HK1036624B - Method for stereochemically controlled production of isomerically pure highly substituted azacyclic compounds - Google Patents
Method for stereochemically controlled production of isomerically pure highly substituted azacyclic compounds Download PDFInfo
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Description
The invention relates to a novel method for the stereochemically controlled production of novel and known, highly substituted nitrogen heterocycles and novel intermediates of said method. The invention furthermore relates to novel highly substituted nitrogen heterocyclic compounds which can be formed isomerically pure and have properties which can be exploited in a number of fields.
Highly substituted stereoisomers of nitrogen heterocyclic compounds, in particular highly substituted pyrrolidine or piperidine derivatives, provide useful starting materials for a number of applications and find use as components of chiral catalysts, for example in asymmetric syntheses (see kobaya)shi et al, chemical communication (1991)1341-1344), as a component of biologically active alkaloids (see Williams et al, Journal of Organic Chemistry (JOC)57(1992)6527 and 6532 and references cited therein; j die der et al, applied chemistry102(1990)1180-1182) and as components of pharmacologically interesting compounds (see lascat et al, synthesis4(1997)475-497). Furthermore, decahydroquinolines and pyrrolidines which can be produced or are structurally closely related according to the methods of the present invention have interesting physiological effects (see, for example, Kuzmitski et al, Vestsi Akad. Navuk BSSR, Ser.Khim. Navuk3(1979) 82-85/chemical Abstract number 91: 117158 c; lash et al, heterocyclic chemistry journal28(1991)1671-1676). In this document, the use of some of the above-mentioned pyrrolidines for the manufacture of porphyrin-ring systems is discussed. Methods for producing such nitrogen heterocycles are also partially known from the literature cited therein. Certain enantiomers of these compounds can be obtained according to methods given in the literature, generally by means of conventional racemic separations. However, the production processes which are not the processes according to the invention are also described, by means of which the selected isomerically pure substituted azacyclic individual compounds can be produced. The general methods for the stereocontrolled synthesis of isomerically pure highly substituted azaheterocyclic compounds have not been reported in the literature mentioned above.
Furthermore, the stereospecific synthesis of some tetrahydrofuran derivatives is known according to the following procedure: by reaction of 2-Alkenyl-sulfimide (2-alkinyl-sulfoximine) with 2-tert-butyldimethyl-siloxy-propionaldehyde (═ TBS-lactaldehyde) and subsequent fluoride-induced cyclization (see Reggelin et al, JACS)118(1996) 4765-4777; reggelin et al, annual chemical Liebigs/RECUEI L (1997) 1881-1886). However, highly substituted nitrogen heterocycles cannot be prepared by the processes described in the abovementioned documents.
From a web site of "www.incr.ac.uk"published literature on internet (m. bolte, part C of crystallography, published literature QA0017[ (IUCr) Acta C Paper QA 0017) for electronization]) Known compounds(2S, 3S, 4S, 5S) - (N-tert-butyloxycarbonyl) -2-benzyl-4, 5-dimethyl-3-hydroxy-pyrrolidine. The manufacture of this compound is not described in the above published literature.
The object of the present invention is to provide a novel, stereochemically controlled process for the preparation of nitrogen heterocycles which are known to be highly substituted, by means of which the type and number of substituents on the compound can be varied widely and which can be formed isomerically pure. The object of the present invention is also to provide novel, in particular isomerically pure, highly substituted nitrogen heterocycles for a large number of applications.
Surprisingly, it has been found that highly substituted nitrogen heterocyclic compounds can be prepared in good yields, in particular in isomerically pure form, if metallated 2-alkenyl-sulfilimide compounds are reacted according to one of the processes of the invention with N-protected α -or β -aminoaldehydes having the substitution patterns indicated in the description in the α -and/or β -position, wherein the type and number of substituents can be varied widely.
The subject of the invention is thus a process for the stereochemically controlled manufacture of compounds of the general formula I and the acid addition salts thereof, where appropriate with the proviso that reactive groups present in the compounds of the formula I may be blocked by suitable protecting groups,
wherein
n represents a number of 0 or 1,
R1represents hydrogen, C1-6Alkyl or phenyl which is optionally substituted in the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy-C1-6-alkyl, and
R2represents hydrogen, or
R1And R2Together represent a doubly-bound methylene group which may be substituted by C1-5Alkyl or phenyl which is optionally substituted on the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy-C1-5-substituted by an alkyl group,
R3represents hydrogen, and
R4represents hydrogen, lower alkyl or phenyl lower alkyl which is substituted, if desired, on the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or
R3And R4Together represent a C2Alkylene chains or C containing 1 to 3 double bonds as required3-6Alkylene chain which may be interrupted by C, optionally substituted once or twice by lower alkyl1-2An alkylene bridge, and a nitrogen bridge,
R5represents hydrogen, lower alkyl, hydroxy, lower alkoxy or phenyl lower alkyl or phenyl lower alkoxy each of which is substituted on the phenyl ring, if desired, one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, and
R6represents hydrogen, and
R7represents hydrogen, and
R8represents hydrogen, cyano, optionally esterified carboxyl, optionally mono-or disubstituted carbonylamino, optionally substituted on nitrogen, an optionally mono-or bicyclic ring system with 3 to 10 ring carbon atoms which can be substituted one or more times by nitrogen, oxygen and/or sulfur and which can be substituted one or more times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or by a lower alkylene chain which is linked to two oxygen atoms bound to adjacent carbon atoms of the ring system, or
Represents a straight or branched chain C optionally containing one or more double bonds1-12-an alkyl group, which alkyl group is present onceOr substituted more than once by halogen atoms, hydroxy, lower alkoxy, optionally esterified carboxy, cyano, thiol, lower alkylthio, amino, lower alkylamino, carbonylamino optionally substituted once or twice on the nitrogen, an optionally mono-or polyunsaturated mono-or bicyclic ring system with 3 to 10 ring carbon atoms which may be substituted once or more than once by nitrogen, oxygen and/or sulfur, and which may be substituted once or more than once by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or by a lower alkylene chain which is linked to two oxygen atoms bound to adjacent carbon atoms of the ring system, or
R5And R8Or together with the carbon atom to which they are attached, form a monocyclic or bicyclic ring system having 5 to 10 ring carbon atoms, optionally containing 1 to 3 double bonds, which does not carry a substituent R5Or R8May be substituted one or more times by sulfur, oxygen and/or nitrogen, and it may be substituted one or more times by lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen or by a lower alkylene chain which is linked to 2 oxygen atoms which are linked to adjacent carbon atoms of the ring system, or
R6And R7Also together form a bond, and
R5and R8Or together with the carbon atom to which they are bound to form an aromatic C6A ring system fused to 2 to 4 further carbon atoms to form a bicyclic ring system containing a total of 8 to 10 ring carbon atoms and a total of 3 to 5 double bonds, which does not carry a substituent R5And R8C of6-C10The carbon atoms of the ring system may be replaced one or more times by sulfur, oxygen and/or nitrogen, and where C is6-C10The ring system may optionally be substituted one or more times by lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen, or by a lower alkylene chain attached to 2 adjacent carbon atoms of the ring systemOn the oxygen atom to which the molecule is attached,
R9represents hydrogen, lower alkyl, phenyl lower alkyl which is optionally substituted on the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy or an amino protecting group, or
R8And R9Or together form a C3-C4An alkylene chain, and
y represents oxygen or NH, and the salt is preferably a salt of hydrogen,
it is characterized in that the preparation method is characterized in that,
a) reacting a compound of the formula II
Wherein R is3And R4As defined above, R101And the above-mentioned R1In the same sense, except for optionally substituted methylene groups,
ar is a phenyl group optionally substituted one or more times by lower alkyl,
R10represents lower alkyl or phenyl which is substituted on the phenyl ring, if desired once, by lower alkyl or by a hydroxy group protected with a suitable protecting group or phenyl lower alkyl which is substituted on the phenyl ring, if desired once, by lower alkyl, and
R1101is a silyl-protecting group which is a silyl-protecting group,
successively with a base suitable for deprotonation, a metal-organic reagent of the formula VII
XM2(OR12)3 VII
Wherein X is halogen, M2Is a tetravalent transition metal, R12Is lower alkyl, phenyl or phenyl lower alkyl, anda stereoisomer of a compound of formula VIII to form a stereoisomer of a compound of formula IX:
wherein R is5,R6,R7And n is as defined above, R801And R8In the same sense, in which the reactive groups which may be present are blocked, if desired, with a protecting group which is stable with bases, R901Is hydrogen or with R801Together form a C3-4Alkylene chain, R13Is an amino protecting group which leaves a nitrogen nucleophile in its decomposition, formula IX
Wherein R is101,R3,R4,R5,R6,R7,R801,R901,R10,R1101,R12,R13N, Ar and M2The significance is given to the above-mentioned,
b) the resulting compound of formula IX is purified by treatment with a suitable solvent for removing R13Reagent treatment of the radicals to convert them into compounds of the general formula Xa,
wherein R is101,R3,R4,R5,R6,R7,R801,R901,R10N and Ar have the meaning given above, R11Is hydrogen or a silyl protecting group, if R901Is hydrogen, the nitrogen atom in the ring skeleton of the formal compound of the formula Xa is blocked with a base-stable protective group and, if appropriate, the silyl-protecting group still presentR11Cracking, and
c) in order to produce the compound of the formula Ia,
wherein R is1,R2,R3,R4,R5,R6,R7,R81And n has the meaning given above, R902Is a base-stable protecting group or with R801Together represent C3-C4-an alkylene chain, the alkylene chain being,
ca) one compound of the formula Xa obtained or by protecting the group R with a silyl group11With a reagent suitable for reductive cleavage of a sulfonimidyl-Alkyl bond (sulfonimidyl-Alkyl-Bindung) to obtain a compound of the general formula Ib,
wherein R is101,R3,R4,R5,R6,R7,R801,R902And n has the above-mentioned meaning, or
cb) in obtaining a compound of formula Xa, wherein R101Not representing hydrogen, the sulfonylimino-alkyl bond is cleaved after electrophilic activation of the sulfonylimino unit under base-induced elimination conditions to give the compound of formula Ic,
wherein R is3,R4,R5,R6,R7,R801,R902And n has the same meaning as R102Represents C1-5-alkyl or is essentialPhenyl lower alkyl which is substituted on the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, which lower alkylene chain may contain from 1 to 5 carbon atoms,
and a compound of formula Ia obtained, if desired, by one or more general transformations (each of which is a change in the configuration of the ring carbon atom at the 3-position of the compound of formula Ia) with a compound suitable for regenerating an OH group or NH group at the 3-position2-nucleophilic reaction of the radicals and/or, if desired, renewed cleavage of protective groups which may be present on the compound of formula Ia, and, if desired, reaction of the imino group (NH-group), which is optionally free in the 1-position of the ring skeleton, with a reagent which enables N-alkylation or amide formation or blocking with an amino protecting group, to give the compound of formula I, and, if desired, conversion of the free compound of formula I into an acid addition salt, or conversion of an acid addition salt of the compound of formula I into the free compound. The invention also relates to novel nitrogen heterocycles.
If a substituent in a compound of formula I or in other compounds described in the scope of the present invention represents a lower alkyl group or comprises a lower alkyl group, this alkyl group may be branched or unbranched and typically comprises from 1 to 4 carbon atoms.
If one or more substituent components, such as groups bonded to a benzene ring, may be included in the definition of substituents for compounds of formula I or formula X, one to 3 such substituent components may be included. If one or more carbon atoms can be replaced by heteroatoms such as oxygen, sulfur or nitrogen in the compounds of the invention, it is generally possible to replace 1 to 3 carbon atoms by heteroatoms. Preferably one carbon atom may be replaced by one heteroatom. If the substituents may contain one or more double bonds, the cyclic substituents may generally contain from 1 to 4 double bonds, depending on the ring size, and may preferably form aromatic systems. The aliphatic substituent groups may have, for example, 1 to 3 double bonds.
Preference is given to preparing compounds of the formula Ia in which the substituent R1And R2Each represents hydrogen. It is particularly preferred that compounds of the formula Ib can be prepared, in particular when the substituent R101Those representing hydrogen.
Substituent R3May preferably represent hydrogen or may be substituted with R4Together forming an optionally bridged C3-6An alkylene chain. Such compounds of formula I are preferably made isomerically pure, wherein R4Instead of hydrogen, it is, for example, lower alkyl. If R is4In a further meaning, which is different from H, the ring closure reaction to the compound of the formula Xa in process step b) proceeds with particularly high selectivity and the compound of the formula Xa gives compounds of the formulae Ia and I with only a particularly small proportion of by-products. If R is3And R4Together represent optionally bridged C3-6An alkylene chain, which preferably may contain from 3 to 4 carbon atoms. If the alkylene chain is bridged, the bridged chain preferably has 1 carbon atom, which may preferably be substituted by a di-lower alkyl group (Diniederalkyl). In particular R3And R4May form together with the carbon atom to which they are attached 7, 7-dimethylbicyclo [3.1.1]Heptane system.
If the substituent R is8Representing or containing carboxyl groups which are esterified if desired, the carboxyl groups may be esterified with conventional, sterically unhindered alcohols, e.g. with cycloaliphatic or straight-chain or branched aliphatic C groups optionally containing 1 or more double bonds1-C6Alcohol esterification, the alcohol being optionally substituted 1 or more times by halogen or lower alkoxy, or also by phenyl lower alkyl alcohols, optionally substituted one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, on the phenyl ring. If R is8Represents or comprises carbonylamino which is optionally substituted once or twice on the nitrogen, the amino group contained therein may, for example, be substituted once by C3-C8Cycloalkyl lower alkanoyl or by straight or branched aliphatic C1-C6Alkanoyl, such alkanoyl being optionally substituted one or more times by halogen or lower alkoxy; or the amino group may be substituted once or more times on the phenyl ring by phenyl lower alkanoyl optionally substituted once or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy; or amino groups, for example, may also be once or twice each optionally onceOr C substituted multiple times by halogen or lower alkoxy3-C8Cycloalkyl lower alkyl or straight or branched aliphatic C1-C6Alkyl, or by phenyl lower alkyl which is substituted, if desired, one or more times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or amino, for example, may be protected with a suitable amino protecting group. If R is8Represents or contains an optionally substituted mono-or bicyclic ring system with 3 to 10 ring carbon atoms, said ring system then representing cyclopropyl, cyclopentyl, cyclohexyl, phenyl, p-bromophenyl or 3-indolyl.
Examples of compounds of the formula I, Ia, Ib and/or Ic according to the invention which can be prepared without problems by the process according to the invention are substituents R8Or R801Is hydrogen, lower alkyl, phenyl, lower alkylphenyl or lower alkoxy lower alkyl or further has for example the formula R8Or R801,R5,R6And R7A fused aromatic 6-ring is formed. Wherein R is the same as801And R901Together form C3-C4The compounds of the formula I, Ia, Ib and/or Ic of the alkylene chain can be prepared without problems.
Suitable protecting groups which can be used for the compounds indicated in the context of the present invention are reported, for example, in McOmie, "protecting groups in organic chemistry", Plenum Press or in Green, Wuts, "protecting groups in organic Synthesis", Wiey Interscience publishing company.
In process step a), the deprotonation of the compound of the formula II with a suitable base and the reaction of the deprotonated compound of the formula II with a metal-organic reagent of the formula VII and subsequently with an aminoaldehyde of the formula VIII to give the compound of the formula IX can be carried out in a polar or weakly polar aprotic solvent which is inert under the reaction conditions, for example in cyclic or open-chain lower alkyl ethers such as diethyl ether (═ diethyl ether) or tetrahydrofuran (═ THF), in low molecular polyglycol ethers such as diethylene dimethyl ether (═ Diglyme (Diglyme)) or in substituted benzenes such as toluene or xylene. May preferably adopt weakPolar solvents such as substituted benzenes, in particular toluene. If toluene is used as solvent, a particularly good yield of the product of formula IX, or of the product of formula Xa obtained therefrom, is obtained. This reaction is preferably carried out as a one-pot reaction in which the preferably isomerically pure 2-alkenylthioimides of the formula II are deprotonated with a suitable base in the appropriate solvent at low temperatures, for example between-100 ℃ and-50 ℃, preferably at-78 ℃ for about 5 to 30 minutes, the compounds of the formula II in the deprotonated form being transmetallized at slightly elevated temperatures, for example between-20 ℃ and 10 ℃, preferably at 0 ℃ with the organometallic reagent of the formula VII, and the intermediate products obtained are then reacted again at low temperatures, for example between-100 ℃ and-50 ℃, preferably at-78 ℃, with the N-protected aminoaldehydes of the formula VIII. Suitable bases for deprotonation of the compounds of the formula II are preferably lithiated lower alkyl compounds such as n-butyllithium. In general, the base may be employed in a slight excess, for example in a molar ratio of from about 1: 1.05 to about 1: 1.20, based on the amount of compound of the formula II added. In the organometallic reagent of formula VII X may represent halogen, preferably chlorine. As tetravalent transition metal M2Zirconium may be used, for example, but titanium is preferred. As substituents R12Suitable are, for example, branched and unbranched lower alkyl radicals, preferably isopropyl. Particularly preferred compounds of the formula VII are titanium tris (isopropoxide) chloride. The metal-organic reagent is preferably employed in a slight excess, for example in a molar ratio of between about 1.1: 1 and 1.3: 1, based on the amount of compound of formula II added.
The compounds of formula VIII represent protected chiral alpha-or beta-aminoaldehydes, which may preferably be isomerically pure. As protecting group R capable of yielding one nucleophilic nitrogen atom in the compound of formula VIII upon cleavage thereof13It is preferably a base-stable protecting group. Particular preference may be given to a fluoren-9-ylmethoxycarbonyl protecting group (═ FMOC) as group R13. Protecting group R13The cleavage and ring closure reactions of (a) may preferably be performed in a single reaction step if FMOC is used as a protecting group.
In the starting compounds of the formula VIII, the substituent R801Of the meaning of (A) and R8Identical, but where appropriate in the substituents R8The reactive groups contained therein, for example the hydroxyl, amino, thiol or carboxyl groups, are each blocked with base-stable protective groups known per se, for example those which are stable to non-nucleophilic or weakly nucleophilic bases, for example pyridine, in order to avoid undesirable side reactions. Isomerically pure aminoaldehydes of the formula VIII are known or can be prepared from known compounds by processes known per se. For example, aldehydes of formula VIII can be obtained from the corresponding primary alcohols of the aldehydes by mild oxidation processes known per se. Such a process is suitable as a mild oxidation process, i.e. it does not lead to racemization of the chiral center in the compounds of the formula VIII, for example oxidation with active oxalyl chloride (═ Swern oxidation), or also oxidation with 1, 1, 1-triacetyl-1, 1-dihydro-1, 2-benzosulfon-ol) -3(1H) -one (═ Periodinan; Dess-Martin-oxidation, see, for example, J.C. Martin et al, JACS113(1991) 7277-7287; dess, j.c. martin, journal of organic chemistry48(1983)4155-4156). If the oxidation is carried out as described above for Dess-Martin, the aminoaldehydes of the formula VIII can be prepared as described in the abovementioned documents or analogously thereto. For example, it is contemplated that the primary alcohol which is a precursor of the aldehyde of formula VIII may be reacted in a dipolar aprotic solvent, e.g., in a halogenated lower alkane such as dichloromethane, with a slight excess of triacetoxy-Periodinan, e.g., at a molar ratio of from 1.2: 1 to about 1.4: 1 based on the amount of compound of formula VIII added. The reaction can be carried out at from-20 ℃ to room temperature, preferably at 0 ℃.
The primary alcohols corresponding to the aldehydes of formula VIII are known or can be prepared from known precursor compounds by methods known per se. For example, primary alcohols can be prepared by reduction methods known per se, for example by reduction from the corresponding free aminocarboxylic acid precursor compounds with a complexed alkali metal hydride, such as lithium aluminum hydride. An aminocarboxylic acid is particularly suitable which is already present in isomerically pure form, for example in enantiomerically pure form, such as the 20 proteinogenic alpha-amino acids known per se to occur in nature. Also commercially available, for example from ChiroTech, Cambridge (catalog "The ChirochemTM Collection,Series1,FMOC unnatom acids for medical and cosmetic chemists ", SCRI P No. 2311/20.02.1998, page 15). For the preparation of compounds of formula I wherein n-1, an appropriate, per se known, isomerically pure β -amino acid may be used as starting material (e.g. from Nohira et al, Japanese chemical Association gazette43(1970)2230 known later). Isomerically pure β -amino acids suitable for use according to the invention can furthermore also be prepared from isomerically pure α -amino acids by homologation, for example by means of Arndt-Eistert homologation according to the method of D, seebach et al (D.Seebach et al, Helvetica Chimica Acta (═ HCA)79(1996) 913-; 2043 p later, and synthetic letters (1997)437 p later). Wherein R is5Alpha-chiral beta-amino acids having other meanings than hydrogen can be obtained by asymmetric alkylation of chiral oxazolidinones with chloromethylamides by methods known per se, for example according to D.Seebach (see D.Seebach et al, synthetic letters (1997) page 437 onwards), or also by other known methods.
The desired protecting group R may be reacted in a manner known per se13Introducing a compound of formula VIII or a precursor compound thereof as described above.
In process step a), the chiral intermediate formed by deprotonation and transmetallization by reaction of a chiral aminoaldehyde of the formula VIII with 2-alkenylsulfimide (2-alkenylsulfoximin) of the formula II gives rise to two new stereogenic carbon atoms in the vinylsulfimide of the formula IX. Such stereogenic carbon atoms are the C-3 and C-4 atoms in the compound of formula IX. Substituent R on C-44And the substituent OM on C-32(OR12)3In the formation of the vinylsulfimides of the formula IX in the process according to the invention, the "counter-orientation" is generally adopted to one another with a high selectivity of at least 95%. The absolute spatial configuration at the newly formed chiral centers C-3 and C-4 is controlled by the absolute spatial configuration at the sulfur atom of the compound of formula II according to regio-and non-stereocontrolled reactions, respectively, when reacting. If the sulfur atom has the R-space configuration in the compounds of the formula II, the prochiral carbonyl group in the aldehyde of the formula VIII is separated from SThe i side is attacked. If, on the other hand, the sulfur atom in the compounds of the formula II has an S-steric configuration, the prochiral carbonyl group in the aldehyde of the formula VIII is attacked from the Re side. The absolute spatial configuration of the compounds of the formula IX determined in this way also determines the stereochemistry of the compounds of the formulae Ia, Ib and Ic as "cis" -oriented at the corresponding chiral centers. The absolute steric configuration at the chiral carbon atom in the aminoaldehyde of formula VIII has little effect on the stereochemistry at the carbon atoms C-3 and C-4 of the compound of formula IX.
The compound of formula IX is protected with a protecting group R13Is treated in process step b) to obtain the compound of formula Xa, which can be carried out directly after process step a) in situ in a manner known per se without the necessity of isolating the compound of formula IX. The reaction can therefore be carried out in the above-indicated solvents and at the above-indicated temperatures, i.e.between-100 ℃ and-50 ℃, preferably-78 ℃. The base-stable protecting group can be cleaved, for example, with non-nucleophilic or weakly nucleophilic organic bases which are soluble in the reaction mixture and are known per se. If the FMOC-group is used as the amino-protecting group R13Piperidine is preferably used as a base for its cleavage. The base is generally added in a superstoichiometric amount, for example in a molar ratio of from about 5: 1 to about 15: 1, preferably about 10: 1, based on the amount of compound of formula IX formed from the compound of formula II added. After the addition of the base has been completed, initially melted at 0 ℃ and thereafter at room temperature, the reaction mixture can be worked up in a customary manner, the by-products formed being separated if necessary by methods known per se, for example by crystallization and/or chromatography.
By amino protecting groups R of compounds of formula IX13Preferably by base-induced cleavage thereof, can cause a ring closure reaction to produce the compound of formula Xa. Especially for R in4The cyclisation of the compound of formula I X, which does not represent hydrogen, is carried out in such a way that the sulfonylimino group in the 5-position of the resulting compound of formula Xa preferably occupies the "trans" position with respect to the hydroxyl group in the 3-position of the resulting ring skeleton.
In the resulting azacycle containing a secondary ring nitrogen atom, this nitrogen atom can then be reacted further with compounds containing groups suitable for reaction with secondary amines in a manner known per se. For example, the nitrogen atom reacts with a carboxylic acid, which is known per se, to form a peptide bond. Likewise, the above-mentioned nitrogen atoms can also be alkylated in a manner known per se, for example by reaction with alkyl halides, such as phenyl lower alkyl halides, for example benzyl chloride. The nitrogen atom can also be blocked by conventional amino-protecting groups, preferably by a base-stable protecting group, in this way or by other methods known per se. It is particularly advantageous if the ring nitrogen atom in the compound of the formula Xa is blocked with a base-stable protecting group, if a compound of the formula Ib is to be prepared. Protective groups capable of urethane formation are preferably used as base-stable protective groups, in particular tert-butoxycarbonyl-protective groups (═ BOC).
From the compounds of the formula Xa, it is also possible, if desired, to selectively re-cleave off protective groups which may be present by methods known per se. Particularly advantageous are silyl protecting groups R which are optionally present after process step b) and which are prepared from compounds of the formula Xa11Cleavage by methods known per se is carried out before reaction with a reagent suitable for reductive cleavage of the sulfonimidoalkyl bond in process step ca), if cleavage of the silyl protecting group in process step b) does not occur spontaneously. As an example of a silyl protecting group which is generally cleaved spontaneously in process step b) without additional work-up, mention may be made of trimethylsilyl (═ TMS).
The compounds of the formula Xa or the compounds obtained from them by cleavage of protecting groups are novel compounds which may have useful properties and can be used, for example, as intermediates for the preparation of the compounds of the formula I. (2S, 3R, 4R, 5R, Ss) -2-benzyl-3-hydroxy-5- { N- [ (S) -1-hydroxy-3-methylbutan-2-yl]-4-methylphenylsulfonyliminomethyl } -4-methyl-1- (4-methylphenylsulfo) pyrrolidine is known from the Internet publication under the addresswww.incr.ac.ukBolte, part C of crystallography, published by electronization, document QA0019[ ═ IUCr) actaC Paper QA0019]. But this is not stated in the publication indicated aboveA method for preparing the compound.
In process step ca) for preparing the compounds of the formula Ib, the reductive cleavage of the sulfonylimino-alkyl bond in the compound of the formula Xa obtained or in a compound obtained from the compound of the formula Xa by reaction on a ring nitrogen atom as described above can be carried out in the polar or weakly polar solvents previously given for the reaction of the compound of the formula II with the compound of the formula VII or in mixtures of these solvents. Tetrahydrofuran is preferably used. The reaction can be carried out at a temperature between-20 ℃ and room temperature, preferably at 0 ℃. For example, the reducing agents Raney nickel, lithium naphthalide (lithium naphthalide) or samarium (II) iodide are suitable as reagents for the cleavage of the sulfonylimino-alkyl bond. Preferably, samarium (II) iodide can be used.
If samarium (II) iodide is used for desulfurization, samarium (II) iodide can be generated in situ from samarium and diiodomethane by methods known per se. Samarium (II) iodide is generally employed in a superstoichiometric amount, for example in a molar ratio of from about 3: 1 to about 7: 1, based on the amount of compound of formula Xa added. To carry out the reaction, a suitable amount of a proton source, such as a protic compound which is soluble in the solvent employed, is added to the mixture consisting of the compound of the formula Xa and samarium (II) iodide. As the proton source, for example, a lower alcohol such as methanol can be used. Preferably, anhydrous methanol is used. An appropriate amount of proton source amounts, for example, to between 2 and 5 equivalents, based on the sulfur equivalents contained in the compound of formula Xa. It is particularly advantageous here to use compounds of the formula Xa in which the secondary ring nitrogen atom is blocked by a carbamate-protecting group, preferably a BOC-protecting group.
In process step ca) for preparing the compound of the formula Ic, under conditions of alkaline-induced reductive elimination, a compound of the formula Xa (in which R is101Not hydrogen), or in a compound obtained from a compound of formula Xa by the above-mentioned reaction on the ring nitrogen atom, in a polar or weakly polar solvent as specified above for the reaction of a compound of formula II with a compound of formula VII, or in a partially halogenated lower alkyl solvent such as dichloromethaneIn an alkane. Dichloromethane is preferably used. Non-nucleophilic organic bases, e.g. bicyclic amidines, e.g. 1, 5-diazabicyclo [4.3.0]-5-nonene (═ DBN) or 1, 8-diazabicyclo [5.4.0]-7-undecene (═ DBU) is suitable as a base for cleaving the sulfonylimino-alkyl bond by β -elimination. Preferably DBU is available. The reaction can be carried out in such a way that the sulfonylimino group of the compound of the formula Xa specified above is activated electrophilically in a manner known per se. For this purpose, the compounds of the formula Xa can be reacted at temperatures between-25 ℃ and-15 ℃ with compounds suitable for forming a good leaving group from the sulfonyl group or with a lower alkyloxonium salt tetrafluoroborate, such as the trimethyloxonium tetrafluoroborate known under the name "Meerwein-salts". Reagents which can form a good leaving group by attack on the sulfonyl group are, for example, esters or halides of sulfonic acids such as methanesulfonyl chloride, trifluoromethanesulfonyl chloride, Methyl trifluoromethanesulfonate (═ Methyl-triflate) or trifluoromethanesulfonyl-trimethylsilyl ester (═ TMS-Trif1 at). Preferably, Methyl-Triflat can be used. The resulting reaction mixture is usually melted at room temperature after the reaction and then the above-mentioned base is obtained.
In the resulting compound of formula Ia, the relative positioning of the sulfonylimino substituent at the 5-position and the hydroxyl group at the 3-position, as present in process step b) of the formation of the compound of formula Xa by ring closure, is determined as the "trans" -positioning of each other. Wherein the substituent YH at the 3-position may represent a hydroxyl group or an amino group and/or wherein the substituent YH at the 3-position and the substituent R at the 5-position1-CHR2The compounds of the formula I which are also able to be positioned "cis" -relative to one another can, if desired, be obtained from the compounds of the formula Ia by one or more nucleophilic substitution reactions carried out in reverse, at the ring carbon atom in the 3-position. Such nucleophilic substitution reactions are known per se and can be carried out, for example, under the conditions of the Mitsunobu-reaction (see, for example, Mitsunobu, et al, for syntheses1(1981)1-28)。
If, for example, a compound of the formula I is desired in which YH represents hydroxyl and in which the substituent OH in the 3-position and the substituent R in the 5-position1-CHR2Are in "cis" -orientation with respect to each other, in such a way thatThe Mitsunobu-reaction is suitably carried out by adding a solution of a compound of the formula Ia, in which the hydroxy group, which may also be present, is blocked with a protecting group, and triphenylphosphine in an organic solvent which is inert under the reaction conditions, such as a cyclic or open-chain lower alkyl ether, for example diethyl ether or tetrahydrofuran, to a pre-addition of a solution of diethyl azodicarboxylate (═ DEAD) and an acid, for example phosphoric acid or a carboxylic acid, for example benzoic acid. The reaction can preferably be carried out at room temperature. The desired ester of the compound of the formula I obtained in this way is, if desired, subsequently cleaved in a manner known per se to give the free hydroxyl group in the 3-position.
If desired, a compound of formula I wherein Y represents NH and wherein the substituent at the 3-position is amino and the substituent at the 5-position is R1-CHR2Which are in "cis" -orientation with respect to each other, is suitably carried out as a Mitsunobu-reaction by adding a solution of DEAD in the above inert solvent to a pre-addition of a solution of triphenylphosphine, a compound of formula Ia, wherein a hydroxy group blocked with a protecting group may also be present, and a suitable reagent for nucleophilic substitution of a hydroxy group by an amino group on an aliphatic group, such as phthalimide. The resulting intermediate, e.g. an N-substituted phthalimide, may then be treated with a reagent suitable for liberating the amine of formula I formed, e.g. hydrazine, in a protic solvent, e.g. a lower alcohol, e.g. ethanol.
If, for example, a compound of the formula I is desired in which Y represents NH and in which the substituent YH in the 3-position and the substituent R in the 5-position1-CHR2In the "trans" -orientation with respect to one another, the abovementioned inversion of the ring carbon atom in the 3-position can be carried out first in the case of a hydroxy substituent in the compounds of the formula Ia indicated above, and the abovementioned hydroxy group can also be substituted by an amino group in the case of a renewed inversion of the ring carbon atom in the 3-position in the intermediates of the formula I.
The compound of the formula I obtained can be isolated from the reaction mixture by methods known per se. Possible protecting groups can, if desired, be cleaved again by methods known per se, optionally with selectivity, and the YH group can, if desired, be blocked by protecting groups known per se. The NH-group liberated in the 1-position of the ring skeleton can, if desired, be reacted with the abovementioned reagents which can be used for N-alkylation or can form amides, or blocked with amino-protecting groups. The compounds of the formula I which, if desired, contain a basic amino group can also be converted into acid addition salts by known methods. Suitable acids are, for example, inorganic acids such as hydrochloric acid or sulfuric acid, or organic acids such as sulfonic acids, for example methanesulfonic acid or p-toluenesulfonic acid, or carboxylic acids, for example acetic acid, trifluoroacetic acid, tartaric acid or citric acid.
The compounds of the formulae Ia, Ib and Ic are novel compounds which provide valuable starting materials, for example for the preparation of chiral catalysts for asymmetric syntheses, for the preparation of biologically active alkaloids or porphyrins and for the preparation of pharmacologically important compounds.
The starting compounds of the formula II can be prepared by methods known per se.
For example compounds of the formula IIa (where R is101,R4,R10,R1101And Ar has the same meaning as above)
Can be prepared by preparing stereoisomers of the compounds of the formula III
Wherein Ar and R10In the same sense, with a compound of the general formula IV,
wherein R is101And R4In the same sense, M1Represents monovalent containing one alkali goldA group of a metal or an alkaline earth metal and a halogen atom, and the hydroxyl group which may be liberated in this reaction is protected with a silyl protecting group R1101And (5) sealing.
The reaction of a stereoisomer of the cyclic sulfonimide salt of formula III (sulfonimide) with a metallated olefin of formula IV to form an isomerically pure 2-alkenylthioimide of formula II can be carried out in the polar or weakly polar aprotic solvent indicated above for the reaction of the compound of formula II with the compound of formula VII. Tetrahydrofuran may be preferably used. The reaction can be carried out by mixing the reactants at a temperature of-100 ℃ to-50 ℃, preferably-78 ℃, in the above-specified solvent, reacting the resulting reaction mixture at the specified temperature in a short time, e.g., 2 to 10 minutes, followed by heating it at a higher temperature lower than room temperature, e.g., -20 ℃ to 0 ℃. If necessary, stirring is continued for a further time at-20 ℃ to 0 ℃ in order to complete the reaction. Advantageously, the compounds of formula IV may be employed in superstoichiometric amounts. For example, 1.5 to 2.5 moles of a compound of formula IV may be reacted with 1 mole of a compound of formula III.
In the cyclic sulfonimide salt of formula III, Ar preferably represents 4-methylphenyl (═ p-tolyl). R20In particular methyl, isopropyl, isobutyl or phenyl, preferably isopropyl.
To achieve a stereochemically controlled preparation of the desired compound of formula I, the sulfonimide salt of formula III should be used in an isomerically pure form. Within the scope of the present invention, isomerically pure is understood to be an isomeric excess (ee enantiomeric excess, or de diastereoisomeric excess) of essentially at least 95% of the pure isomer. In the formulae indicated in the context of the present invention, the symbols "+" (asterisks) indicate a chiral center which is generally isomerically pure or is generally derived from starting materials which are employed isomerically pure. If starting compounds for the preparation of the compounds of the formula I which are nonisomerized, for example racemic, are used, it is of course also possible to obtain isomeric mixtures of the compounds of the formula I according to the preparation process of the invention. If a sulfonimide salt of the formula III in which the chiral sulfur atom and the substituent R are present is used10Have different chiral carbon atomsAbsolute configuration (i.e. with the substituent R if the sulfur atom has, for example, the R-configuration10Having the S-configuration) a product of formula I with particularly good stereochemical purity can be achieved. Particular preference is given to the use of (R)s) -4(R) -isopropyl-2-p-tolyl-4, 5-dihydro- [1, 2. lambda6,3]Oxathiazole-2-oxide and (S)s) - (4R) -isopropyl-2-p-tolyl-4, 5-dihydro- [1, 2. lambda6,3]Oxathiazole-2-oxide as compound of formula III. Label RsAnd SsEach represents an absolute configuration on a chiral sulfur atom. Sulfonylimide salts of formula III are, for example, tetrahedrally communicated from Reggelin et al (═ TL)33(1992)6959-6962 or from Reggelin et al, TL36(1995)5885-5886 and the isomerically pure sulphonylimide salts can be prepared in a manner which is specified in each of these documents or analogously thereto.
In the metallized compounds of the formula IV, a monovalent radical M1Denotes an alkali metal, preferably lithium, or a group containing an alkaline earth metal and an additional halogen atom. Magnesium is preferred as the alkaline earth metal. As halogen, chlorine, bromine or iodine can be used. As the metallated compound of formula IV, a lithiated alkenyl compound known per se or an organomagnesium alkenyl compound known per se, such as an alkenyl-Grignard (Grignard) reagent, may be used.
In general, the hydroxyl group which can be liberated in the reaction of the compounds of the formula III with the compounds of the formula IV to give compounds of the formula IIa is protected with the appropriate silyl-protecting group R1101Blocking to prevent unwanted further reaction. As silyl protecting group R in the compounds of the formula IIa1101Preferably, trimethylsilyl (═ TMS) can be used.
A compound of the general formula IIb,
wherein R is101,R10,R1101And Ar is as defined above and a represents a methylene group orRepresents a C2-C5Alkylene chain which may be interrupted by C, optionally substituted once or twice by lower alkyl1-C2Alkylene bridging, the compounds of the formula IIb can be prepared by reacting one stereoisomer of the compound of the formula V,
wherein R is10,R1101And Ar has the meaning given above, deprotonating it with a suitable base for its deprotonation, reacting the deprotonated compound of the formula V with a compound of the general formula VI in which a has the meaning given above,
the intermediate obtained is treated in turn with a reagent enabling the cleavage of the oxygen atom deriving from the carbonyl group of the compound of formula VI and with a base suitable for deprotonation of the compound of formula V, as described above.
The reaction sequence for the preparation of the cycloalkenylmethyl-sulfoximine compound of the formula IIb by reacting a compound of the formula V with a compound of the formula VI can be carried out in a one-pot reaction sequence. The reaction of stereoisomers of formula V methylsulfimides with a base suitable for deprotonation thereof and subsequent reaction steps are known and can be described in Reggelin et al, JACS118(1996)4765-4777 or the like, the subsequent reaction steps being: reaction of the deprotonated compound of formula V with a compound of formula VI; the intermediate obtained is treated with a reagent enabling the cleavage of the oxygen atom deriving from the carbonyl group of the compound of formula VI; further treatment with the previously specified base. Ar group and substituent R in the compound of formula V10May have the meanings previously indicated for preference for compounds of the formula III. Silyl protecting group R in the compound of formula V1101Tert-butyldimethylsilyl (═ TBS) may be preferably used. With preferred stereochemical strips as previously specified for the compounds of formula IIIAnalogously, the compound of the formula V may preferably be used as [ S ]s,N(1S)]-N- [1- [ [ tert-butyldimethylsilyl ] group]Oxy radical]Methyl radical]-2-methylpropyl]-S-methyl-S- (4-methylphenyl) sulfimide and [ Rs,N(1R)]-N- [1- [ [ tert-butyldimethylsilyl ] group]Oxy radical]Methyl radical]-2-methylpropyl]-S-methyl-S- (4-methylphenyl) sulfimide. For example, lithiated lower alkyl compounds such as n-butyllithium are suitable as bases for deprotonation of compounds of formula V. As reagents enabling cleavage of the oxygen atom derived from the carbonyl group in the compound of formula VI, the compounds mentioned above for the formation of a good leaving group by attack on the oxygen atom in the sulfonyl group on the compound of formula Xa are suitable, TMS-Triflat may preferably be used.
Alicyclic ketones of the formula VI are known, it being possible, for example, to use cyclopentanone, cyclohexanone or nopinone as compounds of the formula VI. If bridged cyclic ketones are used as compounds of the formula VI, it is advantageous if the bridged alkylene chain is attached to at least one of the two carbon atoms which are in the alpha-position to the carbonyl group. In this way, the reaction product is always formed with controlled regioselectivity.
Another possibility for obtaining compounds of the formula IIb is to subject the compounds of the formula XII,
wherein a and Ph are as defined above, are each reacted with a reagent suitable for their lithiating diselenation, and the respectively formed diselenated and lithiated intermediate is subsequently reacted with a stereoisomer of the compound of the formula III.
The selenized compounds of formula XII can be obtained from the corresponding allylic alcohols by halogenation and subsequent reductive selenization using methods known per se. For example, a compound of formula XII can be prepared according to Reggelin et al, JACS118(1996)4765 and 4777 or similar methods. As an example of an allyl alcohol suitable for preparing the selenized compounds of the formula XII, mention may be made of Myrtenol (Myrtenol).
The compounds of formula IIb can be prepared by reacting a compound of formula XII with a compound of formula III by methods known per se, e.g. as disclosed in JACS by Reggelin et al118(1996)4765-4777, which are incorporated herein by reference.
The compounds of formula II, wherein R is101And does not represent hydrogen. In the process, wherein R101A compound of the formula II, which represents hydrogen, is deprotonated once with a suitable base and subsequently alkylated by reaction with a compound of the formula XI,
R103-Z XI
wherein R is103With respect to R101Given the meaning, but with the exception of hydrogen, Z represents a cleavable escape group (Flucht gruppe). For example, lithiated lower alkyl compounds such as n-butyllithium may be suitable as the base required for deprotonation as specified above. For example, halogen, preferably bromine or chlorine, can be used as cleavable leaving group Z in the compound of formula XI. The reaction can be carried out under reaction conditions customary for this type of reaction.
The following examples further illustrate the invention but are not intended to limit its scope.
The numbering of the ring atoms, in particular the chiral carbon atoms, in the example compounds is relevant to the numbering of the ring atoms specified in formula I.
Example 1
(+) - (2S, 3S, 4S, 5S) -2-isobutyl-3-hydroxy-4, 5-dimethyl-N-tert-butoxycarbonyl-pyrrolidine
A) 6.0g of FMOC-amino-protected S-2-amino-4-methylpentanol (obtained by lithium aluminium hydride-reduction of leucine) are suspended in 100ml of dichloromethane under nitrogen and with exclusion of water and cooled at 0 ℃. To this pre-addition was added 10.0g of solid 1, 1, 1-triacetoxy-1, 1-dihydro-1, 2-benzosulfon ol-3 (1H) -one (═ Periodinan) in one portion and the resulting reaction mixture was stirred at room temperature for 2 hours. The reaction mixture is subsequently poured into a solution of 130ml of 10% aqueous sodium thiosulfate and 360ml of saturated aqueous sodium bicarbonate, covered with 100ml of diethyl ether. The aqueous phase is extracted once with 100ml of diethyl ether and the combined organic phases are washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the crude FMOC-protected S-2-amino-4-methylpentanal obtained in this way was used in the following reaction without further purification.
To determine the optical purity, a portion of the resulting aldehyde was crystallized in ether/hexane for isolation. Adding chiral Schiff reagent tri- [3- (heptafluoropropyl-hydroxy methylene) -d-camphorate (camphorato) -praseodymium (III) [ ═ Pr (hfc)3]The enantiomeric excess was determined by NMR spectroscopy under the conditions of (1). By integrating the off-baseline signal of the aldehyde proton, the enantiomeric excess (ee) was calculated to be at most 95%.
B) 1.82g of magnesium turnings were covered with about 10ml of diethyl ether and activated by adding 500mg of freshly distilled crotyl bromide. To this pre-adduct was added dropwise a solution of 10.0g crotyl bromide (═ cis/trans-1-bromo-2-butene) in 100ml diethyl ether (slowly dropwise addition at 0 ℃ under argon protection and with exclusion of moisture). The mixture formed after the addition was heated to boiling for a further 30 minutes. The solution of crotyl magnesium bromide in ether thus formed is separated from the unreacted magnesium and continues the reaction in solution without further treatment.
To determine the content of the Grignard solution prepared above, a solution of 180mg of (-) -menthol with a spatula tip of phenanthroline in 3.0ml of tetrahydrofuran was cooled to 0 ℃. Titration to a color change of red was carried out by adding a grignard solution to this preparation, and the amount of grignard solution required for the following reaction was calculated with the difference in weight (diferenzwagung). The content of the grignard-solution is obtained from the quotient of the weighed amount of menthol in mmol and the mass of the grignard-solution in g required for titration to a color change, expressed in mmol/g.
C) A solution of 46g of the previously obtained crotyl magnesium bromide in 100ml of diethyl ether under argon and with exclusion of moisture was added dropwise to 2.3g of (+) - (R) cooled to-40 deg.Cs) -4(R) -isopropyl-2-p-tolyl-4, 5-dihydro [1, 2. lambda6,3]A solution of oxathiazole-2-oxide in 40ml of tetrahydrofuran. After the addition was complete, the reaction mixture was stirred at the given temperature for a further 5 minutes before warming to 0 ℃. Stirring was continued at this temperature for 45 minutes, then 50ml of saturated aqueous ammonium chloride solution were added. The organic phase was separated, the aqueous phase was extracted twice with diethyl ether and the combined organic phases were dried over sodium sulfate. The solvent is subsequently evaporated under reduced pressure and the residue is chromatographed on silica gel (mobile phase: starting from ethyl acetate/n-hexane 1: 3v/v, the composition changing continuously to 3: 1). Yield 1.4g (R)s1R) -N- [1- (hydroxymethyl) -2-methylpropyl]-S- (2-butenyl) -p-toluenesulfonimide as a colorless oil, IR (thin film) ═ 3440, 1220, 1115cm-1Optical rotation value [ alpha ]]D 20+3.3 ° (c ═ 0.5 in dichloromethane). D) To a solution of 1.4g of the above-obtained sulfimide and 0.7ml of ethyldimethylamine in 13ml of dichloromethane cooled to 0 ℃ under an argon atmosphere and under moisture barrier, 0.6ml of chlorotrimethylsilane was added dropwise. After the addition was complete, stirring was continued at 0 ℃ for a further 15 minutes. Subsequently, it was melted at room temperature, and after completion of the reaction, the reaction mixture was poured into a mixture consisting of 25ml of diethyl ether and 25g of ice. The aqueous phase is extracted three times with 10ml of diethyl ether each, and the organic phases are collected and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue left was purified by chromatography on silica gel (mobile phase: ether/n-hexane 1: 1 v/v). 1.75g (+) - (R) was obtaineds1R) -N- [1- (trimethyl-silyloxymethylpropyl) -2-methyl]-S- (2-butenyl) -p-toluene-thioimide as colorless oil, IR (thin film) ═ 1240, 1080, 840cm-1Optical rotation value [ alpha ]]D 20+15.5 ° (c ═ 1.0 in dichloromethane).
E) A solution of 1.47g of the TMS-protected 2-alkenylthioimide obtained above in 8ml of toluene was cooled at-78 ℃,and mixed under argon with exclusion of water with 2.75ml of a 1.6 molar solution of n-butyllithium in n-hexane. The reaction mixture was stirred at the indicated temperature for 15 minutes, to which was subsequently added 4.8ml of a 1 molar solution of titanium chlorotris (i-propoxy) in n-hexane. Stirring was continued for a further 5 minutes at-78 deg.C, thawing at 0 deg.C and stirring for a further 30 minutes at 0 deg.C. The reaction mixture was then cooled again to-78 ℃. To this preparation was added a solution of 2.8g of the aminoaldehyde previously obtained in A) in 8ml of tetrahydrofuran. Stirring was continued for a further 60 minutes at-78 ℃ and 4ml of piperidine were added and the temperature was allowed to rise to 0 ℃. After 10 hours, the reaction mixture is poured into 120ml of a strongly stirred saturated ammonium carbonate solution covered with 12ml of ethyl acetate (═ EE). The mixture was stirred for 30 minutes, followed by phase separation. The organic phase is washed with 40ml of saturated sodium chloride solution and the combined aqueous phases are extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue which remains is taken up in a suspension of 0.6g of potassium carbonate in 10ml of methanol and stirred for 60 minutes. Undissolved potassium carbonate was then filtered off from it and the filtrate was cooled to 4 ℃. The precipitated solid was filtered, washed with a small amount of cold methanol at 4 ℃ and the filtrate was evaporated under reduced pressure. The resulting residue was taken up in 5ml of toluene and filtered over silica gel (mobile phase: initially diethyl ether/hexane 1: 3v/v, then ethyl acetate). The polar pyrrolidine-containing fraction was concentrated and taken up in 4ml dioxane. To the preform was added 1.0g of di-tert-butyldicarbonate (═ BOC)2O) and 0.7g of sodium bicarbonate in 8ml of water. The mixture was stirred for 10 hours, the solvent was evaporated under reduced pressure and the residue left behind was partitioned between 5ml of water and 10ml of diethyl ether. The aqueous phase was extracted 3 times with diethyl ether and the combined organic phases were dried over sodium sulfate. After re-evaporation of the solvent under reduced pressure, the residue obtained is purified by chromatography on silica gel (mobile phase: ether/hexane 3: 1 v/v). Yield 1.0g (R)s1 'R, 2S, 3S, 4S, 5R) -N' - [ (1-hydroxymethyl) -2- (methyl-propyl)]-S-4-hydroxy-3-methyl-2- (4-methylphenylsulfonyliminomethyl) -5-isobutyl-N-tert-butoxycarbonyl-pyrrolidine as a colorless foam, in optical rotation (. alpha.) - []D 20=-4Degree (c ═ 0.1 in dichloromethane), IR (film) ═ 3419, 1674, 1256, 1097cm-1. F) To a suspension of 1.67g of samarium in 40ml of tetrahydrofuran, cooled to 0 ℃, a total of 2.4g of diiodomethane was added dropwise. The reaction mixture was stirred at 0 ℃ for 15 minutes after the addition was complete before melting at room temperature. Stirring was continued at room temperature for 60 minutes more, and then a solution of 1.0g of the previously obtained 2-sulfonyliminomethyl compound in a mixture of 1.2ml of methanol and 2.5ml of tetrahydrofuran was added thereto. The reaction mixture was stirred for 4 hours and then 110ml of saturated aqueous ammonium chloride solution were added. After the first phase separation, the aqueous phase was added dropwise with 0.5N aqueous hydrochloric acid until the aqueous phase became clear. The aqueous phase was extracted three times with diethyl ether. The combined organic phases were dried over sodium sulfate and the solvent was evaporated off under reduced pressure. Chromatography of the remaining residue on silica gel (mobile phase: ether/n-hexane 3: 1v/v) afforded 0.5g of the title compound as a colourless solid with a melting point of 97 ℃ and an optical rotation [ α ], (ii)]D 20+66 ° (c ═ 1.0 in dichloromethane).
Example 2:
(+) - (2S, 3S, 4S, 5R) -3-hydroxy-5-methyl-2-phenyl- (1-aza-N-tert-butoxycarbonyl) -bicyclo [3.3.0] -octane
A) To 3.98g of (+) -R cooled to-78 deg.Cs-4R-isopropyl-2-p-tolyl-4, 5-dihydro [1, 2. lambda6,3]A solution of oxathiazole-2-oxide in 40ml of tetrahydrofuran was added dropwise under argon and moisture barrier to a solution of 16.6ml of 1.6 molar methyllithium in hexane. The reaction mixture was stirred at the indicated temperature for a further 5 minutes after the addition was complete before warming to 0 ℃. Stirring was continued at this temperature for a further 45 minutes, then 160ml of ammonium chloride were added. After separation of the organic phase, the aqueous phase is extracted twice with 20ml of diethyl ether and the combined organic phases are dried over sodium sulfate. The solvent was then evaporated under reduced pressure. The residue was dissolved in 80ml of methylene chloride at room temperature, and 3.8g of t-butyl-dimethylsilyl chloride, 0.6g N, N-dimethylaminopyridine and 2.4g of ethyl-dimethylamine were added and stirred for 18 hours. The mixture is then poured into 40ml of ice-water, the organic phase is separated off,the aqueous phases are extracted three times with in each case 20ml of dichloromethane. After the combined organic phases were dried over sodium sulfate, the solvent was evaporated under reduced pressure. The residue was purified on silica gel (mobile phase: ether/hexane ═ 1: 1v/v) to give 6.0g (-) -Rs-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) -methyl-2-methylpropyl]-S-methyl-S- (4-methylphenyl) sulfimide as a colorless oil with an optical rotation value [ alpha ]]D 20-43.2 ° (c ═ 0.8 in dichloromethane); IR 1230 cm (film)-1。
B) To a solution of 6.5g of the previously obtained methylsulfimides in 45ml of toluene cooled to-78 ℃ under argon protection and moisture barrier was added dropwise a solution of 12.45ml of 1.6 mol n-butyllithium in n-hexane. Stirring was carried out at the indicated temperature for 15 minutes, followed by dropwise addition of 2.2g of undiluted cyclopentanone. After 10 minutes, the reaction mixture was warmed to room temperature. Stirring was continued at this temperature for 30 minutes, after which the reaction was cooled to-78 ℃ and 9.2g of trimethylsilyl trifluoromethanesulfonate were added dropwise. After 5 minutes, the temperature was raised to room temperature and stirring was continued for 3 hours. Thereafter, the mixture was cooled again to-78 ℃ and 24.9ml of a 1.6 molar solution of n-butyllithium in n-hexane were added dropwise. After stirring at the given temperature for 3 minutes, it was allowed to melt at room temperature and stirred for another 18 hours. The reaction mixture is poured into 160ml of saturated aqueous ammonium chloride solution, extracted twice with acetate and the combined organic phases are dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue left behind was purified over silica gel (mobile phase: ether/n-hexane 1: 6 v/v). 5.5g of (-) -R are obtaineds-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) methyl-2-methylpropyl]-S-cyclopent-1-en-1-ylmethyl) -S- (4-methyl-phenyl) sulfimide as a colorless oil with an optical rotation value [ alpha ]]D 202.5 ° (c 1.6 in dichloromethane), 1240 cm (film) IR (1120 cm)-1。
C) 2.95g of the cyclopentenylsulfimide solution obtained above in 21ml of toluene were mixed with 4.8ml of a 1.6 mol solution of n-butyllithium in n-hexane, 8.3ml of a 1 mol solution of titanium chlorotris (i-propoxy) in n-hexane by the method described above in 1E)A solution of 5.0g FMOC-protected S-. alpha. -aminophenylethane in 40ml tetrahydrofuran was reacted with 7ml piperidine. Chromatography on silica gel (mobile phase: ether/hexane ═ 1: 3v/v) gives 3.9g of (2S, 3S, 4S, 5R) -Rs-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5- (4-methylphenylsulfonyliminomethyl-2-azabicyclo [3.3.0]Octane. Optical rotation value [ alpha ]]D 20+2.8 °, (c ═ 0.6 in dichloromethane); IR (film) ═ 3443, 1251, 1103, 835cm-1。
D) To a solution of 3.9g of the bicyclic substance (Bricyclus) obtained above in 20ml of methylene chloride and 40ml of water were added 0.45g of sodium hydrogencarbonate and 3.0g of di-tert-butyl-dicarbonate and stirred for 12 hours. After evaporation of the solvent under reduced pressure, the residue obtained is partitioned between 5ml of water and 10ml of diethyl ether. The organic phase was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases are dried over sodium sulfate, the solvent is evaporated off under reduced pressure and the residue obtained is purified by chromatography on silica gel (mobile phase: ether/hexane ═ 1: 1v/v) to give 4.39g (-) - (2S, 3S, 4S, 5S) - (-R)s-N (1R) -N- [1- (tert-butyldimethylsilyl) oxy]Methyl-2-methylpropyl) -3-hydroxy-2-phenyl-5- (4-methylphenylsulfanyliminomethyl-2-aza- (N-tert-butoxycarbonyl) -bicyclo [3.3.0]Octane. Optical rotation value [ alpha ]]D 20-6.2 ° (c ═ 0.9 in dichloromethane); IR (film) ═ 3473, 1682, 1253, 837cm-1。
E) A solution of 0.42g of the bicyclic substance protected with nitrogen previously obtained in 6ml of THF was cooled to 0 ℃ and then mixed with 0.25g of tetrabutylammonium fluoride, and after 15 minutes, it was warmed to room temperature and then stirred for another 12 hours. The reaction mixture is poured into 10ml of water covered with 5ml of diethyl ether. After separation of the organic phase, the aqueous phase is extracted three times with diethyl ether, the combined organic phases are dried over sodium sulfate and the solvent is evaporated off under reduced pressure. Chromatography on silica gel (mobile phase: acetate/n-hexane ═ 1: 1v/v) gave 0.35g (-) - (2S, 3S, 4S, 5S) -Rs-N (1R) -N- [1- (hydroxymethyl) -2-methylpropyl]-3-hydroxy-2-phenyl-5- (4-methyl)Phenylsulfonyliminomethyl-2-aza- (N-tert-butoxycarbonyl) -bicyclo [3.3.0]Octane. [ alpha ] to]D 20-14.1 ° (c ═ 2.7 in dichloromethane); IR (film) ═ 3473, 1681, 1252cm-1。
F) To a suspension of 0.56g samarium in 13ml tetrahydrofuran cooled to 0 ℃ was added a total of 0.84g diiodomethane drop by drop. After the addition was complete, the reaction mixture was stirred at the given temperature for 15 minutes before melting at room temperature. Stirring was continued for a further 60 minutes, after which 0.28g of the N-BOC-5-sulfonylimino-compound obtained above in a mixture of 1ml of methanol and 2ml of tetrahydrofuran was added. The reaction mixture was stirred for 4 hours and then poured into 110ml of saturated ammonium chloride solution. After separation of the organic phase, 0.5N hydrochloric acid solution was added to the aqueous phase until the suspension was clear. The clear aqueous phase was extracted twice with diethyl ether, the combined organic phases were dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The residue which remains is chromatographed on silica gel (mobile phase: ether/n-hexane: 1: 4v/v) to give 0.11g of the title compound as a colourless solid at 176.8 ℃ [ α ]]D 20+50.7 ° (c ═ 0.56 in dichloromethane); IR (film) ═ 3439, 1661cm-1。
Example 3
(+) - (2S, 3R, 4R, 5S) -3-hydroxy-5-methyl-2-phenyl-1-aza- (N-tert-butoxycarbonyl) -bicyclo [3.3.0] octane
A)6.3g(-)-Ss-4R-isopropyl-2-p-tolyl-4, 5-dihydro [1, 2. lambda6,3]The oxathiazole-2-oxide was reacted with 6.03g of tert-butyldimethylsilyl chloride in a manner corresponding to that described in example 2A). 8.7g of (+) -S are obtaineds-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) methyl-2-methylpropyl]-S-methyl-S- (4-methylphenyl) sulfimide as a colorless oil with an optical rotation value [ alpha ]]D 2D89.9 ° (c 1.0 in dichloromethane), IR (film): 1251, 1134cm-1。
B) For the method described above in 2B)Method 8.04g of the previously obtained solution of methylsulfimide in 65ml of tetrahydrofuran are reacted with 16.3ml of a 1.6 molar solution of n-butyllithium in n-hexane, 3.1ml of cyclopentanone, 9.83ml of trimethylsilyltrifluoromethanesulfonate and a further 27.19ml of a 1.6 molar solution of n-butyllithium in n-hexane. Chromatography on silica gel (mobile phase: ether/n-hexane ═ 1: 6v/v) gave 7.057g (+) Ss-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) -methyl-2-methylpropyl]-S-cyclopent-1-en-1-ylmethyl) -S- (4-methylphenyl) sulfimide as a colorless oil with an optical rotation value [ alpha ]]D 2054.7 ° (c 1.35 in dichloromethane), 1251, 1131cm IR (film)-1。
C) 3.17g of the cyclopentenylsulftimide solution obtained above in 22ml of toluene were reacted with 5.6ml of a 1.6 molar solution of n-butyllithium in n-hexane, 11.2ml of 1 molar solution of chlorotris (isopropoxy) titanium in n-hexane, 4.0g of FMOC-protected S-. alpha. -aminophenylethanol solution in 20ml of tetrahydrofuran and 7.4m l of piperidine by the method described above in 1E). Chromatography on silica gel (mobile phase: ether/hexane ═ 1: 1v/v) gives 2.4g of (2S, 3R, 4R, 5S) -Ss-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5 (4-methyl-phenylsulfonyliminomethyl-2-azabicyclo [ 3.3.0)]Octane.
D) To a solution of 1.58g of the bicyclic substance obtained above in 17ml of dioxane and 4ml of water were added 0.35g of sodium hydrogencarbonate and 1.21g of di-tert-butyl dicarbonate, followed by stirring for 12 hours. After evaporation of the solvent under reduced pressure, the residue obtained was partitioned between 5ml of water and 10ml of diethyl ether. The organic phase was separated and the aqueous phase was extracted twice with diethyl ether. The combined organic phases were dried over sodium sulfate, the solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (mobile phase: ether/hexane ═ 1: 1v/v) to give 1.52g of (+) - (2S, 3R, 4R, 5S) -Ss-N (1R) -N- [1- ((tert-butyldimethylsilyl) oxy) methyl-2-methylpropyl]-3-hydroxy-2-phenyl-5- (4-methylphenylsulfonyliminomethyl- (2-aza-N-tert-butoxycarbonyl) -bisCyclo [3.3.0]Octane, optical rotation value [ alpha ]]D 20+63.2 ° (c ═ 1.0 in dichloromethane); IR (film) ═ 3473, 1694, 1254, 836cm-1。
E) A solution of 1.52g of the bicyclic substance obtained above, protected with nitrogen, in 14ml of tetrahydrofuran, cooled to 0 ℃ is mixed with 1.43g of tetrabutylammonium fluoride, warmed to room temperature after 15 minutes and then stirred for a further 12 hours. The reaction mixture was poured into 30ml of water covered with 20ml of diethyl ether. After separation of the organic phase, the aqueous phase is extracted three times with diethyl ether, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. Chromatography on silica gel (mobile phase: acetate/hexane ═ 1: 3v/v) gave 0.96g (+) - (2S, 3R, 4R, 5S) -Ss-N (1R) -N- [ 1-hydroxymethyl-2-methylpropyl]-3-hydroxy-2-phenyl-5 (4-methylphenylsulfonyliminomethyl- (2-aza-N-tert-butoxycarbonyl) -bicyclo [3.3.0]Octane, optical rotation value [ alpha ]]D 20+54.3 ° (c ═ 1.03 in dichloromethane); IR (film) ═ 3446, 1690, 1239cm-1。
F) 3.4g of diiodomethane were added to a solution of 2.04g of samarium in 95ml of tetrahydrofuran at room temperature and allowed to stir for 60 minutes. Then 0.955g of the previously obtained 5-sulfonylimino-compound in a mixture of 1.7ml of methanol and 3.4ml of tetrahydrofuran are added. The reaction mixture was stirred for 16 hours and then poured into 100ml of water. To this mixture was added 0.5N hydrochloric acid solution until the suspension became clear. The phases were separated, the aqueous phase was extracted twice with diethyl ether, the combined organic phases were dried over sodium sulfate and the solvent was evaporated off under reduced pressure. The residue which remained was chromatographed on silica gel (mobile phase: ether/n-hexane ═ 1: 3v/v) to give 0.43g of the title compound as a colorless solid oil (foam), optically active value [ α [. alpha. ]]D 20+34.5 ° (c ═ 1.01 in dichloromethane); IR (film) ═ 3447, 1669cm-1。
Example 4
(-) - (2S, 3R, 4R, 5S) -3-hydroxy-5-methyl-2-phenyl-1-azabicyclo [3.3.0] octane
205mg of (+) - (2S, 3R, 4R, 5S) -3-hydroxy-5-methyl-2-phenyl-1-aza- (N-tert-butoxycarbonyl) -bicyclo (3.3.0) octane (preparation see example 3) were dissolved under argon protection and with exclusion of moisture in a mixture of 1.61ml of a 4.0M solution of chlorotrimethylsilane in dichloromethane and 4.84ml of a 4.0M solution of phenol in dichloromethane, and the added mixture was stirred at room temperature for 20 minutes. The organic phase is subsequently separated off by pouring into 10ml of 10% aqueous caustic soda, the aqueous phase is washed twice with 5ml of dichloromethane and extracted once with 5ml of diethyl ether, and the combined organic phases are dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified over silica gel (mobile phase: acetate/n-hexane 10: 1v/v) to give 113mg of the title compound as crystals having a melting point of 84.5 ℃ and an optical rotation (. alpha.) [ alpha. ]]D 20-46.4 ° (c ═ 1.04 in dichloromethane).
Example 5
(+) - (2S, 3S, 4R, 5S) -3-amino-5-methyl-2-phenyl-1-aza- (N-tert-butoxycarbonyl) -bicyclo [3.3.0] octane
A) To a solution of 200mg (-) - (2S, 3R, 4R, 5S) -3-hydroxy-5-methyl-2-phenyl-1-azabicyclo [3.3.0] octane in 1.5ml tetrahydrofuran were added 241mg triphenylphosphine and 135mg phthalimide at room temperature under an argon atmosphere and with exclusion of moisture. Then 0.14ml of DEAD was added over 2 minutes. After a reaction time of 10 hours, the solvent was evaporated under reduced pressure and the residue was taken up in 15ml of diethyl ether. After insoluble residue was filtered off and the solvent was evaporated under reduced pressure, a crude product of (2S, 3S, 4R, 5S) -5-methyl-2-phenyl-3-phthalimido-1-azabicyclo [3.3.0] octane was obtained, which was used in the following reaction without further purification.
B) 174mg of the crude product obtained above were dissolved in 3ml of dioxane. To this pre-charge were added 220mg of di-tert-butyldicarbonate and 63mg of sodium hydrogencarbonate and 0.5ml of water, and the resulting mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue left was taken up in water and diethyl ether. The two phases are separated and the aqueous phase is extracted twice with 5ml of diethyl ether each. The combined organic phases were dried over magnesium sulfate before the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase: ether/N-hexane 1: 3v/v) to give 115mg of (2S, 3S, 4R, 5S) -5-methyl-2-phenyl-3-phthalimido-1-aza- (N-tert-butoxycarbonyl) bicyclo [3.3.0] octane as an oil.
C) 115mg of the phthalimido-bicyclo [3.3.0] obtained above were added]A solution of octane in 2ml of ethanol is mixed with 400mg of hydrazine hydrate (24%), and the mixture thus formed is heated under reflux for 8 hours. The solvent was evaporated under reduced pressure, the residue left behind was taken up in 10ml of diethyl ether and the organic phase was extracted with 10ml of 10% aqueous caustic soda solution. The aqueous phases are extracted twice with 10ml of diethyl ether each, and the combined organic phases are dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 74mg of the title compound as crystals having a melting point of 92.1 ℃, [ α ]]D 20+24.1 ° (c ═ 1.0 in dichloromethane).
The compounds of formula I indicated in the following table can also be prepared according to the above-described process.
The following abbreviations are used in the tables:
i-Bu ═ isobutyl
Bn ═ benzyl
BOC ═ tert-butoxycarbonyl
TBOM ═ tert-butoxymethyl
Ph ═ phenyl
z-decomposition under heating
N.n blank (or none)
Example No. 2 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8 | R9 | Absolute configuration at C-atom | Y | n | Melting Point [. degree.C. ]] | [α]D 20 | ||||
2 | 2a | 3 | 4 | 5 | ||||||||||||||
6 | N.N. | |||||||||||||||||
7 | H | H | H | H | - | - | H | Bn | BOC | S | - | R | - | R | O | 0 | 108.5 | -37.7 |
8 | H | H | H | H | - | - | H | i-Bu | BOC | S | - | R | - | R | O | 0 | Oil | +28.2 |
9 | H | H | H | H | - | - | H | TBOM | BOC | S | - | R | - | R | O | 0 | 115.7 | +24.5 |
10 | H | H | H | CH3 | - | - | H | Bn | BOC | S | - | R | R | R | O | 0 | 127.8 | -37.3 |
11 | H | H | H | CH3 | - | - | H | TBOM | BOC | S | - | R | R | R | O | 0 | Oil | +14.8 |
12 | H | H | H | H | - | - | H | Bn | BOC | S | - | S | - | S | O | 0 | 107.7 | +6.5 |
13 | H | H | H | H | - | - | H | i-Bu | BOC | S | - | S | - | S | O | 0 | Oil | -37.3 |
14 | H | H | H | H | - | - | H | TBOM | BOC | S | - | S | - | S | O | 0 | 93.1 | +1.8 |
15 | H | H | H | CH3 | - | - | H | Bn | BOC | S | - | S | S | S | O | 0 | 91.0 | +26.7 |
16 | H | H | H | CH3 | - | - | H | i-Bu | BOC | S | - | R | R | R | O | 0 | 97.0 | -20.0 |
17 | H | H | H | CH3 | - | - | H | TBOM | BOC | S | - | S | R | S | O | 0 | 187.2 | -20.8 |
18 | H | H | -(CH2)3- | - | - | H | Bn | BOC | S | - | R | R | S | O | 0 | 136.7 | +8.2 | |
19 | H | H | -(CH2)3- | - | - | H | Bn | H | S | - | R | R | S | O | 0 | 117.2 | -60.7 | |
20 | H | H | -(CH2)3- | H | H | H | H | H | - | - | S | R | S | O | 1 | |||
21 | H | H | -(CH2)4- | H | H | H | H | H | - | - | S | R | S | O | 1 | |||
22 | H | H | -(CH2)3- | =CH-CH=CH-CH= | H | - | - | R | R | S | O | 1 | ||||||
23 | H | H | -(CH2)3- | - | - | H | Bn | BOC | S | - | S | S | S | NH | 0 | 94.6 | +48.9 | |
24 | H | H | -(CH2)3- | - | - | H | Bn | H | S | - | S | S | S | NH | 0 | HCl-salt (Z.) | ||
25 | H | H | -(CH2)3- | H | H | H | H | BOC | - | - | S | R | S | O | 1 | Oil | -17.7 | |
26 | H | H | -(CH2)4- | H | H | H | H | BOC | - | - | S | R | S | O | 1 | Oil | -19.8 |
Claims (16)
1. Controlled stereochemical process for the preparation of compounds of formula I and their acid addition salts
Wherein R is at the 5-position of the cyclic skeleton1R2The CH-group and the hydroxyl group in the 3-position of the cyclic skeleton are each in trans position to one another, and wherein the substituent R in the 4-position of the cyclic skeleton4And the hydroxyl groups in the 3-position of the cyclic skeleton are each in cis position to each other,
and wherein
n represents a number of 0 or 1,
R1represents hydrogen, C1-C6Alkyl or phenyl which is substituted once to three times, if necessary, on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy-C1-6-an alkyl group,
R2represents hydrogen, or
R1And R2Together represent a doubly-bound methylene group which may be substituted by C1-5Alkyl or phenyl which is substituted once to three times, if necessary, on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy-C1-5-an alkyl substitution,
R3represents hydrogen, and
R4represents hydrogen, lower alkyl or phenyl lower alkyl which is substituted, if desired, on the phenyl ring one or more times by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or
R3And R4Together represent a C2Alkylene chains or C containing 1 to 3 double bonds as required3-6Alkylene chain, which may be substituted once or twice by lower alkyl if desired1-2An alkylene bridge, and a nitrogen bridge,
R5represents hydrogen, lower alkyl, hydroxy, lower alkoxy or phenyl lower alkyl each of which is substituted, if desired, once to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or represents phenyl lower alkoxy, and
R6represents hydrogen, and
R7represents hydrogen, and
R8represents hydrogen; a cyano group; carboxyl groups optionally esterified with: cycloaliphatic or straight-chain or branched aliphatic C optionally containing one to three double bonds1-C6-alkanols, which are phenyl lower alkanols substituted, if necessary, one to three times by halogen or lower alkoxy, or, if necessary, one to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy; if necessary at the nitrogen atomC last substituted once to three times by halogen or lower alkoxy3-C8Cycloalkyl lower alkanoyl or straight or branched aliphatic C1-C6Alkanoyl or carbonylamino substituted by phenyl lower alkanoyl substituted, if appropriate, once to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or C substituted, if appropriate, once or twice on the nitrogen atom, by halogen or lower alkoxy each once to three times3-C8Cycloalkyl lower alkyl or straight or branched aliphatic C1-C6-alkyl, or carbonylamino substituted by phenyl lower alkyl substituted by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, if desired, once to three times on the phenyl ring, or carbonylamino substituted on the nitrogen atom with a suitable amino protecting group; optionally mono-or tetraunsaturated, mono-or bicyclic ring systems having 3 to 10 ring carbon atoms which can be replaced once to three times by nitrogen, oxygen and/or sulfur, and which can be substituted once to three times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or by a lower alkylene chain which is bonded to two oxygen atoms which are bonded to adjacent carbon atoms in the ring system, or
Represents a straight or branched chain C optionally containing one to three double bonds1-12Alkyl substituted one to three times with the following groups, i.e. halogen; a hydroxyl group; lower alkoxy; carboxyl groups optionally esterified with: cycloaliphatic or straight-chain or branched aliphatic C optionally containing one to three double bonds1-C6-alkanols, which are phenyl lower alkanols substituted, if necessary, one to three times by halogen or lower alkoxy, or, if necessary, one to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy; a cyano group; a thiol group; a lower alkylthio group; an amino group; a lower alkylamino group; c optionally substituted on the nitrogen atom once by one to three times each optionally substituted by halogen or lower alkoxy3-C8Cycloalkyl lower alkanoyl or straight or branched aliphatic C1-C6Alkanoyl or carbonylamino substituted by phenyl lower alkanoyl substituted, if appropriate, once to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or C substituted, if appropriate, once or twice on the nitrogen atom, by halogen or lower alkoxy each once to three times3-C8Cycloalkyl lower alkanoyl or straight or branched aliphatic C1-C6Alkanoyl or carbonylamino substituted by phenyl lower alkanoyl optionally substituted once to three times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or carbonylamino substituted on the nitrogen atom with a suitable amino protecting group; a mono-or bicyclic ring system, optionally mono-or polyunsaturated, having 3 to 10 ring carbon atoms which may be replaced once to three times by nitrogen, oxygen and/or sulfur and which may be substituted once to three times by lower alkyl, lower haloalkyl, lower alkoxy, hydroxy, halogen or by a lower alkylene chain attached to two oxygen atoms bound to adjacent carbon atoms of the ring system, or
R5And R8Or together with the carbon atom to which they are bonded, form a monocyclic or bicyclic ring system having 5 to 10 ring carbon atoms, optionally containing 1 to 3 double bonds, which ring system does not carry a substituent R5Or R8Can be replaced once to three times by sulfur, oxygen and/or nitrogen, the ring system can be substituted once to three times by lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen, or by a lower alkylene chain attached to the oxygen atom attached to two adjacent carbon atoms of the ring system, or
R6And R7May also together form a bond, and
R5and R8Or together with the carbon atom to which they are bonded may form an aromatic C6Ring systems fused with 2 to 4 further carbon atoms (anellieren) to form a bicyclic ring system containing a total of 8 to 10 ring carbon atoms and having a total of 3 to 5 double bondsWherein it does not carry a substituent R5Or R8C of6-10The carbon atoms of the ring system may be replaced once to three times by sulfur, oxygen and/or nitrogen, and where C is6-10-the ring system is optionally substituted once to three times by lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, hydroxy, halogen or by a lower alkylene chain attached to 2 oxygen atoms attached to adjacent carbon atoms of the ring system,
R9represents hydrogen, lower alkyl, phenyl lower alkyl or amino protecting group substituted, if necessary, once to three times, on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy or lower haloalkoxy, or
R8And R9Or together form a C3-4An alkylene chain, and
y represents oxygen, and Y represents oxygen,
wherein the reactive groups present in the compounds of the formula I are blocked, if desired, with suitable protecting groups,
a) reacting a compound of the formula II
Wherein
R3And R4The significance is given to the above-mentioned,
R101and the above-mentioned R1Having the same meaning, with the exception of optionally substituted methylene groups,
ar represents phenyl which is optionally substituted one or more times by lower alkyl,
R10represents lower alkyl, or phenyl which is substituted, if necessary, once on the phenyl ring by lower alkyl or by hydroxy protected by a suitable protecting group, or phenyl lower alkyl which is substituted, if necessary, once on the phenyl ring by lower alkyl, and
R1101is a silyl-protecting group which is a silyl-protecting group,
successively with a base suitable for deprotonation, a metal-organic reagent of the formula VII
XM2(OR12)3 VII
Wherein X is halogen, M2Is a tetravalent transition metal and R12Is lower alkyl, phenyl or phenyl lower alkyl, and a stereoisomer of a compound of formula VIII to form a stereoisomer of a compound of formula IX,
VIII is of the formula:
wherein R is5,R6,R7And n is as defined above, R801And R8In the same sense, where the active groups which may be present are blocked, if desired, with base-stable protecting groups, R901Is hydrogen or with R801Together form C3-4An alkylene chain, and R13Is an amino protecting group which upon cleavage leaves a nitrogen nucleophile,
formula IX is as follows:
wherein R is101、R3、R4、R5、R6、R7、R801、R901,R10,R1101,R12,R13N, Ar and M2As is significant in the above-mentioned sense,
b) the resulting compound of formula IX is purified by treatment with a suitable solvent for removing R13Reagent treatment of the group to convert to a compound of formula Xa,
wherein R is101,R3,R4,R5,R6,R7,R801,R901,R10N and Ar have the same meanings as above, R11Is hydrogen or a silyl protecting group, if R901Is hydrogen, in the ring bone of the compound of the formula Xa formedThe nitrogen atoms in the skeleton being blocked with a base-stable protecting group, if necessary with the silyl-protecting group R still present11Cracking, and
c) for the preparation of compounds of the formula Ia
Wherein R is1,R2,R3,R4,R5,R6,R7,R801And n has the same meaning as R902Is a base-stable protecting group or with R801Together represent a C3-4-an alkylene chain, the alkylene chain being,
ca) reacting the resulting compound of the formula Xa or with a silyl protecting group R11With a reagent suitable for reductive cleavage of the sulfonylimino-alkyl bond to obtain a compound of the general formula Ib,
wherein R is101,R3,R4,R5,R6,R7,R801,R902And n have the same meaning as described above,
cb) in the obtaining of R101In compounds of formula Xa, which do not represent hydrogen, the sulfonylimino-alkyl bond is cleaved after electrophilic activation of the sulfonylimino unit under conditions such that base-induced elimination takes place, to give compounds of the general formula Ic,
wherein R is3,R4,R5,R6,R7,R801,R902And n has the same meaning as R102Represents C1-5Lower alkylene chain of alkyl or represents phenyl lower alkyl optionally substituted one or more times on the phenyl ring by lower alkyl, lower haloalkyl, lower alkoxy and lower haloalkoxyMay contain from 1 to 5 carbon atoms,
and cleaving again the protecting group which may be present in the compound of formula Ia, and, when R9 is other than hydrogen, reacting the NH-group liberated at the 1-position of the ring backbone with a reagent capable of N-alkylation or of amide bond formation, or blocking with an amino protecting group, to give the compound of formula I,
wherein said lower alkyl represents a branched or unbranched alkyl group having 1 to 4 carbon atoms.
2. A process according to claim 1 for the preparation of compounds of the general formula Ib according to claim 1 and of compounds which are obtained starting from compounds of the formula Ib by cleavage of protective groups which may be present and by reaction of NH-groups which may be free in the 1-position of the ring skeleton with a reagent which is capable of N-alkylation or of amide bond formation or by blocking the aforementioned NH-groups which may be free with an amino-protecting group.
3. A process as claimed in claim 1, wherein R is the amino-protecting group in the compound of the formula VIII13A base-stable protecting group is used, and wherein the protecting group R is removed in process step b)13The reagent of (1) is a base.
4. A process according to claim 3, wherein the base-stable protecting group is fluoren-9-yl-methoxycarbonyl.
5. A process as claimed in claim 4, wherein piperidine is used as base.
6. The process according to claim 1, wherein toluene is used as solvent at least in process step a).
7. A process as claimed in claim 1, wherein samarium (II) iodide is used as reagent for the reductive cleavage of the sulfonylimino-alkyl bond in the compound of the formula Xa in process step ca).
8. A process according to claim 1, wherein R in the compounds of the formulae I, Ia, Ib, Ic, II, IX and Xa4Is not hydrogen.
9. A process as claimed in claim 1, wherein tert-butyldimethylsilyl or trimethylsilyl is used as silyl-protecting group R1101。
10. A process for the preparation of a compound of formula I according to claim 1, wherein R8Is hydrogen, lower alkyl, phenyl lower alkyl or lower alkoxy lower alkyl, or R6And R7Together form a bond, and R5And R8Together with the carbon atom to which they are bound form an aromatic C6-a ring system, or wherein R8And R9Together form a C3-C4An alkylene chain.
11. Acid addition salts of compounds of the general formula Xa as defined in claim 1, and of compounds which are obtained by removing protective groups which are optionally present from compounds of the formula Xa and free amines of the formula Xa, wherein the sulfur-containing substituent in the 5-position of the ring skeleton and the hydroxyl group in the 3-position of the ring skeleton are each in trans position to one another, and wherein the substituent R in the 4-position of the ring skeleton4And the hydroxyl groups in the 3-position of the ring skeleton are each in cis position to one another.
12. Compounds of the general formula Xa according to claim 11, which contain a secondary nitrogen atom in the ring skeleton, which secondary nitrogen atom is protected with a tert-butoxycarbonyl-protecting group.
13. Compounds of the general formula Xa according to claim 12, wherein R901Represents hydrogen or with R801Together form a C3-4An alkylene chain.
14. Use of samarium (II) iodide for the reductive desulfurization of alkyl-sulfonylimino-compounds of general formula Xa according to claim 1.
(Rs) -4(S) -isopropyl-2-p-tolyl-4, 5-dihydro [1, 2. lambda6,3]Oxathiazole-2-oxide, (Ss) -4(S) -isopropyl-2-p-tolyl-4, 5-dihydro [1, 2 lambda ] methyl6,3]Oxathiazole-2-oxide, (Rs) -4(R) -isopropyl-2-p-tolyl-4, 5-dihydro [1, 2 lambda ] methyl6,3]Oxathiazole-2-oxide and (Ss) -4(R) -isopropyl-2-p-tolyl-4, 5-dihydro [1, 2 λ6,3]Use of oxathiazole-2-oxides in a process for the controlled preparation of nitrogen heterocycles by a stereochemical process as defined in claim 1.
The use of [ Ss, N (1S) -N- [1- [ [ tert-butyldimethylsilyl ] oxy ] methyl-2-methylpropyl ] -S-methyl-S- [ 4-methylphenyl ] -sulfimide and [ Rs, N (1R) ] -N- [1- [ [ tert-butyldimethylsilyl ] -oxy ] methyl ] -2-methylpropyl ] -S-methyl-S- (4-methylphenyl) -sulfimide in a process for the controlled preparation of nitrogen heterocyclic compounds according to the stereochemistry defined in claim 1.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19821418 | 1998-05-13 | ||
DE19821418.9 | 1998-05-13 | ||
PCT/DE1999/001417 WO1999058500A1 (en) | 1998-05-13 | 1999-05-10 | Method for stereochemically controlled production of isomerically pure highly substituted azacyclic compounds |
Publications (2)
Publication Number | Publication Date |
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HK1036624A1 HK1036624A1 (en) | 2002-01-11 |
HK1036624B true HK1036624B (en) | 2006-11-17 |
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