, cyanamides, azides or amines, under conditions known per se, which are used for SN 2 substitution. so z. As DMF, acetonitrile or NMP as a solvent, optionally in the presence of a base such as. As alkali metal hydroxides, alkoxides or org. Amine bases, converted to the compound of formula (IVc).
  • The compounds of the formula (II) used according to the invention can be obtained by reacting a compound of the general formula (VII)
    Figure 00150001
    in which R 1 , R 2 and X have the abovementioned meaning,
    with a substituted hydrazine derivative, suitably the general formula H 2 N-NR 4 R 5 , wherein R 4 and R 5 have the abovementioned meaning,
    to a compound of general formula (I)
    Figure 00150002
    wherein R 1 , R 2 , R 4 , R 5 and X have the abovementioned meaning, and further reaction in one or more steps with a suitable reducing agent to the target compound of formula (II).
  • Thus directly derivatized hydrazones of the general formula (I) with corresponding substituents R4 and R5 can be obtained. This is z. B. according to a known method (see B. Bildstein et al., Synthesis, 1994, 158-160 ) from dimethylhydrazine and trimethylaluminum an N-dimethylaluminum formed by -N'N'-dimethylhydrazide reagent, which can be reacted with the aryl ketone (VII) to the hydrazone of the formula (I).
  • Advantageously, the compound of the general formula (VII) can be reacted with hydrazine of the formula H 2 N-NH 2 to give a compound of the general formula (Ia)
    Figure 00160001
    in which R 1 , R 2 and X have the abovementioned meaning, with subsequent introduction of at least one nitrogen protective group, such as CBZ or BOC, and further reaction in one or more steps with a suitable reducing agent, if appropriate with the introduction of further nitrogen. Protecting groups to the target compound of the formula (II).
  • The Reaction with hydrazine to give the hydrazone (Ia) is carried out in known manner Wise. In this case, dehydrating agents, such as molecular sieve, Water separator, Orthoester, etc. are used. The reaction can under activation with Lewis acid, such as. For example, titanium isopropoxide, or under acid catalysis, e.g. As acetic acid, trifluoroacetic acid or p-toluenesulfonic acid. Anhydrous hydrazine is preferably used. The reaction will in the usual protic or aprotic solvents, preferably tetrahydrofuran or halogenated hydrocarbons, such as As dichloroethane, at temperatures from room temperature to to the boiling temperature of the particular solvent.
  • Depending on the desired substitution pattern, the hydrazone (Ia) is then monosubstituted or polysubstituted, as exemplified in Scheme 1. Multiple substitutions can be introduced in one step or in two consecutive synthesis steps. For this purpose, the known per se methods of estimating nitrogen functions can be used, such. B. in standard works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenary Press, London and New York 1973 . in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 , in "The Peptides"; Volume 3 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , as in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974 , described. Particularly preferred substituents are carbamates, such as. B: CBZ, BOC (tert-butyl carbamate). For the second derivatization on the same nitrogen atom is preferably used to accelerate the reaction, an activating reagent, for. B .: dimethylaminopyridine added.
  • The Hydrazines of the general formula (II) are obtained by reduction in in a known manner from the corresponding hydrazones of the general Formula (I) prepared. This can be the formation of the new stereo center in position C-8, depending on the reduction conditions, diastereoselective respectively.
  • As a reducing agent here are z. As complex metal hydrides, such as LiAlH 4 in the neutral, Metallborhydride, preferably NaBH 4 , BH 3 · NMe 3 , NaBH 3 (OAc), NaBH (OAc) 3 or NaBH 3 CN, as well as silicon hydrides such. B. Et 3 SiH in each case under activation by Lewis acids or Bronsted acids, for. B.: Trifluoroacetic acid, acetic acid, p-toluenesulfonic acid, hydrochloric acid, etc. Furthermore, metal amalgams, such as Na (Hg), Zn (Hg) or Al (Hg), or metal salts, such as. B. SnCl 2 can be used. Alternatively, hydrogen can be used under homogeneous or heterogeneous catalysis with suitable deactivated catalysts, as well as the conditions known by the name of "Birch reduction", such as, for example, sodium, lithium in ammonia (cf. R. Calabretta et al. Synthesis 1991, 536-539 ).
  • there each become the usual protic or aprotic Solvents, at temperatures of -78 ° C used up to the boiling temperature of the particular solvent.
  • Especially preferred here is the use of metal borohydrides under Acid activation.
  • Subsequently For example, the resulting hydrazine (II) can vary depending on the desired protective group pattern be further derivatized. This can already be done above described methods for estimating amine functions become.
  • alternative it is also possible to use unprotected hydrazones (Ia) reduce and then after the above described Methods to derivatize the nitrogen atoms.
  • By way of example, the routes described in Scheme 1 can be used to represent the desired substitution pattern on the nitrogen atoms. The choice of the radicals R 3 , R 4 and R 5 as well as the stereochemistry at the C8 position influences the diastereomer selectivity of the subsequent reactions. This allows the new stereogenic centers to be generated in C4 and C5 positions with high diastereoselectivity.
  • The 8-hydrazine-8-aryl-octanoyl derivatives of the general formula (II) can be used for the preparation of renin inhibitors of the general Formula (X) can be used. (see Scheme 2).
  • The compounds of the formula (VII) used according to the invention can according to WO 2007/048620 can be obtained by coupling a compound of formula (1)
    Figure 00180001
    wherein R 1 and R 2 have the meaning given for the compound of the formula (VII) and R 20 is , for example, an alkali metal or metal halide, in which the metal may be Mg, Al, B, Mn, Cu, Cd, Zn and Sn,
    to a chiral compound of the formula (2)
    Figure 00180002
    wherein
    W for z. B. is hydrogen or halogen, wherein the group C (O) W and C (O) OR 21 may each be replaced by nitrile, and
    R 21 is branched or unbranched alkyl, where the group OR 21 may also be halogen,
    if appropriate with subsequent derivatization, ie a downstream manipulation of the functional group as a function of the meaning of the radical X of the compound of the formula (VII). The reaction can also be carried out with other than the specified isomers of the respective compounds or mixtures thereof, which leads to corresponding isomers and / or mixtures of the compound of formula (VII).
  • The Reaction temperature can be between -78 ° C and reflux temperature of the solvent, preferably THF is at 0 ° C. or RT.
  • Surprisingly, it has now been found that the coupling advantageously in the presence of a metal catalyst from the group Fe (III), z. For example: Fe (acac) 3 , Ni (0), Pd (0) and V (III), e.g. B. VCl 3 (see also, R. Karl Dieter, Tetrahedron 55 (1999) 4177-4236 ; Scheiper et al, J. Org. Chem. 2004, 69, 3943-3949 ) can be carried out.
  • The coupling required for the chiral compound 2, preferably the diacid with W = OH; R 21 = H, is preferably used as (S, S) compound. To isolate the desired stereoisomer from the diastereomeric mixture is after the WO 2007/048620 expediently a two-stage process is used. In the first stage, the meso is separated from the racemic compound by kinetically controlled crystallization from organic solvents. However, kinetic crystallization can lead to problems especially when "upsampling" the process.
  • Surprisingly, it has now been found that it is advantageous in the aforementioned meso / rac separation to stabilize the kinetic crystallization, preferably by addition of nucleation inhibitors, such as. As surfactants, or by emulsion crystallization (see also: US6428583 ) and / or to carry out the separation under thermodynamic control. For this purpose, the organic salts, for. B. the diacid (compound 2, with W = OH, R 21 = H) separated. Particularly suitable for this salt formation are organic Bases such as diamines, e.g. As piperazine, 1-benzhydrylpiperazine or homopiperazine, and alkylamines, eg. For example, tert-butylamine, tert-octylamine, cyclohexylamine, dicyclohexylamine, and arylamines or arylalkylamines, such as. B. benzylamine, dibenzylamine, 4-methylbenzylamine, 3-picolylamine, 2-phenylethylamine, 2-amino-4,6-dimethylpyrimidine, and cyclic amines, such as. For example, 2,6-dimethylpiperidine or 1-benzyl-4-piperidone. Particularly preferred is piperazine.
  • there are starting from about 50:50 mixtures of meso / rac diacid preferably 1-2 equivalents (with respect to meso compound) of the amine, preferably piperazine, in an organic solvent, z. For example, ethanol or isopropyl acetate. That as a solid salt obtained is strongly enriched with the meso compound, which Mother liquor contains predominantly the racemic Connection. The pre-enriched meso or racemic compounds can each, optionally after salt splitting and removal of the amine with the usual methods such. B. Extraction with organic solvents from an acidic aqueous Solution, by simple recrystallization or "slurry washing" be further enriched in organic solvents. The mother liquors obtained in each case can be in the process be returned, so that the overall yield is almost quantitative.
  • in the For the purposes of the present invention, the term "halogen" to fluorine, chlorine, bromine, iodine, preferably chlorine and bromine.
  • "Alkyl" Unless otherwise indicated, refers to straight-chain or straight chain branched or cyclic saturated hydrocarbons or combinations thereof preferably having 1 to 20 carbon atoms, in particular 1 to 10, particularly preferably 1 to 5 carbon atoms. Examples of such alkyl groups (provided the designated length includes the specific example) are methyl, ethyl, propyl, isopropyl, Butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl, or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, Cycloheptenyl or 1,3-cyclobutadienyl.
  • "Alkoxy" refers to oxygen linked straight chain or branched saturated alkyl having preferably 1 to 20 carbon atoms, in particular 1 to 10, particularly preferred 1 to 5, most preferably 1 to 2 carbon atoms. Examples such alkoxy groups (provided the designated length includes the specific example) are methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy and tert-butoxy.
  • The alkyl and alkoxy groups may be substituted by one or more of the following groups selected from halogen, hydroxy, cyano, C 1 -C 6 alkoxy, nitro, amino, C 1 -C 6 alkylamino, diC 1 -C 6 Alkylamino, carboxy, C 1 -C 6 alkoxycarbonyl, aminocarbonyl, halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, tetrahaloethyl, pentahalogenethyl.
  • Of the The term "aryl" means a cyclic or polycyclic one Ring consisting of preferably 6 to 12 carbon atoms, the may be unsubstituted or substituted by one or more Substituent groups above for the alkyl and alkoxy groups are indicated. Examples of aryl groups are phenyl, 2,6-dichlorophenyl, 2- or 3- or 4-methoxyphenyl, naphthyl, 4-thionaphthyl, Tetralinyl, anthracinyl, phenanthrenyl, benzonaphthenyl, fluorenyl, 2-acetamidofluoren-9-yl and 4'-bromobiphenyl.
  • Of the Term "heterocyclic" means a mono- or bicyclic, heterocyclic ring system. Monocyclic heterocyclic rings consist of about 3 to 7 ring atoms with 1 to 5 heteroatoms selected from N, O or S and preferably 3 to 7 atoms in the ring. bicyclic Heterocycles consist of about 5 to 17 ring atoms, preferably 5 up to 12 ring atoms. Examples of heterocyclic ring systems are phthalimido, morpholino, 1,3,5-dioxacinyl, 2,3-diphenylmaleoyl, and the same.
  • Of the Term "salts" refers preferably to acid addition salts, Salts with bases and metal salts, in particular alkali metal salts.
  • salts Hydrates and solvates of the compounds of the invention are also included. In the invention If necessary, the compounds can be used as salt, hydrate or solvate can be used or obtained.
  • Of the Term "delactonized derivative" means within the scope of the present invention Invention of a lactone with opening of the lactone ring derived derivative, such as. As the free carboxylic acid or corresponding carboxylic acid halides, carboxylic acid amides, Carboxylic esters, etc.
  • The compounds of the formula (II) according to the invention, (III), (IV), (V) and (VI) and the compounds of the formula (I), (VII), (IX) and (X) have chiral centers and can in any stereoisomeric form. This also includes E / Z isomers in the case of compounds of the formula (I). The present invention includes any stereoisomeric forms or mixtures thereof of an inventive Compound or target compound, it being known how the optically active forms (for example, by resolution of the racemic Form by recrystallization process, by synthesis from optical active starting materials, by chiral or asymmetric synthesis or by chromatographic separation using a chiral stationary phase) can be obtained.
  • The functional groups present in the respective compounds, for example carboxy, amino or hydroxy, can be present in protected form instead of in free form. Appropriate suitable protecting groups and their introduction and removal are, for. B. in standard works, such as JFW McOmie, "Protective Groups in Organic Chemistry", Plenary Press, London and New York 1973 , in Th. W. Greene, "Protective Groups in Organic Synthesis", Wiley, New York 1981 , in "The Peptides"; Volume 3 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981 , as in "Methods of Organic Chemistry", Houben-Weyl, 4th Edition, Vol. 15 / I, Georg Thieme Verlag, Stuttgart 1974 , described. A suitable protecting group for a carboxy function is e.g. B. an ester group. An amino group can, for. B. form of an acylamino or arylmethylamino group. By z. B. an acyl radical is protected by a hydroxy function.
  • The inventive method also includes in those embodiments where intermediates isolated, starting materials and reagents are prepared in situ and / or intermediate and final products processed without isolation become.
  • The individual process steps are determined by standard methods, such as in the references given above, if necessary. In the presence of solvents at low temperatures, room temperature or elevated temperatures, preferably in the range of the boiling point of the respective solvent, at atmospheric pressure or overpressure, if appropriate under an inert gas atmosphere carried out.
  • suitable Solvents are water and organic solvents, also as mixtures of at least two solvents can be used.
  • Examples for suitable solvents are optionally halogenated Hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene, Methylene chloride, chloroform, tetrachloroethane or chlorobenzene; ethers, such as diethyl ether, dioxane or tetrahydrofuran; Carbonsäureester and lactones, such as methyl acetate, ethyl acetate or valerolactone; N, N-substituted carboxylic acid amides and Lactams, such as dimethylformamide, dimethylacetamide or N-methylpyrrolidone; Ketones, such as acetone or cyclohexanone; Sulfoxides and sulfones, such as dimethyl sulfoxide or dimethylsulfone; Alcohols, such as methanol, ethanol, hexanol, cyclohexanol, Benzyl alcohol, ethylene glycol, or propanediol; Nitriles, such as acetonitrile or propionitrile; tertiary amines, such as triethylamine, diethylamine, Pyridine, N-methylpyrrolidine or N-methylmorpholine; and organic Acids, such as acetic acid or formic acid.
  • The Target compounds can be isolated by known methods be such. As extraction, crystallization or filtration and their combinations.
  • The following examples serve to illustrate the invention. example 1
    Figure 00230001
    (E / Z) -trans-7- {N, N-dimethyl-hydrazono [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl} -2-isopropyl-8-methyl-non- 4-enoic acid diethylamide (compound I, where R 4 = R 5 = Me; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • To a solution of N, N-dimethylhydrazine (180 mg, 3.0 mmol) in dry toluene (1.5 mL) is tri methylaluminum (2 M in toluene, 1.5 mL, 3.0 mmol) was added and the mixture was stirred at 70 ° C for 2 h. Then, trans-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) -benzoyl] -8-methyl-non-4-enoic acid diethylamide (476 mg, 0.97 mmol) is added and the mixture becomes stirred for 12 h at 90 ° C. The mixture is brought to room temperature and a saturated aqueous saline solution (10 ml) is added. The aqueous phase is extracted with toluene. The combined organic phases are dried over Na 2 SO 4 and concentrated in vacuo. The residue is purified by flash chromatography on SiO 2 (MTBE / heptane 3: 2 + 1% DEA). There are obtained 454 mg (0.85 mmol, 88%) of a green transparent oil.
    1 H-NMR (250 MHz, CDCl 3 , excess isomer): 0.81-1.11 (m, 18H), 1.75-1.90 (m, 2H), 2.01-2.55 (m, 7H), 2.39 (s, 6H), 3.20- 3.28 (m, 4H), 3.30-3.36 (m, 1H), 3.31 (s, 3H), 3.54 (app.t, 2H, J = 6.2 Hz), 3.81 (s, 3H), 4.08 (app.t, 2H, J = 6.4 Hz), 5.26-5.40 (m, 2H), 6.78 (s, 1H), 7.01 (d, 1H, J = 2.0 Hz), 7.07 (d, 1H, J = 2.0 Hz) ppm. Selected data for the deficient isomer: 2.30 (s, 6H), 3.53 (t, 1H, J = 6.2 Hz), 3.82 (s, 3H), 4.04 (t, 1H, J = 6.4 Hz), 6.75 (s, 1H) , 6.85-6.87 (m, 1H), 7.01 (d, 1H, J = 2.0 Hz) ppm. Example 2
    Figure 00240001
    (E / Z) -trans-7- (hydrazono [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-ene-diethylamide (Compound Ia with X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • To a solution of trans-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) -benzoyl] -8-methyl-non-4-ene-diethylamide (790 mg, 1.61 mmol) in dry THF ( 8 mL) is added anhydrous hydrazine (8 mL, 1 M in THF) and titanium tetraisopropoxide (2.76 g) and stirred for 12 h at 80 ° C. The mixture is brought to room temperature, diluted with dichloromethane (30 mL) and water (4.82 g) added. The precipitate is filtered off and the resulting mother liquor is concentrated in vacuo. The title compound is obtained as a colorless oil (810 mg, quant.).
    DC: R f (MTBE 1 + 1% DEA) = 0.32 and 0.37. 1 H-NMR (250 MHz, CDCl 3 , excess isomer): 0.78-0.99 (m, 12H), 0.78-0.99 (m, 12H), 1.00-1.15 (m, 6H), 1.69-1.93 (m, 2H), 2.00-2.56 (m, 7H), 3.18-3.43 (m, 5H), 3.30 (s, 3H), 3.53 (app.t, 1H, J = 6.2 Hz), 3.83 (s, 3H), 4.07 (app. t, 1H, J = 6.6 Hz), 5.00 (bs, 2H), 5.25-5.53 (m, 2H), 6.69-7.11 (m, 3H) ppm. Selected data for the deficient isomer: 3.30 (s, 3H), 3.52 (app.t, 1H, J = 6.2 Hz), 3.82 (s, 3H), 4.04 (app.t, 1H, J = 6.5 Hz) ppm. Example 3
    Figure 00250001
    (E / Z) -trans-7- (N-phenylsemicarbazone [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound Ib, with R 4 = C (O) NHPh, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 50 mg of trans-7- (hydrazono [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (0.10 mmol) are dissolved in Dissolved 1 ml of methylene chloride and treated with 24 mg (0.2 mmol) of phenyl isocyanate and stirred for 1 h at RT. The mixture is purified directly by chromatography on SiO 2 (heptane / MTBE 1: 2 + 1% DEA). The urea derivative is obtained as a clear oil.
    1 H-NMR (250 MHz, CDCl 3 , ca. 1: 1 mixture of E / Z isomers and ca. 1: 1 mixture of rotamers): 0.78-1.21 (m, 36H), 1.71-1.93 (m, 4H), 1.95-2.61 (m, 14H), 3.17-3.44 (m, 10H), 3.29 (s, 1.5H), 3.31 (s, 1.5H), 3.32 (s, 1.5H), 3.34 (s, 1.5 H), 3.53 (app.t, 2H, J = 6.1 Hz), 3.54 (app.t, 2H, J = 6.1 Hz), 3.85 (s, 6H), 4.05 (app.t, 2H, J = 6.4 Hz ), 4.13 (app.t, 2H, J = 6.5 Hz), 5.23-5.56 (m, 4H), 6.29 (bs, 2H), 6.64 (d, 1H, J = 1.8 Hz), 6.70 (dd, 1H, J = 1.9 Hz, J = 8.2 Hz), 6.83 (m, 1H), 6.89 (d, 1H, J = 8.2 Hz), 6.93-7.01 (m, 2H), 7.06 ( dd, 1H, J = 1.9 Hz, J = 8.5 Hz), 7.15 (d, 1H, J = 2.0 Hz), 7.20-7.37 (m, 6H), 7.45 (m, 2H), 7.61 (bs, 0.5 H) , 8.04 (bs, 0.5H), 8.18 (bs, 0.5H), 8.28 (bs, 0.5H) ppm Example 4
    Figure 00260001
    (E / Z) -trans-7- (N-acetyl-hydrazono [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl) -2-isopropyl-8-methyl-non-4- acid diethylamide (compound Ib, with R 4 = Ac, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 25 mg of trans-7- (hydrazone [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (50 μmol) are dissolved in Dissolved 125 μl of pyridine and treated at 0 ° C with 15 mg of acetic anhydride. The mixture is stirred for 1 h and then purified directly by chromatography on SiO 2 (heptane / MTBE 1: 2 + 1% DEA). The isomeric hydrazones are obtained as colorless viscous oils.
    1 H-NMR (250 MHz, CDCl 3 , excess isomer): 0.76-0.93 (m, 12H), 0.99-1.20 (m, 6H), 1.68-1.88 (m, 2H), 2.00-2.40 (m, 7H), 2.24 (s, 3H), 3.17-3.29 (m, 4H), 3.31 (s, 3H), 3.34-3.44 (m, 1H), 3.53 (app.t, 2H, J = 6.1 Hz), 3.84 (s, 3H), 4.03 (app.t, 2H, J = 6.4 Hz), 5.19-5.50 (m, 2H), 6.57 (d, 1H, J = 1.8 Hz), 6.63 (dd, 1H, J = 1.8 Hz, J = 8.2 Hz), 6.86 (d, 1H, J = 8.2 Hz), 8.29 (bs, 1H) ppm. Selected data for the deficient isomer: 2.31 (s, 3H), 3.54 (app.t, 2H, J = 6.1 Hz), 4.10 (app.t, 2H, J = 6.5 Hz), 6.77 (d, 1H, J = 8.5 Hz), 7.08 (dd, 1H, J = 2.1 Hz, J = 8.5 Hz), 7.20 (d, 1H, J = 2.1 Hz), 8.58 (bs, 1H) ppm. Example 5
    Figure 00260002
    (E / Z) -trans-7- (N-Benzylcarboxy-hydrazono [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl) -2-isopropyl-8-methyl-non-4- acid diethylamide (compound Ib, with R 4 = CBZ, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 1.2 g of trans-7- (hydrazone [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide were dissolved in 8 ml of anhydrous pyridine dissolved and slowly added under ice / salt cooling with 512 mg of Cbz-Cl. It was stirred for a further hour at 0 ° C. The solution was diluted with 20 ml of MTBE and hydrolyzed with 9 ml of concentrated hydrochloric acid and 36 ml of water. The aqueous phase was extracted twice with 10 ml of toluene and the combined organic phases were dried over Na 2 SO 4 . The LM was removed in vacuo and the residue was purified by chromatography on SiO 2 (MTBE / heptane 2: 1). 1.25 g of the protected hydrazones are obtained as pale green oils.
    TLC: R f (MTBE / heptane 2: 1) = 0.19 and 0.14. 1 H-NMR (250 MHz, CDCl 3 , excess isomer): 0.77-1.20 (m, 18H), 1.70-1.92 (m, 2H), 2.08-2.37 (m, 7H), 3.16-3.44 (m, 5H), 3.29 (s, 3H), 3.52 (app.t, 2H, J = 6.2 Hz), 3.83 (s, 3H), 4.02 (app.t, 2H, J = 6.5 Hz), 5.23-5.53 (m, 2H) , 5.13 (bm, 2H), 6.58 (d, 1H, J = 1.8 Hz), 6.63 (dd, 1H, J = 1.8 Hz, J = 8.2 Hz), 6.87 (d, 1H, J = 8. 2 Hz) , 7.25-7.34 (m, 5H), 7.70 (bs, 1H) ppm. Selected data for the deficient isomer: 3.30 (s, 3H), 3.52 (app.t, 2H, J = 6.3 Hz), 3.82 (s, 3H), 4.08 (app.t, 2H, J = 6.4 Hz), 5.22 (app. bm, 2 H), 6.74 (d, 1H, J = 8.4 Hz), 7.07 (dd, 1H, J = 2.0 Hz, J = 8.4 Hz), 7.23 (d, 1H, J = 2.0 Hz), 8.05 (bs, 1H) ppm. HPLC (ODS-2 250 / 4.6 150/5 C18; ACN water; ACN: 0-1 min 50%; 30 min 100%) R t = 23.89 (35%) and 26.65 (65%). Example 6
    Figure 00270001
    (E / Z) -trans-7- {tert-butyloxycarbonyl-hydrazono [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl} -2-isopropyl-8-methyl-non-4- acid diethylamide (compound Ib, with R 4 = CO 2 tBu; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 100 mg of trans-7- (hydrazono [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (0.2 mmol) in 220 mg Boc 2 O (0.5 mmol, 5 eq) are melted together and stirred at rt for 30 min. This mixture is purified directly by chromatography on SiO 2 (heptane / MTBE 1: 2 + 1% DEA). 116 mg of the two protected hydrazones are obtained as pale green clear oils.
    DC: R f (MTBE 1 + 1% DEA) = 0.60 and 0.52. 1 H-NMR (250 MHz, CDCl 3 , 54:46 mixture of isomers, not assigned): 0.75-1.20 (m, 18H), 1.48 (s, 9H), 1.69-1.86 (m, 2H), 1.98-2.45 (m, 7H), 3.18-3.42 (m, 5H), 3.30 (s, 3H), 3.52 (app.t, 2H, J = 6.1 Hz), 3.84 (s, 3H), 4.08 (app. 2H, J = 6.4 Hz), 5.26-5.52 (m, 2H), 6.60 (d, 1H, J = 1.7 Hz), 6.64 (dd, 1H, J = 1.7 Hz, J = 8.1 Hz), 6.88 (d, 1H, J = 8.1 Hz), 7.85 (bs, 1H) ppm. Selected data for the other isomer: 1.39 (s, 9H), 3.29 (s, 3H), 3.51 (app.t, 2H, J = 6.3 Hz), 3.80 (s, 3H), 4.03 (app. T, 2H, J = 6.2 Hz), 7.05 (dd, 1H, J = 1.6 Hz, J = 8.4 Hz), 7.26 (d, 1H, J = 1.6 Hz), 6.71 (d, 1H, J = 8.4 Hz), 7.50 (bs , 1H) ppm. HPLC (ODS-2 250 / 4.6 150/5 C18; ACN water; ACN: 0-1 min 50%; 30 min 100%): R t = 23.90 (46%) and 26.21 (54%). Example 7
    Figure 00280001
    trans-7- (Benzylcarboxy-hydrazino- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = R 5 = H, R 4 = CO 2 Bn, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 232 mg (400 μmol) of the CBZ-protected hydrazone (Compound Ib, with R 4 = CO 2 t Bu, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe) were dissolved in 8 g F 3 COOH / THF (1: 1) and cooled to -20 ° C by ice / salt cooling. To the deep green solution was added 76 mg (2 mmol, 5 eq) of NaBH 4 in portions with vigorous stirring. The now colorless solution was stirred for a further 20 min at RT and then poured with cooling to 20 ml of a 10% aqueous NaOH solution. It was extracted 3 times with 5 ml of MTBE each time, the organic phase was dried over Na 2 SO 4 and the solvent was removed in vacuo. Chromatography on SiO 2 (MTBE / heptane 1: 1) gave 245 mg (96%) of the diastereomeric hydrazines as colorless highly viscous oils.
    TLC: R f (MTBE / heptane 2: 1 + 0.5% DEA) = 0.25. 1 H-NMR (250 MHz, CDCl 3 ): 0.78-1.10 (m, 18H), 1.71-1.92 (m, 2H), 1.20-1.27 (m, 7H), 3.16-3.37 (m, 5H), 3.28 ( s, 3H), 3.50 (app.t, 2H, J = 6.1 Hz), 3.78 (s, 3H), 3.88-3.97 (m, 1H), 4.01 (app.t, 2H, J = 6.4 Hz), 4.22 -4.50 (bs, 1H), 4.95-5.50 (m, 4H), 6.03 (bs, 1H), 6.72 (m, 2H), 6.79 (m, 1H), 7.22-7.30 (m, 5H) ppm. Ms (FAB) m / z = 640 (17) [M + H + ], 474 (100) [MC 8 H 9 N 2 O 2 ]. HPLC (ODS-2 250 / 4.6 150/5 C18; ACN water; ACN: 0-1 min 50%; 30 min 100%): R t = 26.1 (68%) and 27.4 (32%). Example 8
    Figure 00290001
    trans-7- (N, N-dimethylhydrazino [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = H, R 4 = R 5 = Me, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • To a solution of 53 mg (100 .mu.mol) of trans -7- {N, N-dimethylhydrazono [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl} -2-isopropyl-8- Methyl-non-4-enoic acid diethylamide in 1 g of THF is slowly added dropwise 1 g of F 3 CCOOH. The now violet solution is cooled to -20 ° C and treated with vigorous stirring with 19 mg (500 .mu.mol) NaBH 4 . The now colorless solution is stirred for a half hour at 0 ° C. The solution is carefully hydrolyzed with 5 ml of 10% NaOH solution and extracted with MTBE. After drying (Na 2 SO 4 ), the LM is removed in vacuo and the residue is purified by chromatography on SiO 2 (MTBE / heptane 1: 1 + 0.5% DEA). 39 mg (73%) of the hydrazine derivative was obtained as a clear, viscous oil.
    TLC: R f (MTBE / heptane 1: 1 + 0.5% DEA) = 0.34. 1 H-NMR (250 MHz, CDCl 3 , excess isomer: 0.84-1.16 (m, 18H), 1.78-1.92 (m, 2H), 2.04-2.31 (m, 7H), 2.44 (s, 6H), 3.24-3.46 (m, 6H), 3.36 (s, 3H), 3.59 (app.t, 2H, J = 6.2 Hz), 3.70 (bs, 1H), 3.86 (s, 3H), 4.12 (app.t, 2H, J = 6.4 Hz), 5.31-5.41 (m, 2H), 6.78-7.05 (m, 3H) ppm Selected data for the deficient isomer: 3.58 (t, 1H, J = 6.2 Hz), 3.84 (s, 3H), 4.08 (t, 1H, J = 7.0 Hz) Example 9
    Figure 00300001
    trans-7- (tert -butylcarboxy-hydrazino- [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound II with R 3 = R 5 = H, R 4 = CO 2 t Bu, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 120 mg (200 μmol) of the mono-Boc-protected hydrazone (compound Ib, with R 4 = CO 2 tBu, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe) are dissolved in 1 ml of THF solved; and 16 mg (240 μmol, 1.2 eq) of NaCNBH 3 were added. The mixture is then added in portions with 38.5 mg (240 .mu.mol, 1.2 eq) of p-TsOH · H 2 O within one hour with vigorous stirring. It is stirred for a further hour at RT. The suspension is mixed with 1 ml of aqueous NaOH solution (1%) and extracted 3 times with MTBE. The LM is dried (Na 2 SO 4 ) and removed under vacuum. The residue is purified by chromatography on SiO 2 (MTBE / heptane 2: 1 + 0.5% DEA). Boc-hydrazine is obtained as a mixture of diastereomers. Example 10
    Figure 00310001
    trans-7- (hydrazino [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = R 4 = R 5 = H, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 50 mg (100 μmol) of the unprotected hydrazone (compound Ia, with X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe) are dissolved in 1 ml of THF and mixed with 16 mg (240 μmol, 2.4 eq ) NaCNBH 3 added. 38.5 mg (240 μmol, 1.2 eq) of p-TsOH · H 2 O are then added in portions within one hour with vigorous stirring. It is stirred for a further hour at RT. The suspension is treated with 1 ml of NaOH solution (1%) and extracted 3 times with MTBE (2 ml). The LM is dried (Na 2 SO 4 ) and removed under vacuum. The residue is purified by chromatography on SiO 2 (MTBE / heptane 2: 1 + 0.5% DEA). The hydrazine is obtained as a mixture of diastereomers. Example 11
    Figure 00310002
    {, N-bis-tert-butyloxycarbonyl-hydrazono [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl} -2 N-isopropyl-8- (E / Z) -trans-7- Methyl-non-4-enoic acid diethylamide (Compound I, with R 4 = R 5 = CO 2 t Bu, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • 60 mg (100 μmol) of the mono-Boc-protected hydrazone (compound Ib, with R 4 = CO 2 tBu, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe), 15 mg dimethylaminopyridine ( 120 μmol) and 218 mg (1.0 mmol) Boc 2 O are dissolved in 500 μl triethylamine and stirred at 40 ° C for 24 h. The solution is treated with saturated NH 4 Cl solution (2 ml) and extracted with MTBE (3 times 2 ml). The organic phase is dried (Na 2 SO 4 ) and the LM removed in vacuo. After purification of the residue by chromatography (SiO 2 , MTBE / heptane 1: 1) the doubly protected hydrazone is obtained. Example 12
    Figure 00320001
    trans-7- {N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl} -2-isopropyl-8-methyl- non-4-enoic acid diethylamide (Compound II, with R 3 = CO 2 tBu; R 4 = R 5 = Me; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 107 mg (200 μmol) of dimethyl hydrazine (Compound II, where R 3 = H, R 4 = R 5 = Me, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe), 1.5 mg of dimethylaminopyridine (cat.) and 109 mg (500 .mu.mol) Boc 2 O are dissolved in 1 ml of triethylamine and stirred for 12 h at RT. The solution is saturated with 2 ml. NH 4 Cl solution and extracted with MTBE (3 times 5 ml). After drying over Na 2 SO 4 , the LM is removed under vacuum and the residue is purified by chromatography (SiO 2 , heptane / MTBE 1: 1 + 0.5 DEA). The tetra-substituted hydrazine is obtained as a mixture of diastereomers. Example 13
    Figure 00320002
    3-isopropyl-5- (1-bromo-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] - butyl) -dihydrofuran-2 (3H) -one (Compound III, with R 3 = CO 2 tBu; R 4 = R 5 = Me; Y = Br; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 41 mg of trans -7-bis-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl} -2-isopropyl 8-methyl-non-4-enoic acid diethylamide is stirred vigorously in two phases with 2 ml DCM / H 2 O 4: 1. While cooling (ice / salt), 14 mg NBS are added in portions and stirred for 2 h. The solution is added with saturated bisulphite solution (1 ml) and extracted (3 times 2 ml MTBE). The organic phase is dried over sodium sulfate and concentrated in vacuo. After purification by column chromatography, the title compound is obtained as a mixture of diastereomers. Example 14
    Figure 00330001
    5- [1- (dimethylamino) -4-isopropyl-5- [4-methoxy-3- (3-methoxypropoxy) phenyl] -pyrrolidin-2-yl] -3-isopropyl-dihydrofuran-2 (3H) -one ( Compound IVa, where R 4 = R 5 = Me; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • The bromolactone (Compound III, with R 3 = CO 2 t Bu; R 4 = R 5 = Me; Y = Br; R 2 = Me; R 1 = (CH 2 ) 3 OMe) is dissolved in ethyl acetate / 3 M HCl (1 : 1) two-phase stirred for 10 min and then the aqueous phase is adjusted to pH = 9 with NaHCO 3 . The solution is stirred for a further 12 h two-phase; then it is extracted with MTBE. The organic phases are dried over Na 2 SO 4 and the LM removed under vacuum. After chromatography (SiO 2 ) the title compound is obtained. Example 15
    Figure 00330002
    3-isopropyl-5- (1-amino-3-isopropyl-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] butyl) -dihydrofuran-2 (3H) -one
  • 20 mg of the pyrrolidine derivative (compound IVa, with R 4 = R 5 = Me; R 2 = Me; R 1 = (CH 2 ) 3 OMe) is hydrogenated in 1 ml EtOAc with 10 mg Pd / C and H 2 in. After completion of the hydrogen uptake is filtered from the catalyst and the LM removed under vacuum. After chromatography on SiO 2 , the amine is obtained. Example 16
    Figure 00340001
    3-isopropyl-5- (1-azido-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] - butyl) -dihydrofuran-2 (3H) -one (Compound IVc, where R 3 = CO 2 t Bu; R 4 = R 5 = Me; Y '= N 3 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 52 mg of 3-isopropyl-5- (1-bromo-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxy-propoxy) -phenyl ] -butyl) -dihydrofuran-2 (3H) -one (Compound III, with R 3 = CO 2 t Bu; R 4 = R 5 = Me; Y = Br; R 2 = Me; R 1 = (CH 2 ) 3 OMe) in 0.5 ml DMPU and 20 mg NaN 3 are stirred for 5 d at 40 ° C. It is diluted with water (20 ml) and extracted with MTBE. The organic phases are dried over Na 2 SO 4 and the LM removed under vacuum. After chromatography, the title compound is obtained. Example 17
    Figure 00340002
    3-isopropyl-5- (1-amino-3-isopropyl-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] butyl) -dihydrofuran-2 (3H) -one
  • 40 mg of 3-isopropyl-5- (1-azido-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxy-propoxy) -phenyl ] -butyl) -dihydrofuran-2 (3H) -one (Compound VI, with R 3 = CO 2 t Bu; R 4 = R 5 = Me; Y '= N 3 ; R 2 = Me; R 1 = (CH 2 3 OMe) is hydrogenated in ethanol (1 ml) with a spatula tip of Rainey nickel and H 2 at RT for 12 h. After completion of the reaction, diluted with EtOH, filtered from the catalyst and concentrated under vacuum. After purification by column chromatography, the title compound is obtained. Example 18
    Figure 00350001
    trans-7- {N, N-bis-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxypropoxy) -phenyl] -methyl} -2-isopropyl-8-methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = H; R 4 = R 5 = CO 2 t Bu; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 60 mg of trans -7- {N, N-bis-tert-butyloxycarbonyl-hydrazono [4-methoxy-3- (3-methoxypropoxy) -phenyl] -methyl} -2-isopropyl-8-methyl-non-4- acid diethylamide (compound I, with R 4 = R 5 = CO 2 tBu; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe) are dissolved in 1 ml of THF and mixed with 8 mg (120 μmol ) NaCNBH 3 added. The mixture is then mixed in portions with 19 mg (120 .mu.mol, 1.2 eq) of p-toluenesulfonic acid · H 2 O within one hour with vigorous stirring. It is stirred for a further hour at RT. The suspension is mixed with 1 ml of aqueous NaOH solution (1%) and extracted 3 times with MTBE. The organic phase is dried (Na 2 SO 4 ) and the LM removed under vacuum. The residue is purified by chromatography on SiO 2 (MTBE / heptane 2: 1 + 0.5% DEA). The title compound is obtained as a mixture of diastereomers. Example 19
    Figure 00350002
    trans-7- {N-benzyl-N ', N'-bis-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxy-propoxy) phenyl] methyl} -2-isopropyl-8- methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = CH 2 Ph; R 4 = R 5 = CO 2 t Bu; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 61 mg of trans-7- {N, N-bis-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxypropoxy) -phenyl] -methyl} -2-isopropyl-8-methyl-non-4- enoic acid diethylamide (compound II, where R 3 = H; R 4 = R 5 = CO 2 tBu; X = NEt 2; R 2 = Me; R 1 = (CH 2) 3 OMe) are mixed with 34 mg of benzyl bromide and a spatula tip NaI in 500 ul acetone at 40 ° C for 24 h. The mixture is washed with sat. NaHCO 3 solution (2 ml) was added and extracted (MTBE, 3 × 2 ml). The organic phases are dried over Na 2 SO 4 and concentrated under vacuum. After chromatographic purification (SiO 2 ), the four-substituted hydrazine derivative is obtained. Example 20
    Figure 00360001
    3-isopropyl-5- (1-bromo-3-isopropyl-4- (N-benzyl-N ', N'-bis-tert-butyloxycarbonyl) hydrazino-4- [4-methoxy-3- (3-methoxypropoxy ) phenyl] -butyl) -dihydrofuran-2 (3H) -one (Compound III, with R 3 = Bn; R 4 = R 5 = CO 2 t Bu; Y = Br; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 45 mg of trans-7- {N-benzyl-N ', N'-bis-tert-butyloxycarbonyl-hydrazino [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl} -2-isopropyl 8-methyl-non-4-enoic acid diethylamide (Compound II, with R 3 = CH 2 Ph; R 4 = R 5 = CO 2 t Bu; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe) is stirred vigorously in two phases with 2 ml DCM / H 2 O (4: 1). While cooling, NBS is added in portions and stirred for a further 12 h. The solution is added with saturated aqueous bisulfite solution (1 ml) and extracted (3 times 2 ml MTBE). The organic phases are dried over Na 2 SO 4 and concentrated under vacuum. After chromatographic purification (SiO 2 ) the title compound is obtained. Example 21
    Figure 00360002
    5- (1-benzyl-5-isopropyl-6- [4-methoxy-3- (3-methoxypropoxy) phenyl] -hexahydropyridazine-3-yl) -3-isopropyl-dihydrofuran-2 (3H) -one. (Compound IVb, where R 3 = Bn; R 4 = H; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • 34 mg of 3-isopropyl-5- (1-bromo-3-isopropyl-4- (N-benzyl-N ', N'-bis-tert-butyloxycarbonyl) -hydrazino-4- [4-methoxy-3- (3 -methoxypropoxy) phenyl] -butyl) -dihydrofuran-2 (3H) -one (Compound III, with R 3 = Bn; R 4 = R 5 = CO 2 t Bu; Y = Br; R 2 = Me; R 1 = ( CH 2 ) 3 OMe) is dissolved in 2 ml of CH 2 Cl 2 / F 3 COOH (10: 1) and stirred for 2 h at RT. The LM is removed in vacuo and the residue taken up in THF (1 ml). Triethylamine (0.2 ml) is added and stirred for 3 h at RT. The solution is washed with water (2 ml), dried over Na 2 SO 4 and concentrated in vacuo. After chromatography (SiO 2 ) the title compound is obtained. Example 22
    Figure 00370001
    3-isopropyl-5- (1-amino-3-isopropyl-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] butyl) -dihydrofuran-2 (3H) -one
  • 22 mg of 5- (1-benzyl-5-isopropyl-6- [4-methoxy-3- (3-methoxypropoxy) phenyl] -hexahydropyridazin-3-yl) -3-isopropyl-dihydrofuran-2 (3H) -one. (Compound IVb, with R 3 = Bn; R 4 = H; R 2 = Me; R 1 = (CH 2 ) 3 OMe) in EtOH (1 mL) with a spatula tip of Rainey nickel and H 2 at RT for 16 hydrogenated h. After completion of the reaction, diluted with EtOH, filtered from the catalyst and concentrated under vacuum. After purification by column chromatography, the title compound is obtained. Example 23
    Figure 00370002
    trans-7- {N ', N'-dimethyl-N-trifluoroacetyl-hydrazino [4-methoxy-3- (3-methoxypropoxy) phenyl] methyl} -2-isopropyl-8-methyl-non-4- acid diethylamide (Compound II, with R 3 = COCF 3 , R 4 = R 5 = Me, X = NEt 2 , R 2 = Me, R 1 = (CH 2 ) 3 OMe)
  • A solution of 107 mg (200 μmol) of dimethyl hydrazine (Compound II, where R 3 = H; R 4 = R 5 = Me; X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe ), 1.5 mg of dimethylaminopyridine (cat.) And 42 mg of trifluoroacetic anhydride in 500 .mu.l of pyridine are stirred for 12 h under a nitrogen atmosphere. Saturated brine (2 ml) is added and extracted with MTBE. The combined organic phases are dried (Na 2 SO 4 ) and the LM removed in vacuo. After chromatographic purification, the title compound is obtained. Example 24
    Figure 00380001
    3-isopropyl-5- (1-hydroxy-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxypropoxy) phenyl] - butyl) -dihydrofuran-2 (3H) -one (compound III, with R 3 = CO 2 tBu; R 4 = R 5 = Me; Y = OH; R 2 = Me; R 1 = (CH 2 ) 3 OMe)
  • To a solution of 3-isopropyl-5- (1-bromo-3-isopropyl-4-N ', N'-dimethyl-N-tert-butyloxycarbonyl-hydrazino-4- [4-methoxy-3- (3-methoxypropoxy ) phenyl] -butyl) -dihydrofuran-2 (3H) -one (56 mg) in 1 ml of isopropanol is added dropwise 5 mg LiOH dissolved in 100 ul H 2 O. The solution is stirred for 2 h and used directly. 300 μl of a 1 N HCl solution are added dropwise to this solution at 0 ° C. The solution is stirred for 4 h, diluted with H 2 O, extracted with TBME and dried over Na 2 SO 4 . Concentration in vacuo gives the title compound. Example 25
    Figure 00380002
    7- (N-tert-butyloxycarbonyl-N ', N'-Dimethylhydrazino- [4-methoxy-3- (3-methoxypropoxy) phenyl] methyl) -2-isopropyl-8-methyl-4,5-epoxy- nonanoic acid diethylamide trans-7- (N-tert-butyloxycarbonyl-N ', N'-dimethylhydrazino [4-methoxy-3- (3-methoxy-propoxy) -phenyl] -methyl) -2-isopropyl-8-methyl- non-4-enoic acid diethylamide (Compound II, with R 3 = Boc; R 4 = R 5 = Me, X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe) (56 mg) is dissolved in Dissolved 2 ml of dichloromethane and cooled to -20 ° C.
  • 19 mg of m-chloroperbenzoic acid are added at once. It is stirred for 30 min at 0 ° C, with sat. NaHCO 3 solution (1 ml), dried over Na 2 SO 4 , and concentrated in vacuo. After chromatography, inter alia, the desired compound can be isolated. Example 26
    Figure 00390001
    7- (N-tert-butyloxycarbonyl-N ', N'-Dimethylhydrazino- [4-methoxy-3- (3-methoxypropoxy) phenyl] methyl) -2-isopropyl-8-methyl-4,5-dihydroxy- nonanoic acid diethylamide
  • Dissolve 20 mg of methanesulfonamide and 280 mg of AD-Mix-alpha in tert-butanol (1 ml) and water (1 ml). It is cooled to 0 ° C., then 107 mg of the hydrazine derivative (compound II, where R 3 = Boc; R 4 = R 5 = Me, X = NEt 2 ; R 2 = Me; R 1 = (CH 2 ) 3 OMe) was added and stirred until the starting material has completely reacted (TLC). After chromatography on SiO 2 , the diol is obtained.
  • Example 27
  • (2S, 7S) -trans-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) -benzoyl] -8-methylnon-4-enoic acid (VII with R 1 = (CH 2 ) 3 OMe and R 2 = Me and X = OH)
  • To a cooled (-78 ° C) solution of 4-bromo-1-methoxy-2- (3-methoxypropyloxy) benzene (2.75 g, 10 mmol) in dry THF (15 mL) was added n-BuLi (4.5 mL; 12.5 M in hexane) was added dropwise and the reaction mixture for 30 min at -78 ° C stirred. Thereafter, a MgCl 2 solution (22.5 ml, 0.50 M in THF, freshly prepared) was added, the reaction mixture stirred for 20 min at -78 ° C, warmed to RT and stirred for a further 30 min. This reaction mixture was added within 2 min to a -78 ° C cooled suspension of (2S, 7S) -trans-2,7-diisopropyl-oct-4-endioic acid chloride (2.93 g, 10 mmol) and Fe (acac) 3 (128 mg, 360 μmol) in dry THF (15 ml). The reaction mixture was stirred at -78 ° C for 5 min and treated with 10 ml of water and 2 ml of HCl and thawed to RT. The aqueous layer was extracted 3x with tert-butyl methyl ether and the organic layer was dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by column chromatography on SiO 2 (heptane, MTBE 2: 1 + 0.5% acetic acid) to give the title compound (IV) (2.0 g, 46% yield) as a pale yellow oil. (2S, 7S) -trans-2-isopropyl-7- [4-methoxy-3- (3-methoxy-propoxy) -benzoyl] -8-methyl-non-4-enoic acid
    TLC: (hexane / MTBE 1: 1 + 0.5% AcOH): Rf = 0.30;
    1 H-NMR (CDCl3, 400 MHz): δ = 0.90 (m, 12H); 1.81 (m, 1H); 1.98-2.29 (m, 6H); 2.45 (m, 1H); 3.21 (m, 1H); 3.38 (s, 3H); 3.59 (dd, J 1 = J 2 = 7Hz, 2H); 3.92 (s, 3H); 4.18 (dd, J 1 = J 2 = 7Hz, 2H); 5.38 (m, 2H); 6.89 (d, J = 9Hz, 1H); 7.04 (m, 2H); 7.75 (bs, 1H).
    13 C-NMR (CDCl 3 , 100.6 MHz): δ = 19.68; 19.75; 2.20; 21:19; 29.39; 29.56; 29.69; 30.49; 32.20; 32.39; 52.30; 56.01; 58.54; 66.18; 69.26; 110.46; 112.50; 122.67; 128.92; 130.10; 131.67; 148.48; 153.57; 179.60; 202.64.
  • Example 28
  • Separation of meso / rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid with piperazine
  • A mixture of meso / rac trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (59.6 g; meso / rac 54:46) and piperazine (14.35 g) in EtOH (277 g). is stirred vigorously for 4 h. The resulting crystals (meso-enriched piperazine salt) are filtered off. The mother liquor is stirred in two phases with 100 ml of 5% strength hydrochloric acid and extracted 3 times with in each case 100 ml of MTBE. The combined organic phases are dried over Na 2 SO 4 and the LM removed in vacuo. The residue is recrystallized from isopropyl acetate (recrystallization step 1). There are obtained 16.5 g of rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (HPLC:> 98.5%) as colorless crystals.
  • The meso-enriched piperazine salt is stirred in two phases with 5% HCl and MTBE. The organic phase is separated and dried over Na 2 SO 4 . After removal of the LM under vacuum, the residue and the mother liquor from the recrystallization step 1 (42 g total) are suspended in 174 g of isopropyl acetate and stirred vigorously for 12 h (crystallization step 2). The solid (23.1 g, meso-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid, HPLC:> 98.5%) is filtered off. 19.3 g of meso / rac, trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (meso / rac 45:55) are removed from the mother liquor of crystallization step 2 by removing the LM under reduced pressure. isolated, which can be separated again according to the same principle.
  • Example 29
  • Separation of meso / rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid by emulsion crystallization
  • A Mixture of meso / rac trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (10g, meso / rac 44:56) in isobutanol / NMP / water / NP10 (58: 11: 14: 17; 10.4 g) is homogenized at 65 ° C. After cooling At 25 ° C, seed crystals of rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (11 mg) is added and the mixture is stirred at room temperature for Stirred for 1 h. The crystals are filtered off, with isobutanol washed and dried. This gives 1.34 g of rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (rac / meso: 94: 6).
  • To the mother liquor is added additional starting material of meso / rac trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (1.3 g, meso / rac 44:56) and the mixture becomes 65 ° C homogenized. After cooling At 25 ° C, seed crystals of meso-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (10 mg) are added and the mixture is stirred at room temperature for 1 h. The crystals are filtered off, washed with isobutanol and dried. This gives 1.5 g of meso-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (rac / meso: 34:66). The resulting mother liquor is then again slightly enriched with rac-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid and can be used again in the 1st step. The meso-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (1.5 g, rac / meso: 34:66) is stirred in 6 g of isopropyl acetate for 16 h at RT. The crystals are filtered off, washed with isopropyl acetate and dried. This gives 0.48 g of meso-trans-2,7-diisopropyl-oct-4-ene-1,8-dionic acid (rac / meso: 6:94). After concentration in vacuo, 1.0 g of the diacid (rac / meso: 47:53) is isolated from the mother liquor, which can be reused in step 1.
  • QUOTES INCLUDE IN THE DESCRIPTION
  • This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.
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Claims (18)

  1. Process for the preparation of 8-aryl-octanoyl derivatives of the general formula (X) or salts thereof
    Figure 00420001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and X is hydrogen, halogen, O - , OR 12 , wherein R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal, or NR 8 R 9 is where R 8 and R 9 independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl, alkyl- NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ; or their stereoisomers or mixtures thereof, characterized in that at least one of the following process steps is carried out A) reaction of a compound of the formula (IV)
    Figure 00420002
    wherein R 1 and R 2 are as defined above and E is a group of the following formulas
    Figure 00430001
    in formula a A is N, and B is NR 4 R 5 , in which R 4 and R 5 independently of one another represent hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched, optionally halogen-substituted alkyl, arylalkyl, preferably benzyl; or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system; and in formula b b1) the single-dotted line represents a single bond; and A is NR 3 wherein R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl; and B is NR 4 wherein R 4 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or b2) the single-dotted line represents no bond; and A is the group NR 3 -NR 4 R 5 , in which R 3 , R 4 and R 5 independently of one another represent hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 CO 2 R 10 , C ( O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system; and B is a nitrogen functionality such as azide, NR 6 R 7 or NH-NR 6 R 7 , wherein R 6 and R 7 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl or trialkylsilyl, or R 6 and R 7 together with the nitrogen atom form a heterocyclic ring system, or their stereoisomers or mixtures thereof or their delactonated derivatives in one or more steps with a suitable reducing agent with removal of the nitrogen functionality in the C 8 position to form an amine group in C 5 Position directly to a compound of formula (X) or to a compound of formula (IX)
    Figure 00440001
    B) opening the lactone ring in the case of a compound of the formula (IV) or (IX), C) optionally converting a compound of the formula (X) or a delactonated derivative of a compound of the formula (IV) into another suitable derivative, preferably one the meanings of X.
  2. Process according to Claim 1, characterized in that the compound of the formula (IVa) or (IVb)
    Figure 00450001
    in which R 1 , R 2 have the abovementioned meaning, A and B have the meaning given above under a) and b 1 ), or their stereoisomers or mixtures thereof, is obtained by reacting a compound of the formula (II)
    Figure 00450002
    wherein R 1 , R 2 , R 3 , R 4 and R 5 and X have the abovementioned meaning, wherein R 3 , R 4 and R 5 are preferably not hydrogen, or their stereoisomers or mixtures thereof with a halogenating agent, such as chlorine , Bromine, NCS, NBS, bromine, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate, an oxidizing agent such as osmium tetroxide, hydrogen peroxide or meta-chloroperbenzoic acid, optionally with the addition of chiral auxiliaries, or a Mercury compound, such as Hg (OAc) 2 or Hg (O 2 CCF 3 ) 2 , or a selenium compound, such as PhSeCl or ArSeOTf, and optionally subsequent treatment with a base, such as LiOH in water, and optionally introducing a protective group, such as mesylate , Tosylate or triflate, with lactonization to give a compound of formula (III)
    Figure 00460001
    in which R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and Y is bromine, chlorine, iodine, OH or OR 18 , in which OR 18 is a leaving group, such as mesylate, tosylate or triflate, or their stereoisomers or mixtures thereof, and subsequent conversion of the compound of formula (III) by intramolecular cyclization into the target compound of formula (IVa) and / or (IVb).
  3. Process according to Claim 1, characterized in that the compound of the formula (IVa) or (IVb)
    Figure 00460002
    in which R 1 , R 2 have the abovementioned meaning, A and B have the meaning given above under a) and b 1 ), or their stereoisomers or mixtures thereof, is obtained by reacting a compound of the formula (II)
    Figure 00470001
    wherein R 1 , R 2 , R 3 , R 4 , R 5 and X have the abovementioned meaning, where at least one of R 3 , R 4 and R 5 is hydrogen, or their stereoisomers or mixtures thereof with a halogenating agent, such as chlorine, bromine, NCS, NBS, bromine, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate, an oxidizing agent such as osmium tetroxide, hydrogen peroxide or meta-chloroperbenzoic acid, optionally with the addition of chiral auxiliaries, or a mercury compound such as Hg (OAc) 2 or Hg (O 2 CCF 3 ) 2 , or a selenium compound such as PhSeCl or ArSeOTf to a compound of the formula
    Figure 00470002
    in which R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and Y is bromine, chlorine, iodine, OH or OR 18 , in which OR 18 is a leaving group, such as mesylate, tosylate or triflate, subsequent conversion of the compound of the formula (Va) or (Vb) by lactonization into the target compound of the formula (IVa) and / or (IVb).
  4. Process according to Claim 1, characterized in that the compound of the formula (IVa) or (IVb)
    Figure 00480001
    wherein R 1 , R 2 have the abovementioned meaning, A and B have the meaning given above under a) and b 1 ), or their stereoisomers or mixtures thereof, is obtained directly by reacting a compound of the formula (II)
    Figure 00480002
    wherein R 1 , R 2 , R 3 , R 4 , R 5 and X have the abovementioned meaning, or their stereoisomers or mixtures thereof with a hypervalent iodine compound, such as PhI (OAc) 2 , PhI (O 2 CCF 3 ) 2 or ( hydroxy (tosyloxy) iodo) benzene.
  5. Process according to Claim 1, characterized in that the compound of the formula (IVc)
    Figure 00480003
    wherein R 1 , R 2 have the abovementioned meaning, A and B have the meaning given above under b2), or their stereoisomers or mixtures thereof, is obtained by reacting a compound of the formula (II)
    Figure 00490001
    in which R 1 , R 2 , R 3 , R 4 and R 5 and X have the abovementioned meaning, or their stereoisomers or mixtures thereof with a halogenating agent such as chlorine, bromine, NCS, NBS, bromine, iodine, I-Cl, I-Br, I-OAc or bispyridine-iodonium tetrafluoroborate, an oxidizing agent such as osmium tetroxide, hydrogen peroxide or meta-chloroperbenzoic acid, optionally with the addition of chiral auxiliaries, and if appropriate subsequent treatment with a base such as LiOH in water, and if necessary. Introduction of a protective group, such as mesylate, tosylate or triflate, under lactonization to give a compound of the formula (III)
    Figure 00490002
    in which R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning and Y is bromine, chlorine, iodine, OH or OR 18 , in which OR 18 is a leaving group, such as mesylate, tosylate or triflate, or their stereoisomers or mixtures thereof, and subsequent conversion of the compound of formula (III) by reaction with a nitrogen nucleophile, such as azide, amines, ammonia or cyanamides in the target compound.
  6. Method according to one of claims 2 to 5, characterized in that the compound of the general my formula (II)
    Figure 00500001
    in which R 1 , R 2 , R 3 , R 4 , R 5 and X have the abovementioned meaning, is obtained by reacting a compound of the general formula (VII)
    Figure 00500002
    wherein R 1 , R 2 and X have the abovementioned meaning, with a substituted hydrazine derivative of the general formula H 2 N-NR 4 R 5 , in which R 4 and R 5 have the abovementioned meaning, to give a compound of the general formula (I)
    Figure 00500003
    wherein R 1 , R 2 , R 4 , R 5 and X have the abovementioned meaning, and further reaction in one or more steps with a suitable reducing agent to the target compound of formula (II).
  7. A method according to claim 6, characterized in that reacting the compound of general formula (VII) with hydrazine of the formula H 2 N-NH 2 to give a compound of general formula (Ia)
    Figure 00510001
    in which R 1 , R 2 and X have the abovementioned meaning, with subsequent introduction of at least one nitrogen protective group, such as CBZ, BOC and the like, and further reaction in one or more steps with a suitable reducing agent, if appropriate with the introduction of further nitrogen. Protecting groups to the target compound of the formula (II).
  8. Process according to one of Claims 6 or 7, characterized in that the compound of the general formula (VII)
    Figure 00510002
    in which R 1 , R 2 and X have the abovementioned meaning, is obtained by coupling a compound of the formula (1)
    Figure 00510003
    wherein R 1 and R 2 are as defined for the compound of formula (VII) and R 20 is alkali metal or metal halide, wherein the metal for Mg, Al, B, Mn, Cu, Cd, Zn, V, Fe, Ni and Sn can be attached to a chiral compound of formula (2)
    Figure 00510004
    wherein W is for z. B. is hydrogen or halogen, wherein the group C (O) W and C (O) OR 21 may each be replaced by nitrile, and R 21 is branched or unbranched alkyl, wherein the group OR 21 are also halogen can, in the presence of a catalyst from the group Fe (III), preferably Fe (acac) 3 , Ni (0), Pd (0) and V (III), optionally with subsequent derivatization.
  9. Process according to Claim 8, characterized in that the compound of formula (2) to be coupled is obtained from a diastereomer separation of a meso / rac mixture of the compound of the formula (2), in particular with W = H and R 21 = OH Reaction with achiral amines, preferably piperazine, and subsequent separation of the salts.
  10. Compounds of the general formula (II)
    Figure 00520001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; X is hydrogen, halogen, O - , OR 12 , wherein R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal, or X is NR 8 R 9 is where R 8 and R 9 independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl, alkyl- NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ; and R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, and R 4 and R 5, independently of one another, are hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom heterocyclic ring system such as phthalimide, morpholine, or their stereoisomers or mixtures thereof.
  11. Compounds according to claim 8, characterized in that R 1 is 1-methoxymethyl, 1-methoxy-2-ethyl, 1-methoxy-3-propyl, 1-methoxy-4-butyl, and R 2 is methyl.
  12. Compound of the general formula (I)
    Figure 00530001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and X is hydrogen, halogen, O - , OR 12 , wherein R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal, or X is NR 8 R 9 wherein R 8 and R 9 independently of one another represent hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl, alkyl -NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ; and R 4 and R 5 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently Is hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system, such as phthalimide, morpholine. or their stereoisomers or mixtures thereof.
  13. Compounds of the general formula (III)
    Figure 00540001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and Y is bromine, chlorine, iodine, OH or OR 18 wherein OR 18 is a leaving group such as mesylate, tosylate or triflate and R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently hydrogen, branched or unbranched alkyl, arylalkyl, before is benzyl, and R 4 and R 5 are each independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or, R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system such as phthalimide, morpholine, or their stereoisomers or mixtures thereof.
  14. Compounds of the general formula (VI)
    Figure 00550001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and Y 'is a nitrogen function such as azide, NR 6 R 7 , wherein R 6 and R 7 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or R 6 and R 7 together with the Nitrogen atom form a heterocyclic ring system such as phthalimido, morpholino, and R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, and R 4 and R 5 are each independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently of one another hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom is a heterocyclic ring system such as Phthalimido, morpholino, form or their stereoisomers or mixtures thereof.
  15. Compounds of the general formula Va
    Figure 00560001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and X is hydrogen, halogen, O - , OR 12 , wherein R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal, or X is NR 8 R 9 wherein R 8 and R 9 independently of one another represent hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl, alkyl -NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ; and Y is bromo, chloro, iodo, OH or OR 18 , wherein OR 18 is a leaving group such as mesylate, tosylate or Triflate and R 4 and R 5 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another represent hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system such as phthalimido, morpholino or their stereoisomers or mixtures thereof.
  16. Compounds of the general formula Vb
    Figure 00570001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and X is hydrogen, halogen, O - , OR 12 , wherein R 12 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, or M, where M is alkali metal or one equivalent of an alkaline earth metal, or X is NR 8 R 9 wherein R 8 and R 9 independently of one another represent hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, hydroxyalkyl, alkoxyalkyl, alkanoyloxyalkyl, HO (O) C-alkyl, NH 2 C (O) -alkyl, alkyl -NHC (O) alkyl, (alkyl) N-alkyl or CH 2 C (CH 3 ) 2 CONH 2 ; and Y is bromine, chlorine, iodine, OH or OR 18 wherein OR 18 is a leaving group such as mesylate, tosylate or triflate and R 3 and R 4 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 are each independently hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or their stereoisomers or mixtures from that.
  17. Compounds of the general formula IVa
    Figure 00580001
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and A is N, and B is NR 4 R 5 , wherein R 4 and R 5 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O NR 10 R 11 wherein R 10 , R 11 are each independently hydrogen, branched or unbranched, optionally halogen-substituted alkyl, arylalkyl Benzyl, mean, stand; or R 4 and R 5 together with the nitrogen atom form a heterocyclic ring system, such as phthalimido, morpholino, or their stereoisomers or mixtures thereof.
  18. Compounds of the general formula IVb
    Figure 00580002
    wherein R 1 and R 2 are independently hydrogen, branched or unbranched alkyl, aryl, arylalkyl, preferably benzyl, alkoxyalkyl or alkoxyaryl; and A is NR 3 wherein R 3 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, and B is NR 4 wherein R 4 is hydrogen, branched or unbranched alkyl, aryl, arylalkyl, C (O) R 10 , CO 2 R 10 , C (O) NR 10 R 11 , wherein R 10 , R 11 each independently of one another are hydrogen, branched or unbranched alkyl, arylalkyl, preferably benzyl, or their stereoisomers or mixtures thereof.
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