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Title:
N-(2-HYDROXYALKANOYL) -N,N'-DIALKYLUREAS AND A PROCESS FOR THEIR PREPARATION
Document Type and Number:
WIPO Patent Application WO/2006/122782
Kind Code:
A1
Abstract:
N-(2-hydroxyalkanoyl) -N, N' -dialkylureas of general formula (I) are described A-X-(A)n, where A: m = 0 or m = 1; when m = 0, X = R''', where R''' is an aliphatic, cycloaliphatic, arylaliphatic radical, C1-C18; when m = 1, X = -(CH2)n-, where n is an integer from 1 and 20, preferably from 2 to 6; R is chosen among H, and alkyl radicals C1-C8, possibly substituted with halogen atoms; R' is an aliphatic, cycloaliphatic, arylaliphatic radical, C1-C18; R'' is chosen among H, aliphatic, cycloaliphatic, arylaliphatic radical, C1-C18. The preparation of said compounds is described, as well as the preparation of corresponding polymers.

Inventors:
GALLIANI GUIDO (IT)
ORLANDI MARCO (IT)
RINDONE BRUNO (IT)
TERRANEO ALBERTO (IT)
Application Number:
PCT/EP2006/004674
Publication Date:
November 23, 2006
Filing Date:
May 17, 2006
Export Citation:
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Assignee:
CHORISIS S R L (IT)
GALLIANI GUIDO (IT)
ORLANDI MARCO (IT)
RINDONE BRUNO (IT)
TERRANEO ALBERTO (IT)
International Classes:
C08G71/00; C07C273/18; C07C275/50
Foreign References:
DE836532C1952-04-15
US5324797A1994-06-28
Other References:
GEFFKEN: "3-Alkoxyoxazolidin-2,4-dione aus N-Alkoxy-2-hydroxycarbonsäureamiden und 1,1'-Carbonyldiimidazol", ARCHIV DER PHARMAZIE, vol. 313, no. 10, 1980, pages 817 - 825, XP009071310
SHAPIRO, ROSE, TESTA, ROSKIN, FREEDMAN: "N-Substituted Oxazolidinediones", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 81, 1959, pages 6498 - 6504, XP002395909
CLARK-LEWIS: "2,4-Oxazolidinediones", CHEMICAL REVIEWS, vol. 58, 1958, pages 63 - 99, XP002395910
Attorney, Agent or Firm:
DE GREGORI, Antonella et al. (Via Borgonuovo 10, Milano, IT)
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Claims:
CLAIMS

1. compounds of general formula (1)

A-X-(A) n , wherein A =

m = 0 or 1; when m = 0, X = R' ' ' , where R' ' ' is an aliphatic, cycloaliphatic, arylaliphatic radical, Ci-Ci 8 ; when m = 1, X = - (CH 2 ) n -, where n is an integer comprised between 1 and 20, preferably between 2 and 6;

R is chosen among H and alkyl radicals C x -C 8 , possibly substituted with halogen atoms; R' is an aliphatic, cycloaliphatic, arylaliphatic radical, Ci-Ci 8 ;

R' ' is chosen among H, aliphatic, cycloaliphatic, arylaliphatic radical Ci-Ci 8 .

2. Compounds according to claim 1, where R''=H. 3. Compounds according to claim 1, wherein, when m = 0, being R' and R' ' ' equal or different, R' and R' ' ' are chosen among alkyl, cycloalkyl, benzyl radicals, bearing 1 to 18 carbon atoms.

4. Compounds according to claim 1, wherein m = 1, X = - (CH 2 ) n - with n from 2 to 6.

5. Compounds according to claim 1, wherein R is CH 3 .

6. Compounds according to claim 1, wherein m = 0, R = methyl; R' ' ' = H and where:

(a) R' = R' ' = n-pentyl;

(b) R' = n-pentyl; R'' = benzyl;

(c) R' = n-pentyl; R' ' = cyclohexyl;

(d) R' = cyclohexyl; R'' = n-pentyl;

(e) R' = cyclohexyl; R' ' = benzyl; (f) R' = R' ' = cyclohexyl;

(g) R' = benzyl; R'' = n-pentyl; (h) R' = R' ' = benzyl. 7. Compounds according to claim 1 with m = 1, of general formula (3) . 8. Procedure for preparing compound of general formula (1) , including the reaction of 3-alkyloxazolidine- 2,4-diones with a mono- or diamine at a temperature between 5O 0 C and 140 0 C.

9. Procedure according to claim 8, wherein temperature is between 80 0 C and 120 0 C.

10. Procedure according to claim 8, wherein the molar ratio between 3-alkyloxazolidine-2 , 4-diones and mono- or diamine is nearly 1:1 for monoamines and 2:1 for diamines . 11. Procedure according to claim 8, characterized by performing the reaction without any solvent. 12. Compounds of general formula (4)

(4)

wherein Z is chosen between radicals (5) and (6)

(5)

-NHR' (6)

R is chosen among H and alkyl radicals Ci-C 8 , possibly substituted with halogen atoms; R' is either H or alkyl; q is an integer between 1 and 20; r is an integer between 1 and 20; s is any integer.

13. Compounds according to claim 12, wherein "q" is an integer between 2 and 8, and "r" is an integer from 2 to 8.

Description:

N- (2 -HYDROXYALKANOYL) -N, N' -DIALKYLUREAS AND A PROCESS FOR THEIR PREPARATION

The present invention describes N- (2-hydroxyalkanoyl) - N, N' -dialkylureas and the procedure to obtain them.

3-alkyloxazolidin-2, 4-diones are heterocylic compounds described in an old review (J.M.Clark-Lewis, "2,4- oxazolidinediones" , Chem.Rev. , 58, 63-99, 1958). This paper describes methods of preparation, reactivity, and possible uses. However, data on the reactivity of oxazolidine-2, 4-diones are scarce, being limited to the description of hydrolysis and a few other reactions . A new method to prepare 3 -alkyloxazolidin-2, 4-diones and 3, 3' -alkylen-bis-3 -oxazolidine-2, 4-diones is described in an application for an Italian patent, filed by Chorisis srl . Such a preparation is based on the reaction of cyclic carbonates with either a monoamine or with a primary diamine, both of which can be aliphatic, cycloaliphatic, or arylaliphatic, followed by the oxidation of the adduct thus obtained with an oxidizing agent, preferably with pyridinium chlorochromate .

Surprisingly, we have found that the reaction of 3- alkyloxazolidin-2, 4-diones with either primary or

secondary amines (or diamines) yields N- ( 2- hydroxyalkanoyl) -N, N' -dialkylureas .

In agreement with that, the presents invention is related with compounds of general formula (1) A-X-(A) n , (1)

Where A =

m = either 0, or 1; when m = 0, then X = R''', where R''' is an aliphatic, cycloaliphatic, arylaliphatic radical, C 1 -Ci 8 ; when m = 1, then X = - (CH 2 ) n - , where n is comprised between 1 and 20, preferably between 2 and 6;

R is chosen among H and alkyl radicals Ci-C 8 , possibly substituted with halogen atoms;

R' is an aliphatic, cycloaliphatic, arylaliphatic radical, C 1 -C 18 ;

R' ' is chosen among hydrogen or an aliphatic, cycloaliphatic, arylaliphatic radical , Ci-Ci 8 .

Typical examples of compounds corresponding to the general formula (1) , when m = 0, are the compounds of

general formula (2)

(2) which can be defined as N- (2-hydroxyalcanoyl) -N, N' - dialkylureas . When R = methyl and R''' = H, compounds of general formula (2) can be classified as N-lactyl- N, N' -dialkylureas . Typical examples of compounds of general formula (2) , whose preparation is described in the experimental part, are:

** Compound (2)1 of general formula (2), where R = methyl; R' = R' ' = n-pentyl; R'' 7 = H;

** Compound (2)2 of general formula (2) where R = methyl; R' = n-pentyl; R'' = benzyl; R' ' ' = H; ** Compound (2)3 of general formula (2) where R = methyl; R' = n-pentyl; R'' = cyclohexyl; R''' = H; ** Compound (2)4 of general formula (2) where R = methyl; R' = cyclohexyl; R'' = n-pentyl; R''' = H; ** Compound (2)5 of general formula (2) where R = methyl; R' = cyclohexyl; R' ' = benzyl; R' ' ' = H;

** Compound (2)6 of general formula (2) where R = methyl; R' = R' ' = cyclohexyl; R' ' ' = H; ** Compound (2)7 of general formula (2) where R = methyl; R' = benzyl; R'' = n-pentyl; R''' = H; ** Compound (2)8 of general formula (2) where R = methyl; R' = R''= benzyl; R''' = H.

Typical examples of compound of general formula (1) when m = 1 are the compounds of general formula (3)

(3) which can be classified as bis- (N- (2-hydroxyalcanoyl) - N, N' -dialkyl-N' -alkylene) -ureas. When R = methyl and R' ' = H, compounds of general formula (3) can be classified as bis- (N-lactyl-N-alkyl-N' -alkylene) -ureas . In the case of N-lactyl-N,N' -dialkylureas, reaction occurs between 3-alkyl-5-methyloxazolidine-2 , 4-diones and a primary monoamine according to scheme (1) SCHEME 1

In the case of bis- (N-lactyl-N-alkyl-N' -alkylene) - ureas, reaction occurs between two molecules of 3- alkyl-5-methyloxazolidine-2, 4-diones and an aliphatic diamine. These N-lactyl-N, N' -dialkylureas and bis-N- lactyl-N, N' -dialkylureas are stable compounds, in some cases crystalline compounds.

Moreover, this invention describes a procedure to prepare compound of general formula (1) , which includes the reaction of 3-alkyloxazolidine-2, 4-diones with a mono- or diamine at a temperature from 5O 0 C to 140 0 C, preferably from 80 0 C to 120 0 C.

In the preferred way to perform the reaction, the molar ratio between 3-alkyloxazolidine-2, 4-diones and the mono- or diamine is nearly 1:1 in the case of monoamines and 2:1 in the case of diamines. However, it is possible to use different molar ratios, even though this implies a more complex purification of the reaction products. The process described by this invention is preferably performed without any solvent, with a considerable advantage to avoid recovering and recycling solvents. N-lactyl-N, N' -dialkylureas represent useful intermediates to prepare new molecules, particularly in

pharmaceutical development, with a special interest for peptidomimetics drugs.

The present invention describes products of general formula (4) as well

where Z is chosen between radicals (5) and (6) :

(5)

-NHR' (6)

R is chosen among H and alkyl radicals Ci-Cs, possibly substituted with halogen atoms; R' is either hydrogen or alkyl; q can range from 1 to 20, preferably from 2 to 8 ; r can range from 1 to 20, preferably from 2 to 8;

s is any integer number.

The aforementioned products of general formula (4) are polymeric products, namely poly-N- (2-hydroxyalkanoyl) - N-alkylidene-N' -alkylidene-ureas, which can be obtained by reacting 3 , 3 ' -alkylidene-bis-oxazolidine-2 , 4-diones with diamines, described in a co-pending patent application in the name of the same applicant. Typical compounds that represent his kind of compounds are poly-N-lactyl-N-alkylidene-N' -alkylideneureas, where R = methyl . Compounds of this kind are a new class of polymers, which can be used for examples, when terminal groups are amino groups, as prepolymers to be further polymerized in order to obtain traditional polymers as polyurethanes and polyureas with a larger degree of crystallinity. The following examples are reported to better understand the present invention. Examples

Examples 1-8. Preparation of compounds (2)1- (2) 8 20 mmoles of 3-alkyl-5-methyloxazolidine-2, 4-dione and 20 mmoles of amine are mixed in a reaction vessel under nitrogen. The mixture is stirred at 100 0 C for 16 hours, cooled at room temperature, and purified in a silica gel column, eluting with a mixture of dichloromethane and ethyl acetate (ratio 3:1). Reaction and

purification are followed by GC-MS. Stoicheiometric yields of N-lactyl-N,N' -dialkylureas (formula 2) are reported in Table 1. The only products obtained in addition to N-lactyl-N, N' -dialkylureas are starting products. All reaction products are characterized by these IR bands: 3300 cm '1 , 1720 cm "1 , as a shoulder, 1680 cm "1 , 1650 cm '1 . Reaction products were characterized by GC-MS and NMR, both 1 H and 13 C (samples dissolved in d 6 - DMSO) . Data referred to the examples of Table 1 are here reported:

(2)-l:

** MS: 272, M + (0.6%), 186 (9.8%), 159 (27.6%), 144

(7.4%), 130 (55.8%), 114 (100.0%), 98 (64.4%), 85

(28.2%), 71 (84.0%), 56 (42.9%); ** 1 H-NMR: (chemical shifts reported in δ units) 7.7

(t,lH), 7.1 (t,lH), 4.8 (qd,lH), 3.0 (τn,2H), 2.9

(m,2H), 1.4 (dd,3H), 1.2 (m, 12H) , 0.8 (m, 6H) ;

** 13 C-NMR: 170 (C=O) 1 154 (C=O), 69 (IH), 40 (2H), 38

(2H), 31 (6C, 2H), 22 (3H), 18 (3H), 14 (3H). (2)-2:

** MS: 292, M + , (0.5%), 206 (2.5%), 179 (16.7%), 161

(32.0%), 133 (17.3%), 106 (31.5%), 91 (100.0%);

** 1 H-NMR: 8.4 (t,lH) , 7.4-7.2 (m, 5+1H) , 4.9 (qd, IH) ,

4.3 (d,2H) , 2.9 (m,2H) , 1.4 (dd,2H) , 1.3 (dd,3H) , 1.2

(m,4H) , 0.8 (td,3H) ;

** 13 C-NMR: 170 (C=O) , 155 (C=O) , 139 (Ar) , 128 (2C, Ar), 126 (2+lC,Ar), 69 (IH), 42 (2H), 40 (2H), 28 (2H),

27 (2H) , 22 (2H) , 18 (3H) , 13 (3H) .

Melting point: 76,7 0 C.

(2)-3:

** MS: 284, M + (0.5%), 203 (16.3%), 186 (42.4%), 171 (6.5%), 159 (54.3%), 142 (4.3%), 130 (100.0%), 114

(39.1%), 102 (18.5%);

** 1 H-NMR: 7.8 (d,lH), 7.3 (t,lH), 4.9 (qd, IH) , 3.6

(m,lH), 2.9 (τn,2H), 1.8 (dd, 3H), 1.7-1.0 (m, 16H) , 0.8

(td,3H) ; ** 13 C-NMR: 168 (C=O), 155 (C=O), 69 (IH), 47 (IH), 40

(2H), 32 (2C,2H), 29 (2H), 28 (2H), 25 (2H), 24

(2C,2H), 22 (2H), 18 (3H), 14 (3H).

(2)-4:

** MS: 284, M + (0.4%), 198 (14.7%), 171 (34.1%), 159 (21.6%), 142 (100.0%), 126 (22.7%), 114 (36.4%), 98

(12.5%) , 83 (43.2%) .

** 1 H-NMR: 7.8 (t,lH), 7.1 (d, IH) , 4.8 (qd, IH) , 3.2

(m,lH), 3.0 (m,2H), 1.7 (dd, 3H), 1.5-1.0 (m,16H), 0.8

(td, 3H);

** 13 C-NMR: 170 (C=O), 156 (C=O), 69 (IH), 49 (IH), 38

(2H), 32 (2C,2H), 25 (2H), 24, (2C,2H), 23 (2H), 22

(2H), 20 (2H), 18 (3H), 14 (3H).

(2)-5: ** MS: 305 (M + +l, 0.3%), 179 (15.4%), 161 (100.0%), 142

(34.5%), 133 (41.7%), 106 (43.4%), 91 (85.7%).

** 1 H-NMR: 8.4 (t,lH), 7.1-7.3 (m,5+lH), 4.9 (qd, IH) ,

4.3 (s,2H), 3.2 (m,lH), 1.0-1.7 (m, 10H) , 1.3 (d,3H).

** 13 C-NMR: 171 (C=O) , 154 (C=O) , 139 (Ar) , 128 (2C, Ar), 126 (2+lC,Ar), 65 (IH), 49 (IH), 42 (2H), 33 (2H),

25 (2C,2H), 24 (2C,2H), 18 (3H).

(2)-6:

** MS: 296 (M + , 0.3%), 215 (3.8%), 207 (4.7%), 198

(11.3%), 171 (38.7%), 153 (3.8%), 142 (50.0%), 126 (21.7%), 97 (56.6%), 83 (100.0%);

** 1 H-NMR: 7.6 (d, IH) , 7.2 (d, IH), 4.8 (q, IH) , 3.5

(m,lH), 3.2 (m,lH), 1.1-1.8 (m,20H), 1.2 (d, IH) ;

** 13 C-NMR: 169 (C=O), 154 (C=O), 69 (IH), 49 (IH), 47

(IH), 33 (2C,2H), 25 (4C,2H), 24 (4C,2H),18 (3H). Melting point: 164.8°C.

(2)-7:

** MS: 292 (M + ,0.2%), 179 (10,1%), 161 (37.7%), 150

(8.7%), 133 (43.5%), 118 (3.7%), 106 (26.1%), 91

(100.0%) ;

IO

** 1 H-NMR: 7.8 (t,lH) , 7.7 (t,lH) , 7.2-7.3 (m,5H) , 4.8

(qd, IH), 4.2 (s,2H) , 3.0 (m,2H) , 1.4 (t,2H) , 1.3

(m,6H) , 0.8 (t,3H) ;

** 13 C-NMR: 170 (C=O), 155 (C=O), 139 (Ar), 129 (2C,Ar), 127 (2+lC,Ar), 69 (IH), 44 (2H), 39 (2H), 29 (2C,2H), 22 (2H) , 18 (3H) , 14 (3H) ; Melting point: 68.7 0 C.

(2)-8:

** MS: 206 (M + +l-benzylamine, 7.5%), 179 (13.9%), 159 (6.9%), 150 (47.2%), 133 (44.4%), 114 (22.0%), 105

(26.4%), 91 (100.0%);

** 1 H-NMR: 8.5 (t,lH), 7.8 (t,lH), 7.2-7.3 (m,10H), 4.9

(qd,lH), 4.3 (S, 2H), 4.2 (s,2H), 1.4 (d,3H); ** 13 C-NMR: 170 (C=O), 155 (C=O), 139 (2C,Ar), 128 (4C,Ar), 127 (4+2C,Ar) , 70 (IH), 44 (2H), 42 (2H), 18

(3H) ;

Melting point: 93.8 0 C.

Example 9. Preparation of a poly-N-lactyl-N- hexamethylene-N' -hexamethyleneurea. The first step of this preparation is the synthesis of 3,3' -hexamethylene-bis- (5-methyloxazolidine-2 , 4-dione) as described in the pending Italian patent filed by Chorisis srl. 10 mmoles of hexamethylenediamine and 20 mmoles of propylene carbonate are mixed and maintained

Il

at 60 0 C for two hours. The adducts mixture thus formed is cooled and dissolved in 120 ml of methylene chloride, then treated at room temperature with 120 mmoles of pyridinium chlorochromate . The mixture is stirred for two hours at room temperature. The liquid is separated from the tarry residue and concentrated under reduced pressure. The residue is eluted with methylene chloride on a silica gel column. Fractions containing the product corresponding to formula 3 , as detected by GC-MS and identified by 1 H and 13 C-NMR, are collected and dried. ** MS: 312 (M + , 7.5%), 241 (7.9%), 184 (37.4%), 170

(12.6%), 156 (5.6%), 143 (7.0%), 129 (3.3%), 116

(100.0%), 82 (44.9%); ** 1 H-NMR: 5.1 (q,2H), 3.4 (m,4H), 1.6 (m,4H), 1.5

(d,6H) .. 1.3 (m,4H) ;

** 13 C-NMR: 174 (C=O) , 156 (C=O) , 76 (IH) , 40 (2H) , 27

(2H) , 26(2H) , 16 (3H) .

The product, 3, 3' -hexamethylene-bis- (5- methyloxazolidine-2,4-dione) thus prepared is reacted with hexamethylenediamine, in a molar ratio 1.2:1

(amine/oxazolidinedione) . The reaction is performed without any solvent, by heating the mixture at 120 0 C and then raising temperature till the product

solidifies. A glassy polymer is formed, with a high melting point.

** IR (film): 3320 cm "1 (broad), 2930 cm "1 , 2860 cm "1 ,

1730 cm "1 , 1650 cm "1 (broad) , 1520 cm "1 (broad), 1250 cm "1

(broad) , 780 cm "1 ;

**PST (polymer stick temperature) : 150-155 0 C.

Table 1