WO2002012185A1

WO2002012185A1 - Process for preparing 2,3-diaminopropanols and synthesis of other compounds using 2,3-diaminopropanols

Info

Publication number: WO2002012185A1
Application number: PCT/KR2001/001362
Authority: WO
Inventors: Won Koo Lee; Seong-Ho Shin; Hyun-Joon Ha
Original assignee: Chembionex Co., Ltd.; Hansol Chemience Co., Ltd.
Priority date: 2000-08-10
Filing date: 2001-08-10
Publication date: 2002-02-14
Also published as: AU2001277801A1; KR20030029816A; KR20000063913A

Abstract

The invention relates to a process for producing 2,3-diaminopropanol of formula (II) from aziridine of formula (I) wherein, R1 is selected from a group consisting of hydrogen, alkyl, cycloalkyl, acyl, aryl, hydrocarbon residues, aralkyl, and those groups substituted with suitable substituent(s); R2 is selected from a group consisting of hydrogen, alkyl, cycloalkyl, C¿2?-C5-alkenyl, aralkyl which may be optionally substituted with suitable substituent(s), aryl which may be optionally substituted with suitable substituent(s), and heteroaryl which may be optionally substituted with suitable substituent(s); each of R?3 and R4¿ is independently selected from a group consisting of hydrogen, C¿1?-C12 alkyl, C1-C12 alkylcarbonyl, C1-C12 alkyloxycarbonyl, aryl, mono- or di(C1-C12)alkylamino, mono- or di(C1-C12)amino carbonyl, wherein C1-C12 may be optionally substituted, or R?3 and R4¿, together with nitrogen atom which they are attached to, may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C¿1?-C12)alkylamino C1-C4 alkylidene.

Description

PROCESS FOR PREPARING 2,3-DIAMINOPROPANOLS AND SYNTHESIS OF OTHER COMPOUNDS USING 2,3-DIAMINOPROPANOLS

Technical Field 2,3-diaminopropanol is an important material used in production of fine chemicals, particularly medicaments or their intermediates or other catalyst and high value-added compounds (D. Lucet, Angew. Chem. Int. Ed. Engl. 1998, 37, 2580-2627). Background Art

Heretofore, the processes for preparing 2,3-diaminopropanol by directly incorporating two amines into alkene, or oxidizing the alkene, and subsequently subjecting to animation (A. Chong, J Am. Chem. Soc. 1977, 99, 3420, and H. C. Kolb, Chem. Rev. 1994, 94, 2483-2547) were known. However, the present invention relates to a process for preparing 2,3-diaminopropanol by regiospecifϊc ring opening of an optically pure aziridine ring using nitrogen nucleophile. Of course, researches have been made as to the method of preparing azide by ring opening an aziridine having no protecting groups on the nitrogen atom, or an activated aziridine ring having a strong electron-withdrawing group such as tosyl on the nitrogen atom (G. Swift, J. Org. Chem. 1967, 32, 511-517 and T. Turoki, Chem. Lett. 1995, 337-338). But, these processes have limitations that the reaction yield is very low, e.g., not more than 40% and only an activated aziridine should be used. Also, these processes have low regioselectivity. Thus, the present inventors propose a process for producing 2,3- diaminopropanol, by ring opening an optically pure aziridine, and reacting it with an amine.

The obtained optically pure 2,3-diaminopropanol is used to produce, for example, hydroxymethylpiperazine which is useful as an intermediate of medicament. The processes for producing an optically active piperazine was proposed via a catalytic hydrogenation (U.S. Patent No. 5,977,364), or resolution of racemic mixture (U.S. Patent No. 5,945,534) were known. The present invention is characterized by a process for preparing 2,3- diaminopropanol from a chiral diamine. In addition, when morpholine is used as amine in the present process, D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol etc. can be produced, which is biologically active. Disclosure of the Invention

The present invention provides a process for producing 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting it with various amines. The obtained 2,3-diaminopropanol is used in the synthesis of high value-added compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2- decanoylamino-3 -morpholino- 1 -propanol, etc.

The object of the present invention is to provide a process for producing 2,3- diaminopropanol derivatives of formula (2) which act as intermediates in the synthesis of medicaments from aziridine alcohol of formula (1) and a process for producing the other useful compounds therefrom. Accordingly, the processes of the present invention can have four preparations as follows.

Preparation 1

A compound of formula (1) was reacted with halotrialkylsilane [Si(R)₃X] to carry out a regiospecific ring opening reaction of the aziridine, and then the resulting intermediate was reacted with an amine (NHR³R⁴) to produce a compound of formula (2). This can be schematically illustrated in the following Scheme 1

Scheme 1

(1 ) (2) wherein R¹ is selected from the group consisting of hydrogen; alkyl; cycloalkyl; 3- triazinyl or pyrimidyl acyl; aryl; hydrocarbon residues; aralkyl; and those substituted with suitable substituent(s), and includes 4-chlorophenyl, 4-methoxyphenyl, benzyl, 2,4- dimethoxyphenyl, (lR)-phenylethyl and (lS)-phenylethyl, preferences are given to (1R)- phenylethyl and (lS)-phenylethyl; R² is selected from the group consisting of hydrogen; alkyl including, but not limiting to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, dodecyl; cycloalkyl including, but not limiting to cyclohexyl, cyclopentyl; C₂-C₅ alkenyl including, but not limiting to ethenyl, propenyl, butenyl, pentenyl; aralkyl; heteroaryl; and those which can be substituted with suitable substituent(s), preferences are given to hydrogen, lower alkyl, C₂-C₆ alkenyl, thiazolyl, phenyl, lower alkyl, lower alkoxy, or phenyl substituted halogen atom(s); and each R³ and R⁴ is independently selected from the group consisting of hydrogen, C_r C₁₂ alkyl, C C_u alkylcarbonyl, C_rC₁₂ alkyloxycarbonyl, aryl, amino, mono- or di(C₁-C₁₂)alkyl amino, mono- or di(Cι-C₁₂)aminocarbonyl, wherein C_rC_n may be optionally substituted with the suitable substituent(s), or R³ and R⁴, together with nitrogen atom which they are attached to, can form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C,- C₁₂)alkylamino(C₁-C₄)alkylidene; with the proviso that Preparation 1 is excluded when R³ and R⁴ are both equal to hydrogen. Where R³ and R⁴ are both hydrogen, Preparation 2 may be applied. In this specification, the term "aryl" includes, but is not limited to, C₅-C₁₄ aromatic hydrocarbon group such as phenyl, indenyl, naphthyl, phenanthrenyl, anthracenyl etc.

The term "heteroaryl" includes, but is not limited to, 1 to 4 unsaturated 3- to 8- membered heterocyclic moieties containing 1 to 4 nitrogen atoms (e.g., pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl etc.); unsaturated condensed heterocyclic moieties containing 1 to 4 nitrogen atom(s) (e.g., indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., oxazolyl, isoxazolyl, oxadiazolyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., morpholinyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzoxazolyl, benzoxadiazolyl); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g., thiazolyl, isothiazolyl, thiadiazolyl, dihydrothiazinyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g., thiazolinyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 or 2 sulfur atom(s) (e.g., thienyl, dihydrodithiinyl, dihydrodithionyl etc.); saturated 3- to 8-membered heterocyclic moieties containing 1 or 2 oxygen atom(s) (e.g., tetrahydrofuryl, tetrahydropyranyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) (e.g., benzothiazolyl, benzothiadiazolyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 oxygen atom (e.g., furyl etc.); spiro heterocyclic moieties containing 1 or 2 oxygen atom(s) (e.g., dioxaspiroundecanyl etc.); unsaturated 3- to 8-membered heterocyclic moieties containing 1 oxygen atom and 1 or 2 sulfur atom(s) (e.g., dihydrooxathiinyl etc.); unsaturated condensed heterocyclic groups containing 1 or 2 sulfur atom(s) (e.g., benzothienyl, benzodithiinyl etc.); unsaturated condensed heterocyclic groups containing 1 oxygen atom and 1 or 2 sulfur atom(s) (e.g., benzoxathiinyl etc.). Preferences are given to pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3 -oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl.

The term "suitable substituent(s)" includes, but is not limited to, lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy etc.), lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1-, 2- or 3-butenyI, 1-, 2-, 3- or 4-pentenyl etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1-butynyl, 5-hexynyl etc.), mono- (or di- or tri-)halo(lower)alkyl (e.g., fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dibromomethyl, 2,2-difluoroethyl etc.), halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl etc.), ar(lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl, nitro, amino, protected imino, di(lower)alkylamino (e.g., dimethylamino, diethylamino, diisopropylamino etc.), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, cyano, mercapto, lower alkylthio, imino. The term "aralkyl" includes, but is not limited to, phenyl(lower)alkyl such as benzyl, phenethyl, phenylpropyl.

The term "haIotrialkylsilane[Si(R)₃X]" includes, but is not limited to, chlorotrimethylsilane, bromotrimethylsilane, iodotriethylsilane. The term "lower" means that the number of carbon is 1 to 6. The term "lower alkyl" indicates, but not limited to C,-C₆ linear or branched moiety(ies) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, and the term "alkyl" includes, but is not limited to, linear or branched C,-C₂₀ alkyl such as methyl, ethyl, propyl, 2-ethylhexyl, octyl, dodecyl, hexadecyl, and octadecyl. Also, all the preparation processes of the present invention are usually carried out in a solvent such as acetonitrile, benzene, N,N-dimethylformamide, tetrahydrofuran, methylene chloride, ethylene chloride, chloroform, diethyl ether or other solvents which do not adversely influence the reaction. Preferably, a conventional organic solvent can be used. More preferably halogenated organic solvent, and most preferably methylene chloride can be used. The reaction temperature is not critical, and the reaction is usually carried out under cooling to warming.

Preparation 2

An azidoaminoalcohol of formula (3) was produced by reacting a compound of formula (1), the same starting material as in Preparation 1 by a known process (Y. Lim, Tetrahedron Letters, 1995, 36, 8431, and B. C. Kim, Tetrahedron, 1996, 52, 12117), reacting the compound with azidotrialkylsilane[Si(R')₃N₃] to carry out a regiospecific ring opening reaction of the aziridine. 2,3-diaminopropanol of formula (4) was produced by reducing the obtained compound of formula (3) using a conventional azido reduction process. According to this procedure, a product wherein R³ and R⁴ are both hydrogen [i.e., a compound of formula (4)] can be produced.

Scheme 2 Si(R')₃N3 reduction

(3) (4)

(1 )

"Azidotrialkylsilane[Si(R')₃N₃]^M as used herein includes, but is not limited to, azidotrimethylsilane or azidotriethylsilane. Preference is given to azidotrimethylsilane. The "reduction" according to this invention can be commonly carried out by the conventional procedures in the art such as chemical reduction and catalytic reduction. The following is a brief introduction of the reduction procedure, which can be used in the present invention.

Suitable reducing agents to be used in the chemical reduction are hydride (e.g., lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride etc.); mixture of borane and tetrahydrofuran or di(lower)alkyl sulfide (e.g., dimethyl sulfide etc.); or mixture of metal (e.g., tin, zinc, iron etc.) or acid compound (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid etc.).

Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalyst (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire etc.), palladium catalyst (e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate etc.), nickel catalyst (e.g., reduced nickel, nickel oxide, Raney nickel etc.), cobalt catalyst (e.g., reduced cobalt, Raney cobalt etc.), iron catalyst (e.g., reduced iron, Raney iron, Ullmann iron etc.) and the like.

The known reduction procedures can be utilized in reducing an azido group to an amino group in Preparation 2, and the typical examples are reduction by LiAlH₄, reduction by Ph₃P and catalytic reduction (catalytic hydrogenation), etc.

The reduction is usually carried out in a solvent such as water, alcohol, tetrahydrofuran, dioxane, N,N-dimethylformamide, or a mixture thereof; or other solvents which do not adversely influence the reaction. When the acid used in chemical reduction is liquid, it can also act as a solvent.

The reaction temperature is not critical and the reaction is usually carried out under cooling to warming.

Preparation 3

A compound of formula (6) can be produced by subjecting 2,3-diaminopropanol of formula (5) (i.e., the compound of formula (2) obtained from Preparation 1, wherein R³ is hydrogen) to reduction as shown in Scheme 3, preferably reduction using a compound having a dialdehyde group and a hydride reducing agent. The compound of formula (6) was subjected to a conventional reduction in the presence of a compound capable of producing an amino protecting group (i.e., amino protector), preferably reduction by catalytic hydrogenation (catalytic reduction) as described above to produce a compound of formula (7). Typical compound of formula (7) includes l,4-di-t-Boc-2(R)-hydroxymethylpiperazine (wherein "Boc" stands for tert-butyloxycarbonyl).

Scheme 3

(5) (6) ^{')

wherein R¹, R² and R⁴ are as defined hereinbefore, and R⁵ is an amino protecting group, which is suitable for protecting (or blocking) an amino group from chemical reaction, and is easily removable after completing the desired reaction on the other site.

Typical examples of this type include substituted or unsubstituted acyl, aryl, aralkoxymethyl or aralkyl group etc. The name or size of amino protecting groups is not critical because they are removed after completing the desired reaction. However, those having 1 to 20 carbon atom(s), particularly 1 to 8 carbon atom(s) can be preferably used.

The term "acyl group" as used herein can have the broadest meaning in regard to this process. It includes an acyl group derived from aliphatic, aromatic aliphatic, aromatic or heterocyclic carboxylic acid or sulfonic acid as well as alkoxycarbonyl, aryloxycarbonyl, particularly aralkoxycarbonyl group. The examples of acyl group include, but are not limited to, alkanoyl such as acetyl, propionyl, butyryl, decanoyl etc.; aralkanoyl such as phenylacetyl etc.; aroyl such as benzoyl or toluyl etc.; aryloxyalkanoyl; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, Boc, 2-iodoethoxycarbonyl etc.; aralkylcarbonyl such as Cbz(carbobenzoxy), 4-methoxybenzyloxycarbonyl, Fmoc (9- fluorenylmethoxycarbonyl) etc.; arylsulfonyl. As the amino protecting group, the preference is given to Boc, and also to Cbz, Fmoc, benzyl or acetyl. Thus, as the "amino protector" in the present invention, t-butyl carbonate, methylcarbamate, ethylcarbamate or 9- fluorenylmethylcarbamate can be preferably used.

The "hydride" includes, but is not limited to, lithium aluminum hydride, sodium borohydride or sodium cyanoborohydride.

The "a compound having a dialdehyde group" is well known in the art, and preferably glyoxal can be used.

Preparation 4

As can be seen in Scheme 4, the compound of formula (8) can be prepared by subjecting R¹ group of the compound of formula (2) to a conventional reduction procedure, preferably to a reduction using catalytic hydrogenation as described hereinbefore, and then reacting it with alkanoyl halide (R⁶X). Typical examples of the compound of formula (8) include D-threo-l-phenyl-2-decanoylamino-3-morpholino-l-propanol.

Scheme 4

(2) (8)

Unless otherwise indicated, R¹, R², R³ and R⁴ and the redction are as defined hereinbefore,

R⁶ includes, but is not limited to, alkanoyl group such as acetyl, propionyl, butyryl, valeryl, pivaloyl, hexanoyl, isobutyryl, 2-ethylbutyryl, 3,3-dimethylbutyryl, decanoyl, preference is given to decanoyl, and X is fluoro, chloro, bromo or iodo.

The following examples are given for the purpose of illustrating the present invention in more detail.

Example

Example 1

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-methylpropanol

N-[(S)-l-phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol (201 mg) was dissolved in methylene chloride, to which azidotrimethylsilane (0.25 ml) was added. The reaction mixture was stirred at ambient temperature for 12 hours, was treated with IN of aqueous hydrochloric acid solution and then was stirred for 1 more hour. The solution was neutralized with sodium hydrogen carbonate, and the reaction product was extracted twice each with 5.0 mi of methylene chloride. The combined organic extracts were dried under anhydrous magnesium sulfate, and the solution was filtered, concentrated in vacuo and purified to give 154 mg of product as an oil. Rf 0.21 (EtOAc/hexane 20:80). [α ]_D ²⁶= -146.3 (c 2.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.38-7.25 (m, 5H), 3.96 (q, J= 6.5 Hz, 1H), 3.64 (m, 2H), 3.35 (dd, J= 12.8, 3.0 Hz, 1H), 2.25 (m, 1H), 1.40 (d, J= 6.4 Hz, 3H), 1.09 (d, J= 6.2 Hz, 3H).

Example 2

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-n-butylpropanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-n-butyl]methanol, the titled compound was produced. Rf 0.24 (EtOAc/hexane 20:80). [α ]_D ²⁷ = -98.6 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.33-7.24 (m, 5H), 3.95 (q, J- 6.5 Hz, IH), 3.63 (dd, J= 12.6, 4.6 Hz, IH), 3.39 (m, 2H), 2.33 (m, 2H), 1.38 (d, J= 6.5 Hz, 3H), 1.23 (m, 5H), 0.86 (m, 3H).

Example 3

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-t-butylpropanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-t-butyl]methanol, the titled compound was produced.

Rf 0.46 (EtOAc/hexane 20:80). [α ]_D ²⁶= -99.2 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.33-7.24 (m, 5H), 3.97 (q, J= 6.6 Hz, IH), 3.64 (dd, J= 12.6, 4.6 Hz, IH), 3.32 (dd, J = 12.6, 4.8 Hz, IH), 2.98 (d, J- 4.9 Hz, IH), 2.77 (m, 2H), 2.62 (q, J = 4.8 Hz, IH), 1.42 (d, J= 6.5 Hz, 3H), 0.70 (s, 9H).

Example 4

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-phenylpropanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [1 (R)-phenyl]methanol, the titled compound was produced.

Rf 0.24 (EtOAc/hexane 20:80). [α ]_D ^2S= -134.2 (c 0.50, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.38-7.17 (m, 10H), 4.43 (d, J= 8.5 Hz, IH), 3.52 (dd, J= 12.8, 4.0 Hz, IH), 3.02 (dd, J= 12.8, 2.9 Hz, IH), 2.56 (m, IH), 1.41 (d, J= 6.5 Hz, 3H).

Example 5

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-methoxy phenyl)propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)-(2-methoxyphenyl)]methanol, the titled compound was produced.

Rf 0.12 (EtOAc/hexane 20:80). [α ]_D ²⁶= -141.0 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.30-7.17 (m, 7H), 6.94-6.78 (m, 2H), 4.83 (d, J= 7.4 Hz, IH), 3.83 (q, J = 7.4 Hz, IH), 3.83 (q, J= 6.4 Hz, IH), 3.69 (s, 3H), 3.51 (dd, J- 12.6, 4.6 Hz, IH), 3.07 (dd, J = 12.8, 3.5 Hz, IH), 2.72 (m, IH), 1.37 (d, J= 6.6 Hz, 3H).

Example 6 Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(4-chlorophenyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)- [l(R)(4-chlorophenyl)]methanol, the titled compound was produced.

Rf 0.26 (EtOAc/hexane 20:80). [α ]_D ²⁶= -114.6 (c 1.00, CHC1₃). 'H NMR (200 MHz, CDC1₃) δ 7.38-7.11 (m, 9H), 4.42 (d, J = 8.3 Hz, IH), 3.92 (q, J = 6.5 Hz, IH), 3.57 (dd, J- 12.9, 4.1 Hz, IH), 3.04 (dd, J- 12.8, 2.8 Hz, IH), 1.42 (d, J- 6.5 Hz, 3H).

Example 7

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(l-hexynyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(l-hexynyl)]methanol, the titled compound was produced.

Rf 0.28 (EtOAc/hexane 20:80). [α ]_D ² - -88.0 (c 1.00, CHC1₃). Η NMR (200

MHz, CDC1₃) δ 7.35-7.23 (m, 5H), 4.22 (m, IH), 3.96 (q, = 6.4 Hz, IH), 3.65 (dd, J= 12.6,

4.4 Hz, IH), 3.52 (dd, J= 12.5, 3.5 Hz, IH), 2.60 (m, IH), 2.18 (m, 2H), 1.39 (m, 7H), 0.88 (t,

J- 7.0 Hz, 3H). Example 8

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(4-fluorophenyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(4-fluorophenyl)]methanol, the titled compound was produced.

Rf 0.22 (EtOAc/hexane 20:80). [α ]_D ²⁸= -136.0 (c 0.50, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.38-6.92 (m, 9H), 4.42 (d, J = 8.4 Hz, IH), 3.93 (q, J = 6.3 Hz, IH), 3.57 (dd, J= 13.0, 3.8 Hz, IH), 3.01 (dd, J- 12.8, 2.4 Hz, IH), 2.48 (m, IH), 1.42 (d, J- 6.2 Hz, 3H).

Example 9

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(3-methylphenyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl] aziridine-2(R)- [ 1 (R)-methyl]methanol with N- [( 1 S)-phenylethyl]aziridine-2(R)- [l(R)-(3-methylphenyl)]methanol, the titled compound was produced.

Rf 0.29 (EtOAc/hexane 20:80). [α ]_D ²⁷= -128.0 (c 1.00, CHC1₃). ^!H NMR (200

MHz, CDC1₃) δ 7.37-6.99 (m, 9H), 4.40 (d, J - 8.4 Hz, IH), 3.91 (q, J = 6.5 Hz, IH), 3.54 (dd, J- 12.8, 4.0 Hz, IH), 3.03 (dd, J= 12.8, 2.7 Hz, IH), 2.54 (m, IH), 2.28 (s, 3H), 1.40 (d, J= 6.5 Hz, 3H).

Example 10

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-thiazolyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l (R)-methyl]methanol with N-[(l S)-phenylethyl]aziridine-2(R)-

[l(R)-(2-thiazolyl)]methanol, the titled compound was produced. mp 68-70 ^°C . Rf 0.27 (EtOAc/hexane 30:70). [α ]_D ²⁶= -81.2 (c 0.50, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.68 (d, J= 3.3 Hz, IH), 7.32-7.16 (m, 6H), 4.79 (d, J= 6.4 Hz, IH), 3.83 (q, J= 6.6 Hz, IH), 3.68 (dd, J= 12.6, 4.7 Hz, IH), 3.59 (dd, J= 12.6, 4.3 Hz, IH), 2.85 (m, IH), 1.38 (d, J= 6.5 Hz, 3H).

Example 11

Synthesis of 2(R)-N-[(lS)-phenylethyl]amino-3-azido-l(R)-(2-propenyl) propanol

Using the analogous procedure described in Example 1, and replacing N-[(1S)- phenylethyl]aziridine-2(R)-[l(R)-methyl]methanol with N-[(lS)-phenylethyl]aziridine-2(R)- [l(R)-(2-propenyl)]methanol, the titled compound was produced.

Rf 0.38 (EtOAc/hexane 30:70). [α ]_D ²⁶= -158.2 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.38-7.25 (m, 5H), 4.96 (d, J - 13.9 Hz, 2H), 3.92 (m, 2H), 3.60 (dd, J = 12.5, 4.5 Hz, IH), 3.30 (dd, J= 12.5, 3.2 Hz, IH), 1.45 (s, 3H), 1.40 (d, J= 6.5 Hz, 3H).

Example 12

Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-pyrrolidinopropanol

N-[(S)-l-phenylethyl]aziridine-2(R)-methanol (60 mg) was dissolved in 1.0 ml of acetonitrile, and then 107 mg of sodium iodide and 86 mg of chlorotnmethylsilane were added to this solution. After stirring the reaction mixture at ambient temperature for 1 hour and 50 minutes, 16.8 mg of pyrrolidine was added, and then the reaction mixture was heated for 2 hours with stirring. After the reaction was completed, the reaction mixture was treated with 1.2N aqueous hydrochloric acid solution, neutralized with sodium hydrogen carbonate and extracted twice each with 5 mi of methylene chloride. The combined organic extracts were rinsed with brine, and dried under anhydrous magnesium sulfate. The solution was filtered, concentrated in vacuo, and purified to give 73 mg of titled product as an oil.

Rf 0.26 (MeOH/EtOAc 30:70). [α ]_D ²⁶= -19.4 (c 1.00, CHC1₃). Η NMR (500 MHz, CDC1₃) δ 7.10-7.36 (m, 10H), 4.80 (d, J = 3.9 Hz, IH), 3.76-3.80 (q, IH), 2.87 (m, IH), 2.61-2.72 (m, 6H), 1.79-1.81 (m, 4H), 1.24-1.25 (d, J= 6.35 Hz, 3H).

Example 13 Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-piperidinopropanol

Using the analogous procedure described in Example 12, and replacing pyrrolidine with piperidine, the titled compound was produced.

Rf 0.21 (MeOH/EtOAc 10:90). [α ]_D ²⁶= -35.5 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.14-7.33 (m, 10H), 4.74-1.80 (d, J= 4.0 Hz, IH), 3.71-3.81 (q, IH), 2.92- 3.00 (m, IH), 2.39-2.47 (m, IH), 1.44-1.80 (m, 6H), 1.21-1.24 (d, J= 6.6 Hz).

Example 14

Synthesis of 2(R)-N-[(S)-l-phenylethyl]amino-3-hexamethyleneimino propanol Using the analogous procedure described in Example 12, and replacing pyrrolidine with hexamethyleneimine, the titled compound was produced.

Rf 0.67 (MeOH/EtOAc 10:90). [α ]_D ²⁶= -33.7 (c 1.00, CHC1₃). Η NMR (200 MHz, CDC1₃) δ 7.17-7.33 (m, 10H), 4.70 (d, IH), 2.83-3.00 (m, IH), 2.55-2.83 (m, 7H), 1.55-1.94 (b, 8H), 1.21-1.24 (d, J= 6.6 Hz, 3H).

Example 15

Synthesis of 2(R)-N-[(S)-l-phenylethyI]amino-3-morpholino-l(R)-phenyl propanol Using the analogous procedure described in Example 12, and replacing pyrrolidine with morpholine, the titled compound was produced.

Rf 0.33 (EtOAc). [α ]_D ²⁶=-32.2 (c 1.00, CHC1₃). Η NMR (300 MHz, CDC1₃) δ 7.08-7.33 (m, 10H), 4.66 (d, J= 4.1 Hz, IH), 3.68-3.73 (m, 5H), 2.40-2.59 (m, 6H), 1.20 (d, J- 6.9 Hz, 3H).

Example 16

Synthesis of D-threo-l-phenyI-2-decanoylamino-3-morpholino-l-propanol 230 mg of 2(R)-N-[(S)-l-phenylethyl]amino-3-morpholino-l(R)-phenylpropanol obtained from Example 14 was dissolved in 3.4 mi of methanol, and 0.8 mi of acetic acid and 69 mg of Pd(OH)₂ (25 wt%) were added to this solution. After thoroughly stirring the mixture, it was allowed to react under the atmospheric pressure and at 40 ^°C for 4 hours. The catalyst was filtered off, the reaction solution was concentrated in vacuo, and the residue was dissolved in 3 mi of tetrahydrofuran. 0.8 mi of 10% NaOH solution, followed by 0.13 mi of decanoyl chloride were added to this solution. After the completion of the reaction was confirmed by TLC, water was added to the reaction container. The solution was separated into an organic phase and an aqueous phase. The organic phase was dried under anhydrous magnesium sulfate. The solution was filtered, concentrated in vacuo and purified to give 212 mg of product as an oil.

Rf 0.40 (EtOAc). [α ]_D ²⁵ = +8.02 (c 0.30, CHC1₃). Η NMR (500 MHz, CDC1₃) δ 7.31 (m, 5H), 5.84 (d, J= 6.83 HZ, IH), 4.96 (d, J- 3.90 Hz, IH), 4.28 (m, IH), 3.72 (t, J = 4.88, 4.39 Hz, 4H), 2.47-2.62 (m, 6H), 2.10 (t, J= 7.32, 7.81 Hz, 2H), 1.50 (m, 2H), 1.23- 1.31 (m, 12H), 0.88 (t, J- 6.83 Hz, 3H).

The present invention produces the known 2,3-diaminopropanol in high yields of more than 90% by ring opening an inactivated optically pure aziridine and reacting with various amines. The obtained 2,3-diaminopropanol can be used in synthesis of high value-added fine chemical compounds, such as hydroxymethylpiperazine, D-threo-l-phenyl-2-decanoylamino- 3 -morpholino-1 -propanol etc.

Claims

Claims:

1. A process for producing 2,3-diaminopropanol, comprising the steps of:

(a) reacting an aziridine alcohol of formula (1) with halotrialkylsilane to carry out an regioselective ring opening reaction of aziridine, and

(b) immediately reacting the intermediate obtained from step (a) with amine

(NHR³R⁴) to produce 2,3-diaminopropanol of formula (2):

(1 ) (2)

wherein, R¹ is selected from the group consisting of hydrogen; alkyl; cycloalkyl; 3- triazinyl or pyrimidyl acyl; aryl; hydrocarbon residues; aralkyl; and those groups substituted with suitable substituent(s);

R² is selected from the group consisting of hydrogen; alkyl including methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl or dodecyl; cycloalkyl including cyclohexyl or cyclopentyl; C₂-C₅ alkenyl including ethenyl, propenyl, butenyl or pentenyl; aralkyl; heteroaryl; and those groups substituted with suitable substituent(s); each of R³ and R⁴ is independently selected from the group consisting of hydrogen, C,-C₁₂ alkyl, C_rC₁₂ alkylcarbonyl, C_rC₁₂ alkyloxycarbonyl, aryl, mono- or di(C,- C₁₂)alkylamino, mono- or di(Cι-C,₂)aminocarbonyl, wherein C,-C₁₂ may be optionally substituted with the suitable substituent(s), or R³ and R⁴, together with nitrogen atom which they are attached to, may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C₁-C₁₂)alkylamino(C₁-C₄)alkylidene; with the proviso that when R³ and R⁴ are not both equal to hydrogen.

2. The process according to Claim 1, wherein R² is hydrogen, lower alkyl, lower alkenyl, thiazolyl, phenyl, or phenyl which may be optionally substituted with substituent(s) selected from a group consisting of lower alkyl, lower alkoxy and halogen atom.

3. The process according to Claim 1 or 2, wherein R¹ is (lR)-phenylethyl or (1S)- phenylethyl.

4. The process according to Claim 1 or 2, wherein said halotrialkylsilane is selected from a group consisting of iodotrimethylsilane, chlorotrimethylsilane and bromotriethylsilane.

5. A process for producing 2,3-diaminopropanol, comprising the steps of:

(a) reacting an aziridine alcohol of formula (1) with azidotrialkylsilane to carry out a regioselective ring opening reaction of aziridine to produce azidoaminoalcohol of formula (3), and

(b) reducing the compound of formula (3) to produce 2,3-diaminopropanol of formula

(4):

(1) (3) (4) wherein R¹ and R² are as defined in Claim 1.

6. The process according to Claim 5, wherein the reduction is selected from a group consisting of a reduction with LiAlH₄, a reduction with Ph₃P and a catalytic hydrogenation.

7. The process according to Claims 5 or 6, wherein the azidotrialkylsilane is azidotrimethylsilane .

8. A process for producing a compound of formula (7), comprising the steps of:

(a) reducing 2,3-diaminopropanol of formula (5) which corresponds to a formula (2) wherein R³ is hydrogen to produce a compound of formula (6); and (b) reducing the compound of formula (6) in the presence of a amino protector to produce the compound of formula (7):

(5) (6) (7) wherein R^s is an amino protecting group, and R¹, R² and R⁴ are as defined in Claim 1.

9. The process according to Claim 8, wherein the reducing step (a) is carried out using a compound having a dialdehyde group and a hydride reducing agent, and the reducing step (b) is carried out by a catalytic hydrogenation.

10. The process according to Claim 9, wherein the compound having a dialdehyde group is glyoxal.

11. The process according to Claims 8 or 9, wherein said amino protector is selected from a group consisting of t-butyl carbonate, methylcarbamate, ethylcarbamate or 9- fluoreny lmethylcarbamate .

12. The process according to Claims 8 or 9, wherein R⁴ is benzyl.

13. A process for producing a compound of formula (8), comprising the steps of: (a) reducing R¹ group of a compound of formula (2); and

(b) reacting the resulting product from step (a) with alkanoyl halide(R⁶X) to produce the compound of formula (8):

(2) (8) wherein R¹, R², R³ and R⁴ are as defined in Claim 1, R⁶ is an alkanoyl group, and X is fluoro, chloro, bromo or iodo.

14. The process according to Claim 13, wherein R³ and R⁴, together with nitrogen atom which they are attached to, form a morpholinyl group.

15. The process according to Claims 13 or 14, wherein the reduction is carried out by a catalytic hydrogenation.

16. The process according to Claims 13 or 14, wherein R⁶ is decanoyl.