SK896A3 - Alcohol to azide sn2 conversion - Google Patents

Abstract

Described is a process for converting an alcohol to an azide with SN2 inversion using a phosphoryl azide, e.g. diphenylphosphoryl azide (DPPA). Good yields of azide in high enantiomeric excess can be achieved specifically for benzylic alcohols and alpha-hydroxy alkyl esters. The process is carried at preferably room temperature in an inert dry aprotic solvent, e.g. toluene, and in the presence of a proton acceptor, e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to afford high yields of high enantiomeric purities.

Description

Method for converting an alcohol group to the corresponding azide by SN2 inversion

Technical field

The invention relates to a novel process for the preparation of azides from the corresponding benzyl alcohols or α-hydroxyalkyl esters by inversion of SN2 using phosphoryl azide and a proton acceptor in a suitable solvent.

BACKGROUND OF THE INVENTION

Synthesis of an orally active elastase inhibitor nas ledu- of formula I has been described in Shah S. K., Dorn C. P., Finke P.E., Hale J. J., Hagman V. K., Brause K.A., Chandler G. 0, Kissinger A.L., Ashe B. M., Veston H., Knight V . B., Maycock A., L. Dellea P. S., Flecher D. S., Hand K. M., Mumford R. A., Underwood D., J., Doherty J. B., J. Med. Chem. 1992, 35, 3745:

(I)

The preparation of closely related active derivatives required amine 3 in enantiomeric form, theoretically obtainable via azide 2.

(2 ^

The first attempt to prepare an amine consisted of activating alcohol 1 by a known method of carrying out the sulfonate followed by an exchange with an alkali azide. However, this procedure could not be used because the activated alcohol decomposed at much lower temperatures than was necessary for the substitution (decomposition was observed at 0 ° C).

Several methods have been known from the literature for converting alcohols to azides while maintaining optical activity in electron-rich benzyl alcohols. Mitsunobu replacement with azide nucleophilic reagent appeared to be the best precursor. (In the first example, where an equivalent amine was prepared under Mitsunobu conditions, phthalimide was used: Mitsunobu 0., Vada M., Sano TJ, Am. Chem. Soc. 1972, 94, 679. Mitsunobu substitution was further reviewed by Hughes. of his article, references can be found to the variability of CN bond formation: Hughes DL, Org. React. 1992, 42, 335). For the first time, it is possible to introduce an azide group under Mitsunobu conditions using azidic acid as the azide source according to Loibner H., Collected E., Helvetica Chimica Acta, 1977, 60, 417, and this method can be extended to chiral α-arylethylamines according to Chen CP. Prasad K., Repic 0. 0, Tetrahedron Leti, 1991, 32, 7175. Alternatively to hydrazoic acid, diphenylphosphoryl azide (DPPA) according to Lal B., Pramanik BN, Manhas MS, Bosse AK, Tetrahedron Lett., 1977, can be used. 1977 and the zinc azide complex with bis-pyridine according to Viaud MC, Rollin P., Synthesis, 1990, 130.

Applying the conditions of Bose et al. (Lal B, Pramanik B N, Manhas M S, Bose A K, Tetrahedron Lett., 1977, 1977) to our substrate resulted in an undesirable direction towards elimination product 5 and recemic azide 4, i.

n ₃

Ar

(PhO) ₂ PON ₂ / DBU

91% yield

97% ee

EtO ₂ CN = NCO ₂ Et 1 (PhO) ₂ PON ₃ / PPh ₃

84% yield

82% ee

6-8%

According to the modified Bose method, alcohol 1 and triphenylphosphine were added sequentially to a solution of diethyl azodicarboxylate and DPPA in THF at 0 ° C. After 30 minutes the product was isolated in water. Azide 4 was isolated in a yield of 81% with a purity of only 82%. 6 to 8% of olefin 5 was also an undesirable reaction product. In addition, azide was contaminated six times its weight with Mitsunobu byproducts, requiring extensive chromatographic purification. Unwanted loss of optical activity as well as olefin formation has been attributed to highly reactive intermediates, which can lead to reaction progress through different ionization (SN1) and substitution (SN2) mechanisms.

A method for the conversion of alcohol to azide is required, which proceeds through a pure inversion mechanism of the SN2 configuration, which results in high yield and enantiomeric purity of the resulting azide.

SUMMARY OF THE INVENTION

SUMMARY OF THE INVENTION The present invention provides a process for converting an alcohol group to the corresponding azide by inversion of SN2. It has been found that Mitsunobu conditions requiring the use of dialkyldiazodicarboxylate and triphenylphosphine can be avoided and the use of diphenyl diphosphoryl azide in the presence of an organic proton acceptor gives directly and unexpectedly excellent results. The process for converting an alcohol to an azide of high enantiomeric purity by substantially inverting SN2 can be accomplished by dissolving alcohol (1 equivalent) and DPPA (1.2 equivalents) in a dry aprotic solvent such as toluene to a final alcohol concentration of about 0.5 to 1 mol / L. and adding a slight excess of 1,8-diazabicyclo [5.4.0] undec-3-ene (DBU) equivalent to the mixture. After stirring for several hours at room temperature, the reaction mixture is simply worked up by washing with water and removing the product. For the above example, after stirring for 5 hours at 23 ° C, azide 4 is isolated in 91% yield by simple water wash. The optical purity of the azide was 97% ee (the enantiomeric excess of the desired isomer) and the elimination product 5 was less than 1%.

The invention provides a method for converting an alcohol group to the corresponding azide by inversion SN2, comprising the step of:

reacting said alcohol I with phosphoryl azide II in a dry inert aprotic solvent in the presence of a proton acceptor soluble therein at a temperature of from -20 ° C to 100 ° C for a sufficient period of time to form the azide III resulting in inversion of SN2 with an asterisked inverted carbon where:

(a) means aromatic

C 1 -C 8 linear or branched alkyl, a 5 to monocyclic or bicyclic fused or heteroaromatic ring, in which the following heteroatoms may be present: 1 to 4 nitrogen atoms, 1 sulfur atom, 1 oxygen atom, 1 to 2 nitrogen atoms and 1 sulfur atom or 1 to 2 nitrogen atoms and 1 oxygen atom, which ring may be substituted with 1 to 3 substituents, designated X, Y or Z, which are independently hydrogen, halogen (Br, C1, F), trihalo-C 1-6 alkyl, C C ₁ -C 6 alkoxy, NH-CO-C 1 -C 6 alkyl, NH-CO-phenyl, NH-CO-OC ₁ -Cgalkyl, NH-CO-phenyl, N (CO-C ₁ -C ₆ alkyl) ₂ , N ( CO-phenyl) 2, O-CO-phenyl or wherein X and Y may be 1,2-methylenedioxy, wherein the C 1 -C 6 alkyl or phenyl radicals in said substituents may be further substituted with 1-3-halogen, C 1 -C 6 alkoxy and in the case of phenyl, C 1 -C 6 alkyl;

b) R 3 is COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, and when R ³ is aromatic or heteroaromatic while the ring may be

R ⁵ (CH) _n -COOC 1 -C 6 alkyl, wherein n = 1 to 5, R ³ is hydrogen, C 1 -C 6 alkyl, and where R can also be a C 1 -C 6 alkylene chain, represented by a full curve, which may contain one sulfur or one oxygen atom attached to R, where R ³ is a 5 to 10 membered monocyclic or bicyclic fused aromatic ring in the ortho position with respect to said alcohol moiety to form a 5-6 membered fused ring linked;

c) R ³ and R ⁴ are independently C 1 -C 6 alkyl or phenyl which may be substituted with 1 to 3 substituents such as

C 1 -C 6 alkoxy, halogen, trihalo-C 1-6 alkyl and, in the case of phenyl, C 1 -C 6 alkyl;

wherein said method is carried out in the absence of a dialkyl azodicarboxylate.

or where

X and Y are independently hydrogen, p-CF3, p-CH2, m-OCH3, p-OCH3, and wherein X and Y may together represent a 1,2-methylenedioxy group.

Wavy lines indicate alpha or beta bond.

The mechanism of the method of the invention is believed to begin with the formation of alcohol phosphate and the release of the DBU salt of azidic acid. In a substrate with a relative electron deficiency, this phosphate intermediate was observed by NMR; for compounds 3 and 4 in Table 1, the benzylic proton of phosphate forms a pair with phosphorus and an apparent quartet appears at δ = 5.5 ppm.

The liberated azide salt resembles quaternary ammonium azide, which dissolves to some extent in organic solvents. This results in the exchange of a sufficiently reactive phosphate group with azide, which is in a form soluble in an organic solvent, at room temperature.

It has been found that the in situ generated azide completely exchanges phosphate without the need for an additional azide source, i. alkali metal azide, NH4 or sodium azide. As soon as the exchange is complete (in compounds 3 and 4, benzyl methine is in δ = 4.3 ppm), the DBU and diphenylphosphate salt forms. This salt is water soluble and can be easily removed by washing with water without the need for extensive chromatographic separation. Any excess DBU can be removed by acidic washing and the remainder is the reaction product azide with only a small amount of the excess DPPA initially used. Analytically pure azide samples can be obtained by chromatography on silica gel. In addition to the simplicity of the reaction, in addition to the Mitsunobu reaction, much less by-products, a higher yield, and retained enantiomeric purity of the desired inverse product are obtained.

The yields of the reaction carried out in this way are from 60 to 95% of theory, calculated on the starting alcohol.

Enantiomeric excess (ee) is the amount of free desired optically active isomer that is present outside the racemate. For example, 96% ee means that 2% of each enantiomer and 96% pure desired enantiomer are present.

The alcohol in the reaction carried out in this manner is subject to the SN2 reaction mechanism, which inverts the carbon associated with the alcohol group to the resulting azide. Thus, alpha alcohol is converted to beta azide and beta alcohol to alpha azide.

The alcohol used in this process has the structure

OH

Where R and R are as defined above.

As used herein, the term C1-C6 alkyl means straight or branched alkyls such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, isohexyl, heptyl, octyl, isooctyl and the like. Preferably methyl is used.

As used herein, the term C 1 -C 6 alkoxy refers to the above -C 6 alkyl radical attached to the ether radical and includes: methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, s-buxoxy, β-butoxy, poxyoxy, hexoxy, isohexoxy, hepoxy, okxyloxy , iso-oxyloxy and the like. Preferably mexo ^x y is used

The term halogen means fluorine, chlorine or bromine. Fluorine is preferably used.

As used herein, the term monocyclic or bicyclic fused aromaxic hexeroaromaxic rings includes:

phenyl, naphthyl, pyridyl, pyrrole, furyl, thienyl, isoxiazolyl, imidazolyl, benzimidazolyl, xexrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzojienyl, pyrazolyl, indolyl, isoindolyl, benzinyl, carbazolyl, Xiazolyl, oxazolyl and 1,4-benzodiazepinyl, wherein the NH group in the indole, isoindolyl, carbazolyl or benzodiazepinyl group is protected during the reaction by a triple-C 1-6 alkanoyl group, for example acetyl. The alkanoyl group can be readily removed by conventional mild alkaline hydrolysis, for example with sodium hydroxide solution.

Aromaxic / hexeroaromaxic rings from the group of phenyl, naphthyl, furyl, thiophenyl, benzoxienyl and benzofuryl are preferably used.

The alcohol is preferably selected from

OH

OH

OH

wherein G is C 2 -C 4 alkylene which may be replaced by C 1 -C 4 alkyl and said alkylene chain may contain in the ring S (O) _n where n = 0 to 2.

wherein G is as defined above

OH

R ²

wherein the result is the corresponding product III with an inverted carbon atom adjacent to the azide.

It is particularly preferred that the alcohol is selected from:

wherein X is hydrogen, p-CF3, p-CH3, m-OCH3, and wherein the wavy line may be an alpha or beta bond

OH

ABOUT

OH

OH

H ₃ C ^X ~ ^X COOC ₂ H ₅

wherein X is hydrogen, p-CF3, p-CH2, m-OCH3, and wherein X and Y may together represent a 1,2-methylenedioxy group, and wherein the wavy line may be an alpha or beta bond.

and the corresponding inverted azide is:

wherein X is hydrogen, p-CF ^, _{p-CH3, m-OCH3, p-OCH3}

ν ₃

H ₃ C ^{x 1 x COOC} ₂ H 5

The invention also relates to the following novel compounds:

wherein X and Y may independently be hydrogen, p-CF ₃ , p-CH 3, m-OCH ₃ , p-OCH _3, and wherein X and Y may together represent 1,2-methylenedioxy and wherein the wavy line may be an alpha or beta bond.

The phosphorylazide used is of the formula:

(R ³ 0) (R ⁴ O) P (O) _N3 wherein R ³ and R ⁴ are independently C ^ -Cgalkyl or phenyl optionally substituted with 1 to 3 substituents of C - ^ - alkoxy, halo, trihalo -C 1-6 alkyl and, in the case of phenyl, in addition C 1 -C 6 alkyl. Preferably R ³ and R ⁴ both represent phenyl.

The phosphorylazides disclosed in the above description are either well known in the art or can be prepared by methods described in the art.

Representatives of phosphorylazides include:

diphenylphosphoryl azide di (p-methoxyphenyl) phosphoryl azide di (p-fluorophenyl) phosphoryl azide di (p-tolyl) phosphoryl azide diethylphosphoryl azide di (n-butyl) phosphoryl azide di (p-CF ₃ phenyl) phosphoryl azide di (2,4-dichlorophenyl) phosphoryl azide and others .

Preferably, diphenylphosphoryl azide is used.

The proton acceptor useful in the process include: Cg-C ^ gdiazabicykloalkány, Cg-C ₁₀ diazabicycloalkenes, 1-5 C, -C ₃ alkyl substituted guanidines, C ^ -Cgheteroaromatické nitrogen-containing compounds or pyridine, mono- or di-C ₁ -C ₄ alkyl amines. All of these proton acceptors are either sufficiently known in the art or can be prepared by methods described in the art.

Examples include:

1,8-diazabicyclo [5.4.0] undec-7-ene (DBU)

1,4-diazabicyclo [2.2.0] octane (Dabco)

1,5-diazabicyclo [4.3.0] non-5-ene (DBN)

1,1-dimethylguanidine

1,1,3,3-tetramethylguanidine

1,1,3,3,4-Pentamethylguanidine pyridine quinoline

4- (dimethylamino) pyridine

4- (diethylamino) pyridine

Preferably, DBU and Dabco are used.

Temperatures in the range of -20 to 100 ° C, preferably 20 to 50 ° C and particularly preferably room temperature are used in the reaction.

For the alcohol, phosphoryl azide and proton acceptor, a dry, inert, aprotic solvent is used in the reaction. Useful solvents include ^ -5 ^ ~ 'i2 ^{us the} characterized ® hydrocarbons, Cg-C ^ Q substituted aromatic hydrocarbons which may be substituted by 1 to halogen (Br, Cl, F), or C - ^ - C ^ alkyl substituents, 1 to 4 halogenated C 1 -C 8 straight or cyclic alkanes, C ₄ -C 8 straight or cyclic ethers, C 1 -C ₂ N, N-dialkylformamides, C 1 -C 2 N, N-dialkylacetamides or C 1 -C 2 alkylnitriles.

These solvents are commercially available and include hexane, benzene, toluene, m-xylene, p-xylene, naphthalene, chlorobenzene, o-dichlorobenzene, methylene chloride, chloroform, carbon tetrachloride, chlorocyclohexane, diethyl ether, dioxane, tetrahydrofuran (THF), 1,2 dimethoxyethane, N, N-dimethylformamide, N, N-diethylformamide, N, N-dimethylacetamide, N, N-diethyl acetamide, acetonitrile and the like. Preferably, THF and toluene are used.

The reaction is preferably carried out in a dry inert atmosphere containing dry nitrogen.

Conventional apparatuses are used.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the main idea of the invention and should not be construed as limiting the scope or spirit of the invention.

The general azidation procedure used in the examples is as follows.

General procedure

The alcohol (1 mmol) and diphenylphosphoryl azide (1.2 mmol) were dissolved in 2 mL of dry solvent (toluene or THF). Undiluted 1,8-diazabicyclo [5.4.0] undec-7-ene (1.2 mmol) was added to the mixture under nitrogen. The mixture is stirred at 20 ° C until completion of the reaction, typically 12 hours. The mixture was diluted with 3 mL of toluene and washed with 2x3 mL of water and 3 mL of 5% HCl. The organic layer was concentrated in vacuo and the pure azide was obtained by silica gel chromatography. Typical yields are 80-95% and excess enantiomer 80-99%. The general procedure is further described for 1-aryl-1-hydroxypropanbenzyl alcohols (Ar = aryl).

This reaction is extended to a variety of alcohols of different structure, as shown in Table 1. Examples of compounds 1 to 5 include the range from electron-deficient alcohols (para-CF 3) to electron-rich alcohols (para OMe). Benzyl alcohol coupled to the methamethoxy-substituted phenyl group (compound 3) has recently been used in conjunction with Mitsunobu exchange to demonstrate chiral amine synthesis (Chen C. P., Prasad K, Repic O., Tetrahedron Lett., 1991, 32, 7175). However, the meta-methoxy substituent actually attracts electrons (positive Hammet value) and is less susceptible to racemization than substituted phenyl (Lowry TM, Richardson KS, Mechanism and Theory in Organic Chemistry, 2nd ed. Harper and Row., 1981, p. 1). 134). We have shown the use of the method for a more general group of benzyl alcohols. It is clear that substrates need not be electron-rich for successful conversion. However, changes in the electron structure of the various substituents on the aryl ring affect the swap step rate. In all cases, the phosphate formed within an hour, but Compound 1 (para-CF 3) required a temperature of 40 ° C to complete the exchange, while the preparation of Compound 1 (para-OMe) was completed at 0 ° C within several hours. Compounds 7 to 9 represent an extension towards electron-rich heterocycles.

Racemization was typically less than 2% in all examples except compound 5 (p-methoxyphenol) and compound 8 (furan, substituted at the 2-position). In these examples, 5% and 10%, respectively, of the opposite enantiomers were formed. Compounds 10-11 show a method using various intermediates (Blacklock TJ, Sohar S, Butcher JV, Lamanec T., Grabowski EJ, J. Organ. Chem., 1993, 58, 1672). Both C-4 cis and trans alcohols are subject to complete inversion. These diastereomers exclude the possibility of azide attack selectively from the sides (Blacklock TJ, Sohar S., Butcher JV, Lamanec T., Grabowski EJJ, J. Organ. Chem., 1993, 58, 1672). This is currently the highest level of stereochemical control reported for the introduction of C-4 amines into these molecules. The method can be extended to obtain protected amino acids (compound 12). In this case, the ester group sufficiently activates the hydroxyl group at the substitution without the adjacent phenyl ring. For an example of substitution of the α-hydroxyester with an amine equivalent, see: Effenberg F., Burkhard U., Villfahrt J. Angew. Chem. Int. Ed. Engl., 1983, 22, 65. For an example of Mitsunobu HN ₃ substitution see: Fabiano E., Golding BT, Sadeghi MM, Synthesis 1987, 190. For an example of the use of protected hydroxylamine under Mitsunobu conditions see: Kolasa T. Miller, MJ, J. Org. Chem., 1987, 52, 4978. For an example of the use of p-nitrobenzenesulfonate see: Hoffmann RV, Kim H. O., Tetrahedron 1992, 48, 3007. : Zallom, J., Roberts, DC, J. Org. Chem. 1981, 46, 5173. Because the products are susceptible to epimerization (see Fabiano E., Golding BT, Sadeghi MM, Synthesis 1987, 190), a slight base deficiency (0.98 equivalents of lent) was used.

The primary alcohol in compound 13 formed azide in toluene or THF at room temperature very slowly (5% conversion after 24 hours). The use of conditions more preferred for SN2 exchange (DMF at 65 ° C for 3 hours) resulted in complete completion of azide formation. (When DPPA and DBU were mixed in a polar solvent such as CH ₃ CN or DMF in the absence of alcohol, gas evolution occurred. The base should always be added last). The secondary alcohol formed a low yield azide even under harsh conditions (compound 14, DMF at 125 ° C for 18 hours). However, this substrate forms azide with good yield under Mitsunobu conditions (Lal B., Pramanik BN, Manhas MS, Bosé AK, Tetrahedron Lett., 1977, 1977). These observations allow the relative reactivities to be aligned using Mitsunobu conditions as compared to the method of the invention. In the Mitsunobu reaction, the reactive intermediate appears to be alkoxyphosphonium (Hughes DL, Org. React., 1992, 42, 335). This highly reactive intermediate permits easy exchange of the non-activated secondary alcohol. Such highly reactive intermediates may not be suitable if the substrate is optically active electron-rich benzyl alcohol. In such a case, the phosphate is suitably balanced so that the racemization is still suppressed and the azide exchange proceeds smoothly at temperatures between 0-25 ° C.

General procedure

_____ n ₃

Ar

Table 1

Compound ALCOHOL________AZ1D ^b ________ Yield

X = meta-OMe ^e 97.5% ee

X = para-CH 3 ® 97% ee

X = para-OMe ® 99.4 ^f % ee

99.5% ee

OH

ABOUT

97.4% ee®

98.7% ee

94.3% ee

94%

96.0% ee

87.6% ee

89%

91%

80%

96.9% ee

Table 1 - continued

Compound ALCOHOL · ³ . AZID ^b _________ EXTRACT,,

99.6% es ® · ⁹

N.

71.3%

92%

OH

2:98 ^h cislrans

92%

Table 1 - continued

compound alcohol ³ AZID ^b YIELD OH n ₃ 12 ^ CO ₂ Et CO ₂ Et 87% 99% eej 98% ee ^ik 13 n-decanol n decylazid 88% 14 cholesterol cholesterylazid 20%

(a) Optical purity was determined by gas chromatography on a Cyclodex-B column.

b) The ratio of enantiomers was determined by reverse phase HPLC after reduction of the azide to the amine with LiAlH 4 and conversion of the amine to methyl carbamate (methyl chloroformate, triethylamine). All examples were compared to independently racemic samples.

c) The alcohol was prepared via enantioselective ketone reduction (Mathre, D.J., Thompson, A.S., Douglas, A.V., Hoogsteen, K., Caroll, JD., Corley, E.G., Grabowski, E.J., J. Org. Chem., 1993, 58, 2880.

d) The alcohol was commercial (Aldrich).

e) The alcohol was prepared via the addition of asymmetric dialkylzinc according to the procedure of: Yoshioka M., Kawakita T., Ohno M., Tetrahedron Lett., 1989, 30, 1657 and Takahashi

H., Kawakita T., Yoshioka M., Kobayashi S., Ohno M., also there, 1989, 30, 7095.

f) Optical purity was determined on a chiracel OD column.

g) Optical purity was determined on a chiracel OB column.

h) The alcohol ratio was determined by reverse phase HPLC, the azide ratio was determined by NMR.

i) Azidations were in THF.

j) Optical purity was taken according to Aldrich data.

k) The ratio of enantiomers was determined on a chiracel crownpack (CR +) column after reduction of the azide to the amine with triphenylphosphine.

The boiling points and the optical rotation of the azides in Table 1 are as follows.

Compound Boiling point / pressure Rotation (° C / kPa)

1 65 / 0.07 [a] D ^ ² = - 69.4 (c = 02, hexane) 2 105-110 / 2.00 [α] D ² = - 115.1 (c = 1.02, hexane) 3 95 / 0.13 [a] D ^ ² = + 155.5 (c = 0, hexane) 4 [a] D ^ ² = + 170.5 (c = 0, hexane) 5 110 / 0.08 [α] D ²² = + 141.2 (c = 0.99, hexane) 6 140 / 2.00 [a] D ^ ² = - 25.3 (c = l, hexane) 7 100 / 4.00 [a] D ^ ² = + 99.2 (c = 0, hexane) 8 105 / 4.67 [a] ² 5 = + 96.7 (c = 0, hexane) 9 [a] ² 5 = _i25 (c = 02, hexane) ¹⁰ melting 118 - 119 [α] D ² = -232 (c = 1, 13, methanol) 11 melting 99 - 101 [a] ² 5 ₌ _53,9 _(c = 02, methanol) 12 105 -110/13, 33 [a] ² 5 = + i7,5 (c = 1.03, hexane)

Claims (8)

PATENT CLAIMS A method for converting an alcohol group to the corresponding azide by inversion SN2, comprising the step of: OH (II) reacting said alcohol I with phosphoryl azide II in a dry inert aprotic solvent in the presence of a proton acceptor soluble therein, at a temperature of from -20 ° C to 100 ° C, for a sufficiently long time to form azide III, in which SN2 inversion results in an asterisk indicating inverted carbon, where: a) ^R1 is C ^ -C straight or branched alkyl of 5 to A 10 membered monocyclic or bicyclic fused aromatic or heteroaromatic ring in which the following heteroatoms may be present: 1-4 nitrogen atoms, 1 sulfur atom, 1 oxygen atom, 1-2 nitrogen atoms and 1 sulfur atom, or 1 to 2 nitrogen atoms, and 1 an oxygen atom, wherein this ring may be substituted with 1 to 3 substituents, designated X, Y or Z, which are independently hydrogen, halogen (Br, Cl, F), trihalo-C 1-6 alkyl, C 1 -C 6 alkoxy, NH- CO-C 1 -C 8 alkyl, NH-CO-phenyl, NH-CO-OCL-C 8 alkyl, NH-CO-phenyl, N (CO-C ₁ -C ₈ alkyl) ₂ , N (CO-phenyl) 2, O-CO- phenyl or wherein X and Y may be 1,2-methylenedioxy, wherein the ^C1 -C6 alkyl or phenyl radicals in said substituents may be further substituted with 1-3-halo, C1-C6 alkoxy and, in the case of phenyl, C1-C6-alkyl ; b) R 1 represents COOC 1 -C 6 alkyl, C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl, and when it is aromatic or heteroaromatic while the ring, R may be R ⁵ (CH) _n -COOC ₁ -C ₈ alkyl wherein n = 1 to 5, R 8 is hydrogen, And wherein R ^ may also be a -C ^ alkylene chain, represented by a full curve, which may contain one sulfur atom or one oxygen atom in the chain, attached to R ^ when R ^ is a 5-10 membered monocyclic or a bicyclic fused aromatic ring at an ortho position relative to said alcohol group to form a 5 to 6 membered fused fused ring; c) R 1 and R ⁴ are independently C 1 -C 6 alkyl or phenyl, which may be substituted with 1 to 3 substituents such as C 1 -C 6 alkoxy, halogen, trihalo-C 1-6 alkyl and, in addition, for C 1 -C 6 alkyl; wherein said method is carried out in the absence of a dialkyl azodicarboxylate. Conversion method according to claim Q is characterized in that both radicals R a 1 R ⁴ are phenyls. 3. The conversion method according to claim 1, wherein the temperature is a claim 1, ranging from 20 to 50 ° C. 4. A method according to any one of the preceding claims, wherein the guanidine acceptor, which c bicycloalkane or alkene according to claim 1; is a C 8 -C 10 diazate of 1 to 5 substituted with a C 8 alkyl, compound or pyridine, C4 to C8 heteroaromatic nitrogen mono or disubstituted to C 4 alkylamine. 5. The method of conversion according to claim 1, wherein D is C characterized in that the solvent is a saturated hydrocarbon to Cg, Cg and C _1Q aromatic hydrocarbon, which may have as substituents 1 to 3 halogens, or-C 4 alkyl groups, halogenated 1-4 C 1 -C 8 alkane, C 4 -C 8 straight or cyclic ether, N, N-di-C 1 -C 2 alkylformamide, N, N-di-C 1 -C 2 alkyl acet26 amide, to C 2 alkylnitrile. 6. The process of claim 1 wherein the radical is an aromatic or heteroaromatic ring selected from the group: phenyl, naphthyl, pyridyl, pyrrole, furyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, thiazolyl, oxazolyl, and 1,4-benzodiazepinyl, wherein the NH group in the indole, isoindolyl, benzyl, isoindolyl, or benzyl group is protected by a leaving C 1 -C 4 alkanoyl group during the reaction. Conversion method according to claim 1, characterized in that the alcohol I is an alcohol from the group: OH wherein G is C 2 -C 4 alkylene which can be replaced by C 1 -C 4 alkyl and said alkylene chain may contain in the ring S (O) _n where n = 0 to 2. OH wherein G is as defined above R OH, R @ 1, R @ 1 O, R @ 1 O, alkyl, and the result of the reaction is the corresponding azide III with an inverted carbon atom adjacent to the azo group. Conversion method according to claim 7, characterized in that the alcohol I is an alcohol from the group: OH wherein X is hydrogen, p-CF ₃ , p-CH 3, m-OCH 3, and wherein the wavy line may be an alpha or beta bond ABOUT OH OH OH • t HaC ^ cooCsHg wherein X is hydrogen, p-CF ^, _p-CH3, m-0CH _3, and wherein X and Y together can represent 1,2-metyléndioxoskupinu and wherein the wavy line indicates an alpha or beta bond. and the corresponding inverted azide is: wherein X is hydrogen, p-CF3, p-CH3, m-OCH3, p-OCH3 N ₃ N ₃ ν ₃ R Ν ₃ η ₃ ο ^ όοοο ₂ η ₅ or Y wherein X and Y independently represent hydrogen, p-CF 4, p-CH 3, m-OCH 4, p-OCH 4, wherein X and Y may together represent a 1,2-methylenedioxy group wherein the wavy line may be an alpha or beta bond.