DE1620628A1 - Process for introducing oxygen into the heterocyclic ring of N-acyl derivatives in polymethyleneimines and azabicycloalkanes - Google Patents

Description

A * "'' ed Hoepp-ansr

R-chisanwäite and notaries 1966

Hr, i> · ^ Joachim Wolff

1., .1..V ₁ -3 Chr. BeU 1620628

Fr e. M.-Höchst

Adelo ^ tr. 5S - Tel. 312649

Our Mr. 12 663

The Upjohn Company
Kalamazoo, Mich., Y.St.A.

Process for introducing τοπ oxygen into the heterocyclic ring of H-aoyl derivatives of polymethyl enimines and azaMcycloalkanes

The invention relates to a new method of running-in of oxygen in the heterocyclic ring of H-acyl derivatives of polymethyleneimines (azacycloalkanes) and azabicycloalkanes, which is characterized by having the same of the oxidizing action of the microorganism Subjects Sporotrichum sulfurescens, whereby certain new products as well as derivatives of the same arise.

The inventive method is particularly suitable for Introduction of oxygen into the heterocyclic, Hing of compounds of the formula

(ΟΗ ₉ ) _1χ

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where η is an integer from 4 to 12, X and X ₁ each represent a hydrogen atom, an!,! ethyl, ethyl or propyl radical and X and X-, taken together, form a bracket that contains 1 to 3 carbon atoms, Z is a _g_j_ »-SO ₂ -Ji or - £ ~ _R group, where R is an aryl substituent having 6 to 12 carbon atoms, such as, for example, B. a phenyl, ToIyI, XyIyI-, H'sphthyl- or biphenylgruppe and iL · an aralkyl substituent with 7 to 16 carbon atoms, such as a benzyl-, p-nitrobenzyl-, 4-iiethylbenzyl-, 3-methylbenzyl-, 4 - ^ Ietnylphenäthy 1-, 4-3ipheny ± buty 1-, cUSiaphthylmethyl- or ß-xTapnthyläthylgrupoe mean.

The above "compounds of formula I result if they subjected to the Biouniwaiid long sverf aar eu according to the invention are, the corresponding compounds in which the heterocyclic Hing by liinführung a hydroxy or Keto group was oxidized.

Obtained by the bioconversion process according to the invention one oxidized polymethyleneimines and azabicycloalkaiie, from some of which are known, but which so far have not been easily obtained by purely chemical synthesis processes. See, for example, Leonard, Record of Chemical Progress, Vol. 17 (iYr. 4), pages 243-257 (1956) and the references which is referred to there.

The Biοumwand.lungsνerfahren according to the invention is special for the preparation of compounds of the general formula 'suitable »

(GH ₂ ),

HO-OH N-Z

¹¹ ^ ⁰ ° * o, _NAL

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where X, } L · and Z have the meaning given above, n .. a whole number from 1 to 5 and n _? is an integer from 2 to S, and the sum of n .. and n _{2 is} not less than 3 and not more than 11.

Those produced by the bioconversion process of the invention Compounds in which the introduced oxygen substituent is a hydroxyl group, for example the compounds of the formula II, according to the following methods described, e.g. using chromic acid, are chemically oxidized to the corresponding keto compounds obtain, in particular those of the formula:

O = G ν H-Z

III

at the n .., n _? , £, X- and Z have the same meaning.

The compounds produced by the conversion process, in which the introduced oil substitution is a keto group, or the low-cost compounds produced in the above-mentioned low-cost oxy-ion stage, can optionally be prepared according to the methods described below ^. ariren reduces sera, for example using hatriufflon orihydride, in order to give the corresponding hydroxy veroic acids.

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Although the inventions "/ experiences are generally applied and for the oxidation of all J-acyldprivate of Polyä ^ thyleniininen and Azabicycloalkaneii of the presenting ? ormel I can be used un the oxidized compounds of the above formulas II and III is to be obtained the inventive method particularly advantageous for Establishing the preferred invention;.; Eriäl3en connection er the following formulas IY, V ", YI and YII:

W.

■ (CH ₂ )

IT-Z

IY

. (CH ₂ K
W SZ

(CH

ⁿ 5

VI

VII,

and

-Z

wherein n, an integer from 2 to 3, n, an integer from 3 to 5 and n, - is an integer from 6 to 8, and

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the sum of η, and η. not less than 5 and not more than 7 and the sum of n. and n ^ 11; Wine Carbonyl or hydroxyraethylene radical and Z is the above has given meaning. The compounds of the above Porraeln IY, V, VI and VII are also converted by bioconversion of the corresponding non-oxidized compounds and subsequent chemical oxidation of the compounds in which. W is hydroxymethylene, made when you get compounds want, in which Vf is an Oarbonylrest.

The with the help of the bio-fce & uriwandlungs- and Oxidation process oxidized compounds, including those produced by the preceding paragraphs II, III, IV, V, VI and VII are shown, as well as the compounds prepared in the following examples and the acylates of the compounds in which the oxygen substituent is a hydroxyl group and the functional derivatives of the compounds in which the oxygen substituent is a Keto group are suitable insecticides, fungicides, parasiticides, Protein denaturants, insect repellants, high boiling solvents, synthetic levelers Resins, crosslinking agents for the synthesis of asers pharmacological agents for combating mental states as well as intermediates for dyes, polymers and fibers.

To be used as intermediate products, for example the compounds in which the oxygen substituent is a keto group (the hydroxy compounds can be oxidized to keto groups) can be converted into lactams according to the US patents 2,579,851 and 2,569,114 amino acid methods can be hydrolyzed. For example, the ketones are converted into oximes by using them with Reacts hydroxylamine or a salt thereof. The oximes

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then become a Beokmanian rearrangement through housing with sulfuric acid or the like with the formation of lactams, subject. The leaks obtained in this way are valuable intermediates that give amino acids after hydrolysis. The lactams and amino acids thus obtained are used to manufacture valuable products, for example of polyamides, as in the LfSA patent above 2,579,851 is described, suitable.

For use as insect control agents, the inventive Compounds mixed with aqueous or non-aqueous carriers according to methods known in the art be, for example nacii of the Ij SA patent font 3,131,215 »

The microbiological method of the invention is thereby characterized in that one i \ i-aromatic acyl ^ erivat of a methylenimine (I) of the oxidizing effect of the species of the IPungus Sporotrichum sulfurescens. The genus Sporotrichum belongs to the family of the Moniliaceal of the order of the Moniliales of the class / Deuteromyeeteii.

The typical preferred strain for the purposes of the present invention is Sporotrichum sulfurescens, available from the American Type Culture Collection, Washington, DC; Collection ITr. ATGG 7159 can be obtained. It is obvious, however, that other Sporotrichum sulfurescens strains are also suitable for the purposes of the present invention.

The starting materials (I) for the process according to the invention, some of which are known, are prepared from polymethyleneimines (azacycloalkanes) and azabioycloalkanes of the general formula

(CH ₂ ) _n NH

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CH ₂ ) _n

O- T -

in. the η, X and X. have the meaning given before, naci! acylation processes of polymethyleneimines known in the art. For example, the corresponding polymethyleneimine or azabieycloalkane is dissolved in an aqueous sodium hydroxide solution, mixed or suspended with it and treated with the acid halide of the corresponding monobasic aryl or aralkyl carboxylic acid, ie those listed below as acylating agents, or with the acid halide of the- corresponding monobasic arylsulfonic acid, for example benzenesulfonic acid, o-, m_ and p-toluenesulfonic acids , OL- and ßr-ilaphthiialinsulfonic acid, p-chlorobenzenesulfonic acid, as explained below in Preparation Examples 1 to 10. The acylation can also be carried out in hydrocarbon solvents such as, for example, Skellysolve B (iiexangeuiiivchen), benzene or toluene. When the bioconversion process according to the invention is carried out, those process and implementation conditions known in the field of bioconversion, which are explained by!, Iurray and others in the USA patents 2,602,769 and 2,735,800, are used weraen, and zv.'ar using the oxidizing effect of the microorganism Sporotrichum sulfurescens.

In the practice of the present invention, the bio-conversion can be carried out by a growing or dormant culture of the microorganism or by spores, washed cells or Enzymes of the Liikr ο organism are effected.

The culture of the microorganism suitable for the purposes and implementation of the present invention is located in or on a medium that supports the development of the microorganism boggled. In the culture medium, nitrogen or sources of carbon are present, and sufficient Supply of sterile air should be used during the conversion

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take place, for example according to the conventional 'procedures, with a large surface area of the liedium being ventilated or air is passed through a submerged culture.

Assimilable nitrogen can be obtained from common sources such as corn steep liquor, soybean nehi, Yeast extracts, peptone, soluble or insoluble vegetable or animal protein, lactalbumin, casein, whey, Stillage, amino acids, nitrates and ammonium compounds, such as ammonium tartrate, nitrate or sulfate.

Carbon can also be obtained from sources that are normally used in bioinv / and treatment procedures, e.g. glucose, fructose, lactose, maltose, dextrins, starches, meat extracts, peptones, amino acids, proteins, fatty acids, G-lycerin or lolke. These substances can either used in a purified state or as concentrates, such as Icloud concentrate, ilaisquellwaüser or G-emisclie, or as G-emisclie of the same. Yiele aieser above-mentioned carbon sources can also be used as Serve nitrogen source.

Depending on the requirements, the medium can be used before the Vaccination have a pK- '. Vert of about 4 to about 7, although a lower or higher ph-./ert can also be used can. A temperature of about 2b to 32 0 is required for the ", ■ / axis of the microorganism are preferred, but are also higher or lower temperatures within a proportionate suitable for a wide range.

The substrate can be used during the growth period of the microorganism can be added in a single addition or gradually during the conversion period, or it can be added before or after sterilization or vaccination, depending on the pH and / or temperature

009834/1853 ^BAD

can be adjusted according to the resistance of the substrate used. The preferred but not limited The concentration range of the substrate in the culture medium is approximately 0.1 to 10 s / l. The substrate becomes the iuedium on a suitable // added, in particular on a / that a large surface of the substrate with the oxidizing acting JuLikroorganismus comes into contact, for example by having the solid substrate in an organic one Dissolves solvent and mixes the solution carefully with the medium, or by adding to the Iuedium finely comminuted particles of the substrate, e.g. micronized Particles, preferably 90 wt. $ Less than 20 / U, either as a dry powder or, preferably for mechanical purposes, as an aqueous suspension. In the In the preparation of the aqueous suspension, the use of dispersants or suspending agents is advantageous.

The temperature during fermentation can be the same like those who: 'for the growth of the microorganism suitable is. It just has to be within a range that supports the preservation of life, the active // aehstum or the enzyme action is guaranteed; the range between 20 and 35 C is preferred. “Pure growth of the microorganism During bioconversion, a pH of about 4 to 6 is generally preferred for those sensitive to acid However, the pH should be around 7 during fermentation. Aeration can be by surface culture or, preferably, under submerged cooking conditions take place according to known methods. The necessary for oxidation by the enzymatic system of the microorganism Time can vary considerably. A range of about 2 to 120 hours is common but is not a limitation dar; 72 hours is generally sufficient. The progress of the bioconversion and its completion are expedient by paper tire chromatography, steam

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phase chromatography or thin-screen chromatography; raphie ■ determined / Seftman, Chromatography (1961), ^ einholä Publishing Company Go., Liew York_J7 ·

The oxidation of the corresponding substrate can also take place under aerobic conditions take place in that one aas substrate the oxidizing effect of the one isolated from the idi-organism oxidizing .änzyms the action of the spore.i des i,: ikroorganisniUB as well as the effect of the isolated cells of the microorganism; -j exposes. Isolated dnzyrripreparations can according to the general, through Zuidweg and others in Biochim. Biophys. Acta, Vol. 58, pp. 131-133 (19 ^ 2) Process are produced. Oxidation can be caused by spores in accordance with the general method described in the Ü3A-Patentscnr 3,031,379 and 3,031,382 methods described oewirict will. The separation of the washed skins from the G-ar medium is well known in the art; see for example JSA patent 2,831,789.

The term "oxidizing effect" used in the present Description is used, denotes the enzymatic effect of a growing or dormant culture of the L-Ii kr o organism or by spores, washed cells, or isolated enzymes of liikroox \: anism, by means of which oxygen into the molecule of the substrate under aerobic yellowing conditions is introduced.

After completion of the fermentation, the obtained are oxidized Products obtained from the fermentation broth using conventional methods For example, the entire broth can be extracted with a water-immiscible organic solvent are »for example with Nae-fchylene chloride, chloroform, Carbon tetrachloride, ethylene chloride, trichlorethylene, ether, amyl acetate or benzene or the broth and the mycelia can be separated and then individually using conventional methods, e.g. centrifugation or filtration

009834/1853

extracted with suitable solvents. The liyzele can be extracted with either water-miscible or water-immiscible solvents; If there is only a small amount of the product or no product at all in the liyzel, they can only be washed with water; the washing barrel becomes the filter broth • 3e "/. even. The raycelium-free" broth can then be extracted with the solvents which are not miscible with Ytasser and which have been mentioned above. The extracts are combined, dried over, for example, anhydrous sodium sulfate, and the solvent τ / ird according to conventional methods ζ.3. removed by puffing or distilling at atmospheric or reduced pressure. The oxidized products thus obtained can be further purified by customary methods, e.g. by recrystallization, chromatography, or distillation in the jelly of liquids.

The -re jii-in ^ of the various oxidized products obtained from fermentation can be carried out by conventional methods, such as, for example, by chromatography and / or fractional crystallization and, in the case of liquids, by distillation. If the separation of the hydroxyl compounds is difficult, a suitable and advantageous process is to first oxidize the crude oxidized polymethyleneimines or azabicycloalkanes obtained from the batch under neutral or slightly basic conditions according to processes known for the oxidation of secondary hydroxyl groups to ketones; see, for example, this and this, xiatural Products Related to Phenanthrene, 3 «ed., pages 127-12i, 193 and 194, Relnhold Publisning Gorporration, Ji ew Tork, Έ. Y. Here, the crude bioconversion products are dissolved in an inert organic solvent, eg acetone, benzene, methylene chloride, or t-3utanol, and then with aqueous chromic acid, potassium permanganate, t-butyl hypochlorite or similar ozydation

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agents oxidized to the existing secondary hydroxyl groups to convert to keto groups and thereby obtain a ü-emic of the corresponding keto compound, which in in some cases easier by chromatography and / or crystallization or distillation in the case of liquids be separated.

The compounds obtained by the bio-conversion in which the introduced oxygen substituent is a keto oxygen is, or those compounds produced by the above chemical oxidation of the corresponding hydroxy compounds were obtained, for example / erbindungen der Formula III, can optionally, preferably, under neutral or acidic conditions, according to the reduction of Carboxyl groups are known methods are reduced, wherein the corresponding.Hydroxyverbindungen arise. the Reduction can, for example, be rectangular with hydrogen in the presence of a catalyst such as palladium, platinum. or Saney-fi'ickel under neutral conditions, with matrium in an alkanol or with a reducing agent, e.g. 3. Lithium aluminum hydride, sodium borohydride, primary isobutyl magnesium bromide or lithium titrated butoxyaluminum hydride be performed*

The compounds obtained through the bioconversion, at where the introduced oxygen substituent is a hydroxyl group, for example a compound of the formula II, can be used for the acylation of secondary oxy groups known processes are acylated to give the corresponding acyloxy compounds, for example by reaction with the corresponding acid anhydride or acid halide, by reaction with the corresponding ester or by reaction with the corresponding acid in the presence an esterification catalyst. Suitable acylating agents are organic carboxylic acids, in particular

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Hydrocarbon carboxylic acids having 1 to 16 carbon atoms, or their acid anhydrides or acid halides. Examples of hydrocarbon carboxylic acids that are used for acylation are saturated and unsaturated aliphatic and aromatic acids such as vinegar, propionic, butter, isobutter, tert-butyl acetic, valerian, isovaleric, Gapron-, Öapryl-, Gaprin-, Laurin-, Acryl- * ·, Kroton-, Hexynon-, Heptynon-, Octynon-, Gyclobutancarbon-, Oyclopentancarbon-, Gyclopentencarbon-, Oyclohexanearbon-, DimethyIcyclohexanarbon-, Benzoin-, Toluyl-, Naphthoe-, ethylbenzoe-, phenylessig-, iiaphthalenessig-, phen / lvalerian-, cinnamon-, phenylpropiol-, phenylpropion-, p-3utoxypheriylpropion-, amber-, G-lutar-, dimethy lut ar-, maleein-, \

! G2 / clopenty propionic acid and the like 1st = the acylating; el a free acid, the reaction is preferably in 'the presence of a Vex'esterungskatalysators performed, such as p-ioluolsulfonylchlorid, l'rifluoressigsäureanhydrid, pl ^A oluolsulfonsäure, trifluoroacetic acid or S ciiv / ef e 1 sä.ur e.

The compounds obtained by the Bioimwandlung in which the introduced oxygen substituent is a keto oxygen or by chemical oxidation of the corresponding jdydr oxy nnectivity Ketoverbindungenj obtained, for example, compounds of formula III may be converted into M ordinary Garbonylderivaten, including oximes, hydrazones, semicarbazones, cyclic AlkylenketaIe and the like, can be converted by known methods. The carbonyl group can, for example, be ketalifjiert by reacting the corresponding compound with an alkanediol, for example with an adjacent alkane-1, 2-diol or alkane-1,3-diol with up to 8 carbon atoms, e.g. 'ethylene, propylene, l'rimethylene, 2,3-butylene, 2,4-pentylene, 4-methyl-1,2-pentylene, 1,3-hexylene, ί, 2-heptylene, 3,4- "heptylene or 1,3-octylene, preferably in one

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organic solvents, for example benzene, jolaol, xylene or ethylene chloride and in the presence of an acid catalyst, such as p-Coluenesulfonic acid. The reaction is "effected at a temperature between about 20 and about 2υΟ G, preferably about 40 and about 1 50 0th The time required for the reaction is not critical and can be between about 1 and 43 hours .je after the 'temperature fluctuate .

The acylates and Oarbonylderivate can optionally by hydrolysis according to known methods, z.3. can be removed with diluted acids or alkalis.

The following production examples and games should explain the procedure.

Preparation 1 1-.3enzoy! Hexamethyleneimine

60 ecm 3enzoyl chloride in 200 ccia Skellysolve J were stirring a cooled (egg bath) Losaiv; from 200 ecm Hexamethyleneimine in 800 ecm Skellysolve B to ^ e ^ even. That Mixture was then several times with in-hydrochloric acid and ./asser washed and filtered through anhydrous atrium sulfate. After evaporation of the Skellysolve B- ^ exane (hereinafter Called Skellysolve B) and distillation of the oily residue 40.5 g of l-3enzoy! hexamethyleneimine were obtained; Boiling point 150 ~ 160 ° / 1 torr.

KO-. ■ '

Analysis calculated for O ₁ → H ₁ →: 0 = 76.81; H = 8.43 »ii = 6.89.

found t 0 = 75.49; H = 8.43; 1 = 6.54.

Preparation 2 1- (p-Toluenesulfonyl) -hexamethyleneimine

A mixture of 9.92 g of hexamethyleneimine, 100 ecm of a 2N sodium hydroxide solution and 18 g of p-toluenesulfonyl chloride

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was shaken vigorously for 15 minutes (heat of reaction was determined) and let out for two hours. The product \ _f 7ttrde filtered washed with water, dried and recrystallized from aqueous acetone; to give 23.0 g of 1- (p-toluenesulfonyl) -hexamethyleniminf Melting point: 71-73 ⁰ C,

Analysis calculated for G ₁ → H _{10 IiO 9} S: 0 = 61.62; H = 7.56; S =

^{15 Iy ά} 12.66

found: 0 = 61.83 * H = 7.72j S *

12.94

Preparation 3 1-Benzoylheptamethyleneimine

A mixture of 30 g of heptamethyleneimine, 100 ml of 50% riatric hydroxide solution and 540 ml of water was cooled to 15 ° C. 43 Z 3enzoylchlorid was added dropwise with vigorous äliliren held on and at a 15-2o ⁰ C! Temperature "added Bach .Beendigung the addition was stirred for an additional hour, and recovering the oily product by A'therextraktion. Ur.ch evaporation of the ether resulted in 55 g 1-3eiii5oylheptamethyleneimine in the form of an oil.

Preparation 4 I-Benzoyloctamethyleneimine

A mixture of 10 g of octaiaethyleneimine, 20 g of 50%

ITatriumhydroxyd and 100 cc // ater was cooled to about 15 ° C, and with vigorous stirring at a temperature of .. 15-20 ⁰ C was added 12.5 g 3enzoylchlorid dropwise ilach completion of jSenzoylchloridzugabe an additional hour was stirred, and the product was obtained by extraction of ethylene chloride. After evaporation of the solvent, 17.6 g of 1-benzoyloctamethyleneimine were obtained as an oil *

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Production: 5 1-3enzoylalky / piperidine

According to production process 4, 2-propy! piperidine was used in "1-benzoyl-2-propylpiperidine; 4-propylpiperidine in 1-benzoyl-4-propy! Piperidine and 2-methyl-5-ethy! Piperidine converted into 1-benzoyl-2-methyl-5-ethyl! piperidine.

Preparation 6 1-Benzoyldode came thy lenimin

40 g of azacyclotridecanr2- ^ one 7 / are extracted continuously in a Soxhlet apparatus under reflux with a solution of 15 g of lithium aluminum hydride in one liter of ether. üAfter adding all of the amide, the extraction was continued for four hours. In order to decompose excess hydride, water was added, the ether phase was separated off, filtered through sodium sulphate and concentrated in vacuo, so that 36.8 g of oily dodecamethyleneimine were obtained. This was added to 30 ml of 50 ml sodium hydroxide in 170 ml of water, cooled to 20 G in an ice bath, and 30 g of benzoyl chloride were slowly added with vigorous stirring. The 1-benzoyldodecamethyleneimine which had precipitated out of the solution was filtered and washed with water. After recrystallization from an acetone-Skellysolve-BG mixture, 47.5 g of 1-3enzoyldodecamethyleneimine were obtained; Melting point: 51-53 °; for analysis, a sample was recrystallized twice from an acetone-Skellysolve-BG egg; Melting point: 54-56 ⁰ G.

Analysis calculated for G ₁₉ H ₃₉ ITO: 0 = 79.39; H = 10.17; N = 4.87. found: 0 = 79.43? H = 1O, 4O; E = 5, O3

Preparation 7 denzyl-3-azabicyclo- ^, 2, 27-nonane-3-carboxy

lat

A suspension of 12.5 g of 3-azabicyclo ~ ^ 3.2, g7-n.onan in 115 ecm 2n-E sodium hydroxide was stirred and cooled,

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and .ßeioehaltung a temperature of 17-20 ⁰ G 17 g Garbobenzoxychloriu were added. The mixture was stirred for one hour without temperature control and then extracted with ether. The extract was washed with dilute hydrochloric acid, v / ater, dilute sodium bicarbonate and water, dried over Ifatriuriisulfat, and the solvent Ynxrda over 500 g Florisil (synthetic magnesium silicate, referred to as J? Lorisil in the following) and chromatographed with okellysolve B and increasing proportions of acetone containing Skellysolve B. (2 to 6 - / ■> acetone) "comparable thinned those fractions which b.ei determined by DünnschichtchzOiiii-tograpiiie v / urde that they contained the desired product were combined and evaporated to give ä 15 , 30 g of i3enzyl-3-axabicyclo- _< / 3> 2,27-nonane-3-carboxylate was obtained as a colorless oil.

Analysis calculated for G ₁₆ H ₂₁ ITO ₂ : C = 74.1O; H = S, 16; ϊΓ = 5.40. found: 0 = 74.68; H = 8.22j 1 = 5.49.

Preparation 8 3- (pI-oluolsulfj3njl) -3-azabicyclo- / 5, 2,27-

nonane ^;

A suspension of 12.5 g of 3-azabicyclo- / 3,2,27-nonane in 100 ecm of 2n-iiatrium hydroxide was treated with 19.1 g of p-toluenesulfonyl chloride. The mixture was shaken vigorously "It v / urde no äeaktionsv / Slee found, so the g mixture was heated for several minutes to boiling temperature and cooled to Eaumtemperatur. The lumpy product obtained in this way was filtered, washed with water and recrystallized from acetone / water. Yield 21.0 g of 3- (p-toluenesulfonyl) -3-azabioyolo- _< / 5.2.27- n.onanj melting point:

115-118 ⁰ Oj an analysis sample from methanol melted at 115-

Analysis calculated for O ₁₅ H ₂₁ ITO ₂ S: 0 = 64.48j H = 7.58; ,

N * 5.01 | 3 * 11.48.

found t 0-64.20 »H * 7> 76» -

M = 5.04? a »11 _f 53-

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Preparation 9 3-3enzoyl-3-azab ± cyclo- / 3,2,27-nonane.

500 ecm of benzoyl chloride were added with vigorous stirring to a mixture of 500 ζ 3-azabicyclo- / 3,2,27-nonane and 3,200 ecm of 10; iiger la triolhydric oxide solution. Ha ch 15 Linuten were further 250 cc of benzoyl chloride was added, and three IHRT v / urther hours ger ^r. The product was washed, washed with water and dried; Yield: 900 g 3-3enzo;>"l-3-azabicyclo- / 3,2,27-ionane; melting point: 92-95 ° C.; an analytical sample from an ether hexane mixture melted at 93-94-Upper Austria.

Analysis calculated for C ₁ JH ₁ OlO: 0 = 78.56; H = 8.35j IT = 6.11, found: 0 = 78.79; H = 8.52; 1T = 6.26,

Preparation 10 2-Benzoy 1-2-azcrbicy clo- / 2 ~, 2,27-octane

50 ecm of benzoylochloride were mixed with stirring 50 g of raw 2-azabicyclo- ^ 2 ", 2,27-octane, 100 ecm 50 .jiger B'atriumhydroxydlösans and 300 ecm IIis plus ./asser added, After the addition, the mixture was stirred for a further hour and the crude product was filtered off and washed with water. That so solid product obtained was taken up in methanol chloride and filtered through about 100 ecm Slorisil, with 1 Liter of methylene chloride and then mitb 1 liter of a 10 -iigen Mixture of acetone and Skellysolve B washed. Let off steam and recrystallization from an acetone-Skollyaolve-B-G-mixture 33.8 g of 2-benzoyl-2-azabicyclo- / 2 ", 2,27-octane were obtained; Melting point: 100-104 C.

For analysis, a sample was taken three times from the same solution smitte! paar recrystallized to a melting point of 115-118 °.

Analysis , calculated for G ₁ -H ₁₇ NOi 0 = 78.10 H = 7.9 & N = 6.51 «found ι 0 = 77.85 ■ H - ?, 22 Μ = ό, 22.

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Example 1 Oxidation of 1-3enzoy! .Piperidine

ban produced a medium as 200 g of lais spring water (60> o solids), 100 g of commercially available dextrose and 10 l of tap water. The pH was adjusted to 4.8-5 and 10 cc of lard oil was added as an anti-foam agent. This medium was sterilized and inoculated with a 72-hour old vegetative 7 / ax of Sporotrichum sulfurescens, Al ¹ CO 7159, and after incubation for 24 hours at a temperature of about 280, an aeration rate of 0.5 1 per minute and stirring with 3OP-ü / iin. the substrate, namely 2 g of 1-benzoylpiperidine in solution in a minimal amount of acetone (about 20 ecm) for fermentation was pulled. i \ Tacib. a further incubation of 72 hours at the same temperature and aeration, broth and lyzel were through The mycelium was washed with water, and the Yfe's water was added to the broth filtrate. The broth filtrate thus obtained was extracted four times with methylene chloride in an amount equal to a quarter of the amount of the filtrate. The combined extracts were added to a quarter of the amount of the Washed distilled water, the solvent was distilled off, and i-ßenzovl-4-hydroxypiperidine was obtained as residue.

ITach chromatography of the residual extract over Plorisil d and elixirs with ^ Bkellysolve B, the growing Ac et contained on-proportions, to give 407 mg of crude 1-benzoyl-4-hydroxypiperidine in the last eluate fractions fo of 25 acetone and Skellysolve consisted B . The product was characterized by the following derivatives.

The oxidation of 151 mg of crude 4-hydroxy compound with Jones chromic acid Rea r ens yielded 137 mg of crude 1-benzoyl-4-oxopiperidine as "89 mg of 2-, 4-dinitrophenylhydrazone revealed. Melting point: 196 to 198 C. The remaining crude 4-hydroxy compound was treated with phenyl isocyanate to obtain after

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Chromatography over JTlorisil to give 89 mg of phenylure than. Melting point: 134.5 to 186.5 ° C

Example 2 Oxidation of 1-benzoyl hexamethyleneimine

The conversion and extraction procedures of Example 1 were repeated using 2 g of 1-3enzoy! Hexamethyleneimine as the substrate. The residue obtained was over. F.lorisil chromatographed and washed out with Skellysolve 3 containing growing acetone-ICengen. The eluate obtained using Skellysolve 3 containing 25 / acetone gave 250 mg of 1-3enzoyl-4-oxohexamethyleneimine and the acetone eluate gave i-benzoyl-4-hydroxyhexamethyleneimine, which was determined by dichloromethane chromatography.

The i-benzoyl-4-hydroxyhexametnylenimine obtained in this way was dissolved in acetone and at room temperature by adding OrTIeS ₁ visible excess of Jones reagent (2.67 m chromic acid reagent, which is made from 26.7 g chromium trioxide and 23 ecm sulfuric acid, which had been diluted to 100 ecm with V / as2er) was oxidized. The excess oxidizing agent was decomposed by adding isopropyl alcohol and the mixture was evaporated to dryness. 20 ecm t / barrel of water were added and the product was ^{extracted with 20 ecm iu of} ethylene chloride. The jüxti-act was evaporated to dryness and the remaining i-benzoyl-4-oxohexamethyleneimine was immediately converted to bioconversion with the same The combined product was enromatographed on a iHorisil column. The column was eluted with Skellysolve B containing increasing amounts of acetone and the fractions containing the desired product, as determined by thin layer chromatography, were combined and evaporated, yielding about 770 mg 1-3enzoyl-4-

009834/1853 bad original

oxohex? metliylenimin were obtained as an oil, its Melting point was 170 to 174 ° C / 0.3 i'orr and that slowly crystallized.

Analysis calculated for O ₁₅ H ^ MO ₂ : 0 = 71.86 H = 6.96 Ii = 6 ', 45. found: 0 = 71 »51 H = 7.25 1 = 6.46

The 2,4-dinitrophenylydrazone derivative of 1-benzoyl-4-oxohexainethyleneimine has a melting point of 173.5 to 18O ⁰ G.

.Example 3 Oxidation of 1- (p- ^r uoluenesulfonyl) -hexamethyleneimine.

The Bioumy / andlungs- and jixtraktionsverfahren of the example 3 a

1 were repeated using 2 g of 1- (p-Ioj / luenesulfonyl) -nexametrtylenimine as ouostrate. The liquid from the broth extract obtained in this way was over. 100 g Ji ¹ IOrISiI Duroia stepped Bluieren The! Chromatographierfc residue was passed through ilorisil en 75 com lie thy 1 chloride. Bs was eluted ./.it 4 1 Skellysolve B, which contained from 0 to 30 4 7% aohfiende acetone compounds. There were fractions of 105 ecm uuf-efi-n ;; en each. The fractions containing the desired product, which was 1- (p-loluolsalphonyl) -4-hydrox7hexamethyleneimine (determined by thin light chromatography), were pooled, evaporated to remove the solution solvent, again; dissolved in acetone and iait the Jones Reagent ™

oxidized in the same manner as in Example 2 above to give a crude yellow solid which was crystallized from ether to give 0.33 g of 1- (p-toluenesulfonyl) -4-oxohexamethyleneimine. Schmelzpunktί 81 ^0C.

Analysis calculated for O ₁₅ H ₁ → HO ₅ S: O = 58.40 H = 6.64

il = 5.24 -8 = 12.00. found ; 0 = 58.40 H = 6.47

JJT = 5.26 S = 12.24.

Recrystallization of 1- (toluenesulfonyl) -4-QXohexamethylenimina, containing the thus obtained aua acetone Skellyeolve B v / was orden gave a crystalline modification with a melting point of 89 or 90 ⁰ O.

00 9 834 / 18S3 bad original

Example 4 Oxidation of 1-jenco / lüeptc- ^ iet.-; leni "_in

The Sioumv / iUi ^ lanjB- unl "'iirtrukticnavarii.: Hrcn: iS3. ^ Eicoielo 1 waraen using I-Benso.yllie ^ xaiiietnyleiii.r.iials substrate \ iederholt. Dor on Jiene .'leine er_ _i; Itevie backward Extract, which consists of a: G-emisc! :: of 1-ienzo; 1-4-hydroxyheptainethj-leniniin and 1 - "3enzoyl-5-iiyaroxy-i: crtametLylenimin be.stana, was obtained via i'lorisil c ^ ro: :: ato ^ ru; hiert. The hydroxylated I-Benzo ^ lheptametliyleniniine "vurdeii.: I-eluted with acetone and i-i-iit via acliüssi ^: ei: i Jones Gnrom3; A. reagent to the corresponding x-cetoaxides, which are oxidized by chromatography over ii'lorisil. ^ Etreint and with growing The more polar iCetoaniid was eluted with a gel of 25% acetone and Skellysolve B and crystallized from acetone-containing Skellysolve B and had a melting point of 1-> eii2oyl-5-oxylenoheptylated up to 124 G.

Analysis calculated for C ^ xi-jy-.iüp: 0 = 72.7C H = 7.41 ίί = 6, .. 6. found: 0 = 72.63 H = 7 _t 59 J = U, 31

The less polar 1-3eiizoyl-4-oxoii'iitametiiyleni.iiin <v was obtained as an oil from the first slurry fractions obtained by the i-i-i-io from 2o - 'j acetone and Skeilysolve B.

Example 5 Oxidation of I-Benzoyldodecaniethylenimine

The bio-conversion and extraction processes as an example 1 were under Ver ^ endun ^ vcn I-Beniäoylaodecc.iaethylenimin repeated as a substrate. The residual extract obtained was subjected to fluid chromatography analyzed and it was found that he came from a u-emic of Hydroxy-i-benzoyldodecamethvleniminen, whose Main components i-Benzoyl-S-hydroxydodecamethyleneimine,

BAD OR1G «NAL

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1-benzo; -l-δ-hydroxydodecainythylenarain and 1-3enzoyl-7-hydroxydodecamethyleneimine. The residual extract was then chromatographed over .ilorisil and the mixed itydroxy-i-beiizoyldodecanietiiylenimines were eluted with acetone and oxidized in acetone with excess Jones reagent by the same procedure as in Example 2. The ketoamide mixture obtained was cnroisato ^ rapnated over Florisil. Elution with a mixture of 25% acetone and Skellysolve β and then with acetone gave successively 1-benzoy 1-5-oxododecamethyleneimine, 1-benzoy L-6-1 , oxodouecaciothylenimine and 1-tieiizoyl-T-oxododecamethyleneimine.

Example 6 Oxidation of 2-benzoyl-2-azabicyclo _< / 2,2,27-octane

"The" iiioumv-andlunjs- and> ^r Jxtraktionsverf Ears of corn of Example 1, using 2 g 2-3enzOyl-.2-azabi-cyolo /?., 2, 27-0ctan repeated as a substrate "

Der- al ·; -.? The extract obtained back was processed via ilorisil c.arouiato / ra. ? Eluting with a mixture of acetone 25 New York Convention Skeil3 ^r solve ß ^ he .from 2-benzoyl-2-azabicyclo / 2,2,27 * - octane - ^ - ol containing from acetone Skellysolve 3 recrystallized v / Urde . Melting point: 139 to 141 ⁰ C.

Analysis calculated for C ₁₄ H ₁₇ ITO ₂ : 0 = 72.70 H-7.4-1 1T = 6, O6. found: 0 = 72.52 E = 1.19 -1 = 6.18.

The obtained 2-beiizoyl-5-hydroxy-2-asabicyclo _< / 2,2,27-octane was oxidized with the .Jones reagent in the same way as in Example 2 above, whereby 2-3enzoyl-2-azabicyclo / 2, 2.27 ~ octan-5-one was obtained.

009834/1863 _ba d

jeisp iel 7 Oxidation of 3- (p-toluenesulfonyl) -3-azabi eyclo- / 5,2, 2J-

The bioa: nwandlun £ 3 and oil extraction methods of the example 1 were using 2 g of 3- (p-l'oluolsulfonyl) - ',; - azauicyclo / 5, 2, 27-nonan air- ·, substrate repeated.

The extract obtained as residue v / urie over a j'lorisilcäule chrowiatOi -.- rapJaiert. The; 3 ^; iule ^ urde with okelly «solve 3 ;; iit '.; 3 cn send acetoimiengen partseii eluted and uie r' ^ 'aictionsn which, as darch EüniiGohichtcoromctograoLie he-.aittelt -' / LU - JtS, contained the desired products, were combined and evaporated to dryness to give 3- (p-i'oluolsulf oii "l) -3 ~ az. bicyclo ^, 2,27-nonan-u-one and 3- (p-toluene sulf orivi) -3-azaOicvclo / J3 , 2, 27-i'ionan-6-ol to give.

The eriic, l ~ en9 3- (p-l'oluenesulfonyl) 3-aza'oicyclo- / 3, 2, Z / - nons.n-6-ΰΙ v; urae after the experience of Example 2 with dera Jones Reagent oxidized, whereby J-ip-'iOluolsufloir l) -3- £ izabicyclo / 3, 2, 27-nonan-6-one obtained -.rarde.

Example 8 Oxidation of Jispüntacethylene urea

The -diouinv-andluntiS- and extraction process of each example 1 v / are repeated using 5 J 3ispenta: ethylene urea as substrate. The residue obtained as a residue was chromatographed over ilorisil. The iSluioren luit increasing Aco: clay proportions containing dkelly solve B and with acetone gave i-Pentamethylenecaroamyl-s - nyuroi:.; piperidine in the Bluaten consisting of the mixture of 2Ό ^ acetone and Skellysolve B and in de. ^! · First -j.eetoneluaten. These fractions were combined by evaporation, ην -.i: t far-unrefined solvent, redissolved in .iCcton and with ubGi ^ ac.lTUssi. / Er Jones ühi'o, .. '..u'erdajens

BAD ORfOiNAL

009834/1863

oxidized. The Ke t over binding was grapnated via .F'lorisil chroma to-. The elution: uit a mixture of 1Q ~ .o acetone and Sicollysolve B and later with a mixture of 25% acetone and Skellysolve .B gave the desired 1-penta-retnylenecarböuiyl-4-oxopiperidine, which was repeatedly made from Skellysolve B until one was obtained Melting point of 66 to 67 ⁰ G was recrystallized.

Analysis calculated for O _1. , H ₁₈ N ₂ O ₂ : 0 = 62.83 H = 8.63 1 = 13.32. found: 0 = 62.84 H = 8.36 N = 13.35 «

Example 9 Oxidation of 1-3enzoyl-2-propy! Piperidine

The conversion and extraction procedures of the example 1 were made using 2 g of i-Benzoyl-2-propylpiperidir. repeated as a substrate. The residue thus obtained was chromatographed on a Jlorisil column, and the column was diluted with Skellysolve B containing increasing amounts of acetone. The eluate fractions were analyzed by thin-sight chromatography analyzed, and those fractions containing the desired product were combined, and the solvent was evaporated to give 1-3enzoyl-4-hydroxy-2-propy! piperidine receives.

The product thus obtained was tested with the Jones Jieagens, such as

described in Example 2, oxidized, whereby i-Benzoyl-4- ™ oxo-2-propylpiperidine obtained from.

10 Oxidation of i-benzoyl-4-propy! Piperidine

The bio-conversion and extraction processes of the example 1 - were obtained using 2 g of 1-Benzoy! -4-propylpiperidine repeated as a substrate. The residue obtained in this way was chromatographed on a Jlorisil column, and the

3 /, / 1 8 S % ^{BATHROOM 0RIGINAL}

3'iule was :: iit vpoiasenäe.-Icetonaeiigeiiaiitclle eaxj ,, Vä ^ i ^ er SkGlI _1- .. Γ, οΐνβ 3 ciirouiato - ^ 'ap'i-iert. Dia jrilua ^ x ^ actions "vureen analized through thin layer aliro ^ ato ^ rapale, to ^ those ■ fractions uie the winning: elite product β.ΐΐΐιϊβίτ, βΐι, were united and the solution was v / urde from ^ ed -. ^ pft, v = oaJirch man 1-: enzoyl-4-hydro :: y-4 - ,; ropylpip ^c ; riüiii received.

Example 11 Ozjuc.tion of 1- ^: 3ea2O l-2 - keti: _t l-5 -:?. Tl:.; - l-

• piperidine.

The Biouiruandliings- and ^^ rcruir

1 were under / he. o; ^ ar: _; ? o: 2 3 i-J ^ i-

"äthylpiperidin als ouostr ·. ΐ. -ie ^ ernolb.

stood ": urae dber einer ^ lorisil-ü ^ Alo ο · ^ ΰ, ΐα ^; -" ^ iiisrt, und dia column ^ urde; ait ^r -iao:.; --- onae _ic rüonau: -a ^ aiitjil ^ suthalt -naer okullysolve 3 before thins. The .ilu ;, ϊχγ -! Ctxontii ■ -uräeu analyzed by thin-layer chromatography, and the fresh fractions, which contained the green product, were combined, and the solution was removed -jau. £: .i; ipv "c, '.voaarch man 1 -j3enzoyl-2-meth3 ^ir l-4-iydroxy-5-ätiiylpipöriaiu -Gi * Iiie" lt.

The product obtained was made according to the Jones test, as in Example 2 described, o;: ydiert, '.by. one "i-Jeii3oyl-2-methyl-4-oxo-13-ethylpiperidine received.

Example 12 Oxidation of 3-benzoyl-3-asa i ^ c ^ -olo- ^, 2.27-

nonan.

From 2.5 Ic ₁ J iviaiHquellWfcu'.ser (60: 'Featf.tcTL'e), 1 k _t iiaudnlsüblieber dextrons and 12b 1 Leitunßiv.vaoser a Ledium was divided and set to a pH- * V "zv / itichen 4 , ^ and ^ ciugeoLellt. This liedium was ateriliuiort, i-iit «iiieu 72-tjtunden old ve ;; e bativen, (achstum vou 3;> oror.riehum si;. f'urescens, A ¹ L ¹ UC 7159,; ; eim: .t't and 19 hours at an ieiapor ^ of about 28 ⁰ O with a .cielüftunj; s ^; üsciiv.'iiidi ability of -, 2 l / lüin.üül about 300 ti / i.iin. '', vaccinated. .Oa a Uu airufc, "n ^. ::;] AAx

ORIGINAL

2ο ζ 3-äeizojl-3- ^ za-jlGjclo- / 3,2,27-noniiii in solution in elü-ir .linaest lenge acetone (et ^T "/ a 2pü ecm) 7.'urde aann zur Ύ: ro. nn su ^ e ^ just, and the intubation% ^{; was} continued under the same conditions of about 50 ecm ■ tfänronä uer bio-conversion was added. Broth and llycelium were aan :: äareli ^ filter separated, the lyael was with V / ater = 'ev. ^r c;' jc-: ßii, and aas iaccliwaaoer became dera Srliheniiltrat nu ^ ej-rbeii. The so ariialten broth Filtrst wury.e vieriiial ..iit «inesi Yierxel des iPiltratvoluniens j..ietir.-le ': ichlorid extra- -lated. The Tereiiii ^ th extracts were with a' quarter / olümeii eiitioni. iiei'teia ./asser washed, and aas solution -.-. littftl>;'urde b -.- A verx "in ^ a" tem pressure, so that ..uai £ i'j., 8 g eiii ^ a äückstaiias received by Dännscnicntc: ^ir:; i: 'to_ rspfiie οχιά χβΘ-ΙΊ'αΒΒΧ ^ εχΐΒΥεΓΐ βχ ^ η ^ οϊίΓοίηΗΐο- _: ;? c- ~ - lie (Dnmpf -hase) was analyzed and, as found v.'urae, non- 'umjev-Hiidelöeö substrate, 3-3enzoyl-3-azebicyclo- / 3, 2 , 27-nonan-. -cn una J-Benzoyl - ^ - iizaoicyclo - / ^, 2, 27-n.onanc-ol contains. ZjIe 'JaGCi-roinato ^ rarl ^ ie he ^ ab that the residue is not um.-evfundeltas ouostrat, 5-i.eton- and 6- £ ydro;: ylvur'oindun.ten in proportions of 1: 4.33: 8.33 contained.

The iSxtraktrüc ^ f.taucL from the 3ioujii.vandlung (? 2i, 3 g) was dissolved in acetone and Bog ccs by adding 32 cc of Jones .ie- * - = ns - "erring b minutes while maintaining a LÖsunjste. ^ p.ir: ttir oxidized below 30 °. After the addition of 7 / urae the iemiscii v / more 10 days without temperature control, and the excess oxidizing agent was then decomposed by the rate of 10 ccia isopropanol. Ja chi err. 1 Liters of water had been flushed and the deposits had been roasted by xiahx'en, -; the mixture was extracted three times with 230 ecm of ethylene chloride each time. / ater gen, ü ^ er i.atriaiüsu.lf at getrocioiet, and the solution ami ttel

_{Λ Λ Λ Λ} BATH ORIGINAL

009834/1853

distilled off, later reduced pressure aii.:ewancit. The yield of ro η em jdückst £: na ir: JOrm unites; üls deception 2;., 2 g. The 'ä-as- and Di'iru'icIiicLtcr.'rornato ^ ri.phie showed that £ the ol iiautv.sii.ci lic-i 5- "ieazov 1-3-az :.» oieyclc- £ 1 , 2,27-iionaii-b-on with a --erin ^ en uonye not vice-. na old Suts-rat .Tar. This substance jurue dissolved in 2pC cc.-i Listnyleiichlorid., aurci: a Layer of 175 £. ^ Lorisil 'iltri -.- rt, with ^ CC ecm ^ etirylenchlor'ia unä ansciiii-i. "End j.üuU ecm 1c; · ί acetone entlialteaier Skallysolve J verä!". Lint. The combined eluate was dried and distilled through a 1C, 16 cm 7i _: .; Reux column under reduced pressure to give 12.17 g of 3-j3enzovl-3-azabicyclo- / 5.2, 27-iionan-6 -on received; Boiling point: 190-195 C / o.3 Torr ₀

The following derivatives -j.es i-Jäenzoj'l-J-azabicyclo- ^, 2, 2j nonan-6-one "were made to confirm the structure j

rbason; Melting point: 197-200 g

Analysis oerec ^ .net for: C ₁ ^ 1W ₁ E, O ₂ : G = i 5, y β .1 = 6.71 iT = 13, ö5 found: 0 = 64, Ob £ = 6, S2 .V = I 8, 29

Ozim: Melting point: 156-158 ⁰ O.

, -Uiaiyse calculates for: G ₁ ^ H _{1 K} IT ₂ 0 ₂ : 0 = 69.74 H = 7.02 i; =. 1 0.85 found. : 0 = 69.71, 1 = 7.16 i> ^! = 10.87

2,4-Sinitropheny lhydr-zon: Melting point: 198-201 C

Analysis calculated for: ^ 21 ^H 21 ¹ ^ ⁰ P ^{s O = 59} » ⁵⁶ H = 5, üO ii = 16.54 found: 0 = 59.57 H = 4.94 N = 16.65

Example 13 Oxidation of benzyl-3-i23bicyclo- ^ 5, 2, Z / ~

nonane-3-carboxylate

The conversion and extraction processes of Example 12 were _{repeated using 50 g of benzyl 3-aza-o} -r-nonane-3-carboxylate as the substrate.

0 0 9 8 3 4/1853. BATH original

The broth extract of the ^T ieazjl-6- hydroxy-3-azabicyclo- / 5.2, 27-nonane-3-carbo ^ ylate obtained from the residue contained 7 / og 22.0 g. It was dissolved in 500 com acetone and 50 ecm of the Jones reagent was slowly added with stirring and the temperature was maintained at 25 to 30 ° C for five minutes. Then, the G-emic was stirred additional 10 minutes at etv / a 23 ⁰ C and the excess oxidant was durcii addition of 15 cc. Isopropanol decomposes. Most of the acetone was removed under reduced pressure, the mixture was diluted with 500 ecm of water and extracted once with 200 ecm and four times with 100 ecm of methylene chloride. The combined extract was washed once with 250 ecm of water , dried over sodium sulfate and the solvent was removed. 19.1 g of oil were obtained, which was chromatographed over 500 g of Florisil, v / whether 150 ecm /. Ethylene chloride were placed on the column. After the step process, acetone was eluted with 8 l Skellysolve B plus from 0 to 20 ρ. " to 20 contained a Ketonumwandlungsprodukt, which was characterized as a iCoaponente by Da.npfphaeenchromatographie ₀ the fractions containing the desired product H to 20 were combined and the solvent was distilled off under reduced pressure to give 8.93 g of benzyl-6-oxo-3- azabicyclo- _< / 3,2,27-nonane-3-carboxylate were obtained as a yellow oil.

Analysis calculated for C ₁₆ H ₁₉ IO ₅ : 0 = 70.31 H = 7.01 'W = 5.13 found: 0 = 70.58 H = 7.41 N = 5.53

Was the melting point of 2,4-Dinitrophenylhydrazonderivats of benzyl-6-oxo-3-azabicyclo _(/ 3,2,27-nonane-3-carboxylate 84 has Dis 86 ⁰ C. '

Ana 1.738, calculated for C ₃₂ H _{2 ν} ίϊ ^ 0 ₆ ; ΰ = 5β, 27 H = 5.11 ii = 15.45 found: C = 5 &, 43 H = 5.21 1: 1 = 15.32

009834/1853

.Example 14 oxidation before. 1-

The 3ioum; ^ analun ~ s and 1-jxtraktionsvepxcui ^ en aes example 12 v / are repeated using 15 g 1-3enz, o. \ Ioctametnyleniniir as oubstrat. 0er -. "Lg äückstano. obtained extract, which is mainly i-Jeasoyl ^ -hjdroicyocuu.iietnyleniLiin and 1-Jenzo ^ lS-hydroxyocta ^ etrr / leiiiaiin enu-i ^ lt, vmrde in es. 1 liter of acetone on ^ eiiovxieii and; -.:. It -iinev.i excess i, it Jones Haasens oxidizes »The obtained." Otca-id ^ aiüi ^ ch "■. / Urüe over" Tlorisil chro.:,ato- ; raphiert.i> - s w3 ii ^ er polar d, 4-Oxo-i-banzoyloctamst ^ yl'jniiiiin, .v / urus ait öinem

s: us 25, ■> ücet.5ii j.nl ji- ^ allysolve .3 eluitirt and r ^ s more polar Ketootaid, ij-Cxo-1-beiiao iocu-iaetii i ^ nimin, .- / urde acetone elaiart.

■ 3 rinse 15

Jiina slogan "from 700 ^ 1- l ^ -. Zoyl— ^l j-cxou.e _: .t ^ ii ~ -zh _u ieni ^ in (aas deü *. Vorsteli'iiiuen /. Example 4) in 12 ccij. - etliäiiol.ur-de iu.it a solvent \; of 150 hl; ..c.tria ^ iborhydrid i ^ i 2 ocni n / 1 ü ii'atrianiiiydroxyd bei .iaaaue ^ puj-'c-tur about .. ". ^. ■. = ^ Lined. The product was by niiK ^ uerii Liit jJsoi / :. v ^: ui * e, ii, 'ii: - ..: yieu des j_.:röi3ten i'eils des nethauols unter rsauaierteiu jjx'uci; and distribution between, / aaser and Uethylene chloride jaworiuen. The chromatography of the or ^ a.iiüchen Lo ε an j over j'lorisil er.tab 657 mg of 1-bensoyl-5-iiydror: yheptaiaethyleniniin in the acetone eluate. j? for the JiHaI ₁ . ae \; arac aer otofi ¹ from a mixture of acetone and cSkellysolve 3 unicrystallized. Melting point: 116-118 ⁰ G.

Analysis , calculated for C ₁ ^, H ₁ QiQO ₂ : C = 72, ü7 li = ü, 21: Ι = υ, 00 found: 0 = 72, K: H = S ₁ 01 N = 6, .03

if following the procedure of Example 5 kötinen Lu same Ibo · other erf indun_; s-'öiaä 3e i ^ otoVorbinaatiy ^ in ^ u den

BATH ORIGINAL 009834/1853

corresponding -väroxyvor "biridu.njen reduced thereby" ■: -r. "· y, --a."'i..an instead of d, ES 1-, 3enzoyl-D-oxohepta: r-etl \ ^; len i, .ii. ·: "'-o ie β: ηΐο": ·''βciieiide ^ eto connection ver' / en-let. The fol- ;; enie: .i üai'vand.linjeii are intended as examples:

. 1, ·· ■ ^"3O: l-i-oxoiiept imethvleniniiii to 1-JenzoTl-4-b.Tdro2: T-ίο-.ti: vi _t: -leni; in

1 - (. - _; oluoleu ± iouyl) -4-oxoliexamGtIi3rlenimin to 1- (PI ¹ OIaOl-3ul ^ o_ijl) -4-n / aro :: 3 ^r iiex - :. äet.22'lsniriin

1- -ti ^ zoyl - ^ - Oj ·: -'-. "O.iecaui-tlij'lenimiia zu 1-üenaojl-i-n \ -ärox; -do- .: I -.:^ .: -. tryleniuin

1-, c-üzo-'l-ü-Ouiodoüecaraethyleniiain to 1-3enzoyl-6-liydroxv - .. ο λ · ί 3 ^ iT9thyloi: ii-iiix

1- l. '^ - izoj'l-T-CTOiicascöiautuylenimin to 1-Beiizoyl-T-iiyurox- ic- «. > i c .-: su "tl-y 1 eni-iiii

ylöninin to 1 -Benzoy 1-4 -i '~ y ar oxy cct.i-

yyn su 1-3Giyyy coii ..; i3i; '- = yl "i ^ i -. in

3-ii -: Jol-ioi .-- .if ouyl) -3-: iZabicyclo / 3, 2, 27- ^ onan-b-on zu (p-i'olaoiβ-ilfoiiyl) -3-3ZaOiCJcIoZ ^, 2, 27-nonan-6-ol.

00 9 834/1853

Claims (2)

"" 1 "61ZO 628 claims: 1. Method of introducing oxygen into the heterocyclic Ring a compound of the following formula: (CH ₂ ) NZ
η ^X 1 f where η is an integer from 4 to 12, X and X ₁ each represent a hydrogen atom, a methyl, ethyl or propyl group and X and X _{1 taken} together form a bridge which contains 1 to 3 carbon atoms, Z a g_ _H -SOp-R- or _) i _Ο τ> _ group, where & denotes an aryl substituent with 6 to 12 carbon atoms and R ₁ denotes an aralkyl substituent with 7 to 16 carbon atoms, characterized in that the compound of the oxidizing action of Sporotrichum sulfurescens subjects. 2. The method according to claim 1, characterized in that the daii ^ Oxidation in a v / äaeri ^ en ilährmediuai under su :: iersen aerobic conditions takes place. 3β Method according to claim 1 and 2 for rierstellun ^ a oxidized compound of the föl / * end formula: - X HO-OH Xi-Z 009834/1853 BAD OR1Q'NA ^L where n ^ is an integer from 1 to 5, n _{2 is} an integer from 2 to 8 and the sum of n .. and n _{2 is} not below 3 and not above 11, X and X _{1 are} each a methyl, Mean ethyl or propyl group and X and X ₁ together ^ enoianen form a bridge which 1 to 3 Q contains carbon atoms and Z contains an S ", -SO ₀ -H- or Q - Ο— Ά— c. V, _IYO denotes a group in which S denotes an aryl substituent having 6 to 12 carbon atoms and IL denotes an aralkyl substituent Liit 7 to 16 carbon atoms, characterized in that a compound of the following formula is used (CHp) Ii-Z χ., _1st where η denotes an integer from 4 to 12 and X, X ₁ and Z have the above meaning, subject to oxidizing ^ 'of Sporotrichuci sulfurescens. "/ experience according to claim 1 and 2, characterized in that that as the compound to be oxidized 1-3enzoylhepta- ™ met-i / lenimin, 1- (p- ^r foluenesulfonyl) -heptamethyleneimine, 1-i3enzoyloctamethyleneimine, 1-uenzoyldodecamethyleneimine, bispentamethylurea, 2-berizoyl-2-azab ± cyclo - ^, 2,27-oetane, ^ -jenzoyl- U-azubicycio - / ^ »2,27-nonane or '-; - * Benz-yl-3-azabicyclo- / 3, 2,27-nonane-3-carbox.ylat used, For l'iie Upjohn Company Kalamazoo, Hich. V, 3t.A. "Lecftx attorney 009834/1853