CA2085716A1

CA2085716A1 - Heterocyclically substituted carbamates and process for their preparation

Info

Publication number: CA2085716A1
Application number: CA002085716A
Authority: CA
Inventors: Dieter Hoppe; Joerg Schwerdtfeger
Original assignee: Individual
Current assignee: Bayer AG
Priority date: 1991-12-20
Filing date: 1992-12-17
Publication date: 1993-06-21
Also published as: EP0549927A3; JPH05286928A; DE4142188A1; EP0549927A2

Abstract

Heterocyclically substituted carbamates and process for their preparation Abstract The invention relates to a new process for the preparation of new heterocyclically substituted carbamates, which are important imtermediates for the synthesis of pharmaceutical active substances, in particular for the synthesis of biologically active peptides and peptide mimetics.

Le A 28 841

Description

The invention relates to a new process for the preparation of new heterocyclically substituted carbamates, which are important intermediates for the synthesis of pharmaceutical active substances, in particular for the synthesis of biologically active peptide~ and peptide mimetics.

The invention also relates to new heterocyclically substituted carbamates of the general formula (I) oR3 Rl A (1).

in which 0 R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 heteroatoms from the series comprising S and 0 or having a group of the formula -NR', -SiR5RsR7 or -SnR5R6R7, in which R' denote~ hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or Le A 28 841 - 1 -, , .
.,..... . ,~

, ' , ,.
, . - . .

`` ~ 7~;

benzyl, Rs, R6 and R' are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, S where these substitutents can optionally be sub-stituted up to 3 times b~ identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsat-urated heterocycle having up to 3 heteroatoms from the series comprising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiRsR6R7, in which Rs, R6 and R7 have the abovementioned meaning, R3 represents a group of the formula -CO-NRl0R1l, in which Le A 28 841 - 2 -.

Rl and R1l, together with the nitrogen atom, form a heterocyclic radical of the formula R~<RI3 N O
Rl, ¦ I Rl4 Rl6 Rls in which Rl2 Rl3 R14, Rl5, Rl0 and Rl7 are identical or dif-S ferent and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and Rl3, Rl4 and Rls and/or Rl6 and Rl7 together form a 3- to 6-membered, saturated carbocycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally sub6tituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NRl0Rl9 -HN-CO-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which Rl8 and Rl9 have the abovementioned meaning of R4 and are identical to or different from this Le A 28 841 - 3 -..-` ~ : -:

~c~

and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 have the abovementioned meaning of Rs, R6 and R7 and are identical to or different from this, or represents straight-chain or branched acyl Xaving up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiRZ1R22R23, -SnR21R22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which i8 optionally substituted up to 3 times by phenyl or by the group of the Le A 28 841 - 4 -' .

2~
formula -NH-CO-OR20, in which R20 has the abovementioned meaning.

In the sub-substitution, heterocycle in general S represents a 5- to 7-membered, preferably 5- to 6-membered, saturated or unsaturated ring which as heteroatoms can contain up to 2 oxygen, sulphur and/or nitrogen stoms. Preferred S- and 6-membered rings are those having an oxygen, sulphur and/or up to 2 nitrogen atoms. The following are mentioned as being particularly preferred: pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, imidazolyl, isoxazolyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrazolyl or morpholinyl.

A 3- to 8-membered, saturated heterocycle is in general represented by pyrrolidine, piperidine, pyrazolidine, imidazolidine or oxazolan. Pyrrolidine and oxazolan are preferred.
Preferred compounds of the general formula (I) are those in which R2 represents a heterocyclic radical of the formula Le A 28 841 - 5 -........ ...... ..
,: - ~ . . . . . . . :

. , . . . - ::

;.
.: . - : .
. - .. ~ . ..

\

R~ H3C
or O y N-R~

in which R~ denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRlRll, in which R10 and Rll, together with the nitrogen atom, form a heterocyclic radical of the formula Rl2 R~3 O
¦ ¦ Rl4 Rl6 Rl5 in which Rl2 Rl3 R1~, Rls, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-Le A 28 841 - 6 -chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and Rl3, Rl~
and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different substituents from the group comprising hydroxyl, phenyl, cyclobutyl, cyclopentyl and cyclohexyl or by a group of the formula -NR1~R19, _NH_co-OR20, -SiR2lR22R23 or -SnR2lR22R23 in which R19 and Rl9 have the abovementioned meaning of R~
and are identical to or different from this, R20 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally sub-stituted by phenyl, R21, R22 and R23 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or Le A 28 841 - 7 -' . .
., ~ .
', ...

~s~l6 represents straight-chain or branched acyl having up to 6 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiRZlR22R23, -SnR2lR22R23 or R24-co in which R21, R22 and R23 have the abovementioned meaning and RZ4 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -N~-CO-ORZ, in which RZ has the abovementioned meaning.

Particularly preferred compounds of the general formula (I) are those in which Le A 28 841 - 8 -~, .. ' :

~ ¢~ 5 ~ 6 R2 represents a heterocyclic radical of the formula N-R4 H3C ~
or N-R4 in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, Rl represents hydrogen, R3 represents a group of the formula -CO-NRl0R1l, in which Rl and Rll, together with the nitrogen atom, form a heterocyclic ring of the formula \NXO
R" ~ R~4 R~6 R15 in which R12 R'3 Rl~, Rls, Rls and Rl7 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 Le A 28 841 - 9 -. ~
.. - - ~ ~ - - . ~ ............... :
. ; - .

carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case Rl2 and R1~, Rl4 and Rls or Rl6 and Rl7 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR~8R~9 -NH-CO-OR20, -SiR2~R22~23 or -SnR2lR22R23 in which Rl3 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R2l, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydxoxyl, Le A 28 841 - 10 -~?.G~57~fi) represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR2~R22R23 or R24-co_, in which R2l, R22 and R23 have the abovementioned meaning and R2~ denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.

Additionally, a new process for the preparation of the compounds of the general formula (I) according to the invention has been found, characterised in that carbamates of the general formula (II) Le A 28 841 - 11 -~, , .

~¢~5~

Rl Rl in which Rl, R2, Rl and Rll have the abovemen~ioned meaning, are first enantio electively deprotonated in inert solvents, in the presence of a selective base, preferably S sec-butyllithium, and of a chelate-forming di~mine (in the following designated by D) to give the carbanion complex compounds of the general formula (III) Rlo ~ N`
~ B ~0 in which Rl, R2, R10 and Rll have the abovementioned meaning, 0 B represents a lithium, magnesium, titanium, zirconium or potassium atom, preferably lithium, and Le ~ 28 841 - 12 -D represents a chelate-forming diamine such as, for example, tetramethylethylenediamine (TMEDA) or (-)-sparteine, preferably TNEDA, and then reacted with electrophiles of the general formulae (IV) and (V) o A-M (rV) T ~ T' in which A has the abovementioned meaning, M represents halogen, C,-C,-alkoxy or another typical leaving group, preferably chlorine, and T and T' are identical or different and represent hydrogen or a chemi- cally useful radical shown under the substituent A, or with CO2.

The process according to the invention can be illustrated by way of example by the following reaction scheme:

Le A 28 841 - 13 -. ~ ' ''' :

-U ~ ~EDA
CH2 u~ auU / TMEDA ~ o CH
s ~ 2 O-C~ C~ H,C,~ ~CH, CHJ HaC

S u r -- HCC~'H~C Cl 1, 0 C- H, prisin gly, the proce~s according to the invention gives the desired compounds of the general formula ~I) in high yields.

The process is distinguished by ~everal advantages: in contrast to the prior art, stoichiometric amounts of bases, preferably sec-butyllithium, are adequate for deprotonation. Additionally, the process according to the invention enables both control of the diastereo-selectivity by the choice of the electrophilic sub-stituents and the influencing of asymmetric induction in the case of prochiral carbamates in the presence of chiral complex-forming diamines.

By the use of enantiomerically pure diamine compounds such a~, for example, TMEDA, deprotonation of the compounds of the formula (II) takes place enantioselectlvely and in very good yields to give the Le A 28 841 - 14 --35~

corresponding chiral compounds, preferably to give the (S)-lithium compounds of the formula (III), which can preferably be converted into the R-configuration by further reaction with electrophiles.

It is additionally surprising with knowledge of the prior art that the metallated compounds of the general formula (III) undergo no decomposition and a deprotonation in the benzyl radical. In particular, a high diastereo-selectivity and stereochemical control in the attack of the electrophile due to the induction of the stereocentre already present is of great advantage.

In addition to chlorine, bromine and iodine, the radicals tosylate, meaylate or -OS02-CF3 are also covered under the definition leaving group. Chlorine is preferred.

Suitable solvents for the deprotonation are preferably inert organic solvents such a6 hydrocarbons such as hexane, pentane, ligroin or toluene, and ethers, for example tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, diglyme, triglyme or tert-butyl methyl ether. Tetrahydrofuran and diethyl ether are particularly preferred.

Deprotonation is carried out in a temperature range from -lOO-C to room temperature, preferably at about -78-C to O-C .

Deprotonation can be carried out either at normal Le A 28 841 - 15 --' .- ~ ~ . .

.

;7~6 pressure or at elevated or reduced pressure (for example 0.5 to 2 bar)l preferably at normal pressure.

Suitable selective bases are alkyllithium compounds having up to 6 C atoms in the alkyl group, preferably n-butyllithium or sec-butyllithium.

The base is employed in an amount from 0.5 to 5 mol, preferably in stoichiometric amounts, relative to 1 mol of the compounds of the general formula (II).

Electrophilic substitution likewise takes place in the abovementioned solvents, preferably in tetrahydrofuran at normal pressure.

Electrophilic substitution is carried out in a tempera-ture range from about -100-C to +40-C, preferably in the range from -78-C to room temperature.

The compounds of the general formula (II) are also new and can be prepared by a process in which compounds of the general formula (VI) Rl ~C-OH (Vl), I

in which Le A 28 841 - 16 -: . . .: . .

: . ~
-. ...
,: ' , :-: '.:. ~
. .: ; . . .:

.. . . ::, - ~:

7~Lfi R' and R2 have the abovementioned meaning are reacted with compounds of the general formula (VII) O
Il Z - C NRlR~l (VII), in which R10 and R11 have the abovementioned meaning and Z represents halogen, preferably chlorine, in one of the abovementioned solvents, preferably ether, in the presence of a base, preferably sodium hydride.

The compounds of the general formulae (VI) and (VII) are known or can be prepared by a customary method [cf., for example, J. Chem. Soc., Perkin Trans l, 1074, 1101].

The compound of the general formula (III) are new and can be prepared by the process indicated above.

The compounds of the general formulae (IV) and (V) are known or can be prepared by customary methods.

The compounds according to the invention are also Le A 28 841 - 17 -' : ' ,. ~ .

5~ 3L6 distinguished by the fact that, after the enantio-selective introduction of the electrophile, the pro-tective group -CO-NR10Rl1 can be very easily removed with the formation of the free hydroxyl group.

Removal of the protective groups (carbamic acid esters) i8 carried out by a customary method, for example by sequential treatment with acids and bases, preferably in methanol.

Suitable acids are strong inorganic acids and organic sulphonic or carboxylic acids such as, for example, methanesulphonic acid, ethanesulphonic acid, benzene-sulphonic acid, toluenesulphonic acid, acetic acid or propionic acid.

Suitable bases are alkali metal and alkaline earth metal hydroxides such as, for example, sodium hydroxide, potassium hydroxide or barium hydroxide. Barium hydroxide is preferred.

The acids and bases are employed in an amount from 0.01 to 10 mol, preferably l mol, relative to 1 mol of the compounds of the general formula (I).

Removal of the protective groups is carried out at normal pressure in a temperature range from 0C to +130-C, preferably from +20-C to +lOO-C.

Le A 28 841 - 18 -, ,~ -.
...

35~3~fi Removal can al80 be carried out with lithium aluminium hydride in one of the abovementioned solvents, preferably tetrahydrofuran.

The compounds according to the invention are thus useful S intermediates for the preparation of hydroxy-substituted heterocycles, some of which are known and some of which are new, in particular proline derivatives, which are of great importance for the synthesis of biologically active peptidec or peptide mimetics.

The abbreviations a and b used in the following have the following meaning:

0~
-C-N ~ 0 0~
Il /
b= -C-N~x~O
/\

Le A 28 841 - 19 -;, ., . ' ; -. ' ~ . ~ ` ' .

:

~,2~q~6 ,startinq Compounds Example I

(S)-2-(Hydroxymethyl)-l-benzyl-pyrrolidine ~CH2C~s C~H

3.79 g (37.5 mmol) of (S)-prolinol and 5.5 ml (47.4 mmol) of benzyl chloride are heated under reflux for~48 h with 3.7 g of potassium carbonate in 100 ml of ~toluene.
Contrary to the literature procedure;, the mixture is fractionated in vacuo. 5.52 g (77%, Lit.s66%) of the title compound are obtained a~ a colourless oil. The ~pectro~copic~data correspond to those given in the literature.

~U
(S)-(-)-(l-Benzylpyrrolidinyl)-methyl 2,2,4,4_ eetramethy~ 3-oxazolidine-3-carboxylate CH2-C,H, ~ ~O-b 402 mg (14 mmol) of sodium hydride (80% strength in mineral oi}) are initially introduced into 10 ml of ether at room temperature. 1.91 g (10 mmol) of the compound from ~xample I are added dropwi~e to thi~ mixture. It 1 Le A 28 841 - 20 -= ...... . . . .
- : - ~, . . - : .

.. ...

5~:~L6 stirred for 1 h for complete deprotonation and then treated with 2.30 g (12 mmol) of the carbamoyl chloride, dissolved in 5 ml of ether. The reaction mixture is stirred for 5 days at room tempersture. Hydrolysi~ i8 then carried out with 5 ml of water. The aqueous pha~e is extracted three times with 5 ml of ether each time, and the combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on silica gel (ether~pentane = 1:2, silica gel 0.2-0.06), 2.84 g (82%) of the title compound are obtained as a colourless oil.
R~ = 0.37 (silica gel, ether/pentane = 1:1) la]20 = -60.2 (c = 2.1, CHC13).

Preparation Examples Example 1 (lR,2'S)-(-)-(l-Benzylpyrrolidinyl)ethyl 2,2,4,4-tetra-methyl-1,3-oxazolidine-3-carboxylate a) Precursor CH2-C~
N
C~b U x T~ED~

Le A 28 841 - 21 -Zj,~

CH2-C,H~
b) N/
r ~ O~b CH~

346 mg (1.0 mmol) of the compound from Example II and 446 ~1 of tetramethylethylenediamine (TMEDA, 3.0 mmol) are dissolved in 8 ml of ether. This solution is treated at -78C with 2.17 ml (3.0 mmol) of sec-butyllithium (1.4M in cyclohexane/isopentane); in this process the solution changes colour to orange-yellow (a). The mixture is stirred at this temperature for 3 h and 187 ~1 (3.0 mmol) of iodomethane are then in~ected. The mixture is additionally stirred at this temperature for a further 1 h and the cooling bath is then removed. After thawing at room temperature, the solution is hydrolysed with 2 ml of water. After separation of the phases, the aqueous phase is extracted a further three times with 5 ml of ether cach time. The combined organic phases are dried over magnesium sulphate and concentrated in vacuo. After separation by column chromatography on alumina (activity stage II), 259 mg (72~) of the title compound are isolated as colourless crystals.
M.p.: 52-C ~from the melt) R~ = 0.67 (a~umina, ether/pentane = 1:1) [a]20 = -51.0 (c = 0.5, CHCl3).

Le A 28 841 - 22 -- -- - , ': . . -,..-.
-~5~

Example 2 (IR,2'S)~ (l-Benzylpyrrolidinyl)-trimethylsilyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate ~ H2-C,Hs N

r ~. Ob By the method described above, in the case of the reaction of 346 mg (1.0 mmol) of the compound from Example II with 2.17 ml (3.0 mmol) of sec-butyllithium, 446 ~1 (3.0 mmol) of TMEDA and 378 ~1 of trimethylsilyl chloride, 140 mg (33%) of the title compound are obtained as a waxy ~olid. M.p.: 45C (from the melt) Rf = 0.55 (alumina, ether/pentane = 1:1) t]20 = -54.8 (c = 1.5, CHCl3).

Example 3 (IR,2'S)-(-)-(l-Benzylpyrrolidinyl)tributylstannyl-methyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate Le A 28 841 - 23 -:
' '~

. . .
:
' ~ :

7~Ç~

CH2 C6Hs r s Ob Sn(C~H~
Analogously, from 346 mg (1.O mmol) of the compound from Example II and 865 ~1 (3.0 mmol) of tributylstannyl chloride, 451 mg (71~) of the title compound are obtained as a colourless oil.
R~ = O.66 (alumina, ether/pentane = 1:1) t~]20 = -69.6 (c = 1.0, CHCl3).

Example 4 Methyl (2S,2'S)-(-)-2-[1-benzylpyrrolidinyl-(2,2,4,4-tetramethyl-1,3-oxazolidin-3-yl-carbonyl)oxy]ethanoate CH2 C,~s r S. 0~

COOCH, 346 mg ll.0 mmol) of the compound from Example II are metallated for 3 h by the method described above. Carbon dioxide is then introduced at -78C for 1 h and the mixture is warmed to room temperature under a carbon dioxide atmosphere. The reaction solution is hydrolysed with 10 ml of 2N hydrochloric acid. The aqueous pha~e is Le A 28 841 - 24 -.
' , , .

.. . ... ..

~C~357~6 extracted a further three times with 10 ml of ether each time. The combined ethereal phases are dried over magnesium sulphate and concentrated in vacuo. The residue is dissolved in 10 ml of ether and treated with diazomethane (0.6M in ether) until a yellow coloration remains; excess diazomethane is destroyed using ~ilica gel. The solution is freed of solvent in vacuo and purified by column chromatography on silica gel (ether/pentane = 1:4). 162 mg (40%) of the title compound are obtained as a colourless oil.
Rf = 0.46 (silica gel, ether/pentane = 1:1) ta]20 = -19.2 (c = 1.0, CHC13).

Example 5 (lS;2'S)-(-)-l-(l-Benzylpyrrolidinyl)-2-hydroxymethyl-propyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,H5 ~O b ~--OH

In the metallation 346 mg (1.0 mmol) of the compound from Example II with 446 ~1 (3.0 mmol) of TNEDA and 2.1~ ml (3.0 mmol) of sec-butyllithium and subsequent reaction with 220 ~1 (3.0 mmol) of acetone, 135 mg (35%) of the title compound result as colourless crystals.
N.p.: 102-C (ether/pentane) Le A 28 841 - 25 -~C~71fi Rf = 0.20 (silica gel, ether/pentane = 1:1) [a]236S = -17.4 (c = 1.0, CHC13).

Example 6 (lS,2RS, 2'S)-(-)-1-(1-Benzylpyrrolidinyl)-2-hydroxy-3-methylbutyl 2,2,4,4-tetramethyl-1,3-oxazolidine-3-carboxylate CH2-C,Hs ~' H3C ~ OH

Two dia~tereomers are obtained from the reaction of 346 mg (1.O mmol) of the compound from Example II with 273 ~l (3.0 mmol) of isobutyraldehyde. One diastereomer is isolated as colourless crystals in 23% (95 mg) yield.
M.p.: 64C
Rr = O.52 (alumina, ether/pentane = 1:1) ta]D = -8.1; [a]2355 = -13.7 (c = 1.2; CHC13).
The second diastereomer is obtained as 8 colourless oil in 62% (260 mg) yield.
Rf = O . 43 (alumina, ether/pentane = 1:1) [a]20 = -1.3; [a]235S = -15.8 (c = 1.2; CHCl3).

By Examples A and B, it is intended to illustrate by way of example how the compounds of the general formula (I) according to the invention can be converted into the Le A 28 841 - 26 -corresponding hydroxy compound~.

Example A

(IR, 2'Sj-(-)-(1-Benzylpyrrolidinyl)-ethanol ~ 1'12 C~Hs r s 0 ~ ',~
CH, 1.41 g (3.9 mmol) of the compound from Example 1 are heated under reflux for 16 h with 74Q ~1 (11.4 mmol) of mathanesulphonic acid in 15 ml of methanol. After addi-tion of 5 g of barium hydroxide, the mixt ~-e is then heated under reflux for a further 4 h. After cooling to room temperature, the inorganic residue is filtered off on a short silica gel column. The filtrate i8 concen-trated in vacuo, the residue is taken up with ether and the solution is dried over magnesium sulphate. After removal of the solvent in vacuo, the residual oil is purified on alumina (activity stage III, ether/pentane = 1:2). 532 mg (66~) of the title compound are obtained as a colourless, slightly unstable oil.
Rr = 0.56 (alumina, ether/pentane = 1:1) t]20 = -85.0 (c = 0.7, CHCl3).

Example B

(2S, 3S)-(-)-2-(Hydroxyethyl)-pyrrolidine Le A 28 841 - 27 -.- -, , 2~35716 ~OH

CH, For the removal of the benzyl group, 481 mg (2.3 mmol) of the compound from Example A are hydrogenated for 8 h under a slight hydrogen overpressure using 488 mg (0.46 mmol) of palladium (10% strength on carbon) in lS ml of methanol and 0.5 ml of formic acid. After completion of the reaction, the palladium is filtered off through a thin silica gel layer. The filtrate is concen-trated in vacuo and taken up with 5 ml of SN hydrochloric acid. The hydrochloric acid solution is extracted three times with 5 ml of ether each time and the extracts are discarded. After careful neutralisation with 30% strength sodium hydroxide solution, the aqueous phase is extracted three times with 10 ml of ethyl acetate each time. The combined organic ethyl acetate phases are dried over magnesium sulphate and freed of solvents in vacuo. The residue is recrystallised from ethyl acetate/pentane.
112 mg (42%) of the title compound are thus obtained as slightly unstable, colourless crystals.
M.p.: 86C
[a]20 = -36.4 (c = 1.0, CH30H).

Le A 28 841 - 28 -- ' ' . ' ''' ~ ~ ',' .

: ~ . .

Claims

1. Heterocyclically substituted carbamates of the general formula (I) (I), in which R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 hetero-atoms from the series comprising S and O or having a group of the formula -NR4, -SiR5R6R7 or -SnR5R6R7, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or benzyl, R5, R6 and R7 are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, where these substitutents can optionally be Le A 28 841 - 29 -substitued up to 3 times by identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsaturated heterocylce having up to 3 heteratoms from the series comprising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiR5R6R7, in which R5, R6 and R7 have the abovementioned meaning, R3 represents a group of the formula -CO-NR10R11, in which R10 and R11, together with the nitrogen atom, form a heterocyclic radical of the formula Le A 28 841 - 30 - in which R12 Rl3 R14 R15, R16 and R17 are identical or different and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and R13, R14 and R15 and/or R16 and R17 together form a 3- to 6-membered, saturated carbo-cycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NR18R19, -HN-CO-OR20, -SiR21R22R23 or -SnR21R22R23 in which R18 and R19 have the abovementioned meaning of R4 and are identical to or different from this Le A 28 841 - 31 -and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally sub-stituted by phenyl, R21, R22 and R23 have the abovementioned meaning of R5, R6 and R7 and are identical to or different from this, or represents straight-chain or branched acyl having up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by Le A 28 841 - 32 -phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.

2. Compounds of the general formula (I) according to Claim 1, in which R2 represents a heterocyclic radical of the formula or in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or benzyl, R1 represents hydrogen, R3 represents a group of the formula -CO-NR10R11, in which R10 and R11, together with the nitrogen atom, form Le A 28 841 - 33 -a heterocyclic radical of the formula in which R12, R13, R14, R15, R16 and R17 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case R12 and R13, R14 and R15 or R16 and R17 together form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, each of which is optionally substituted up to 2 times by identical or different substituents from the group comprising hydroxyl, phentl, cyclobutyl, cyclopentyl and cyclohexyl or by a group of the formula -NR18R19, -NH-CO-OR20, -SiR21R22R23 or -SnR21R22R23, in which R18 and R19 have the abovementioned meaning of R4 Le A 28 841 - 34 -and are identical to or different from this, R20 denotes straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms or phenyl, or represents straight-chain or branched acyl having up to 6 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to

3 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each havinq up to 6 Le A 28 841 - 35 -carbon atoms, each of which is optionally substituted by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning.

3. Compounds of the general formula (I) according to Claim 1, in which R2 represents a heterocyclic radical of the formula or in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, phenyl or benzyl, R1 represents hydrogen, R3 represents a group of the formula -CO-NR10R11, in which Le A 28 841 - 36 -R10 and R11, together with the nitrogen atom, form a heterocyclic ring of the formula in which R12 R13 R14 R15, R16 and R17 are identical or dif-ferent and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclopentyl or cyclohexyl, or in each case R12 and R13, R14 and R15 or R16 and R17 toqether form a cyclopropyl, cyclopentyl or cyclohexyl ring, A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by hydroxyl, phenyl, cyclobutyl or cyclohexyl or by a group of the formula -NR18R19, -NH-CO-OR20, -SiR21R22R23 or -SnR21R22R23 in which Le A 28 841 - 37 -R18 and R19 are identical or different and have the abovementioned meaning of R4 and are identical to or different from this, R20 denotes methyl or ethyl, each of which is optionally substituted by phenyl, R21, R22 and R23 denote straight-chain or branched alkyl having up to 4 carbon atoms, or represents straight-chain or branched acyl having up to 4 carbon atoms, represents cyclobutyl or cyclohexyl, each of which is optionally substituted by hydroxyl, represents carboxyl, alkoxycarbonyl having up to 3 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-in which R21, R22 and R23 have the abovementioned meaning and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, each of which is optionally substituted by phenyl or by the qroup of the Le A 28 841 - 38 -formula -NH-CO-OR20, in which R20 has the abovementioned meaning.

4. Process for the preparation of compounds of the general formula (I) (I), in which R2 represents a 3- to 8-membered, saturated or unsaturated heterocycle having up to 2 hetero-atoms from the series comprising S and O or having a group of the formula -NR4, -SiRsR6R7 or -SnR5R6R7, in which R4 denotes hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, phenyl or benzyl, Le A 28 841 - 39 -R5, R6 and R7 are identical or different and denote straight-chain or branched alkyl having up to 8 carbon atoms or phenyl, where these substitutents can optionally be substituted up to 3 times by identical or different straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms, hydroxyl, phenoxy or benzyl or by a 5- to 7-membered, saturated or unsaturated heterocycle having up to 3 heteroatoms from the series com-prising S, N and O, by aryl having 6 to 10 carbon atoms or by a group of the formula -NR8R9, in which R8 and R9 are identical or different and have the abovementioned meaning of R4, R1 represents hydrogen or the group -SiR5R6R7, in which R5, R6, R7 have the abovementioned meaning, R3 represents a group of the formula -CON-R10R11, in which Le A 28 841 - 40 -R10 and R11, together with the nitrogen atom, form a heterocyclic radical of the formula in which R12, R13, R14, R15, R16 and R17 are identical or different and denote hydrogen, staight-chain or branched alkyl having up to 8 carbon atoms, phenyl or cycloalkyl having 3 to 6 carbon atoms or in each case R12 and R13, R14 and R15 and/or R16 and R17 together form a 3-to 6-membered, saturated carbocycle, A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by identical or different substituents from the series comprising hydroxyl, phenyl and cycloalkyl having 3 to 7 carbon atoms or by a group of the formula -NR18R19 -HN-CO-OR20, -SiR21R22R23 or Le A 28 841 - 41 --SnR21R22R23 in which R18 and R19 have the abovementioned meaning of R4 and are identical to or different from this and R20 denotes straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by phenyl, R21, R22 and R23 have the abovementioned meaning of R5, R6 and R7 and are identical to or dif-ferent from this, or represents straight-chain or branched acyl having up to 8 carbon atoms, represents cycloalkyl or cycloalkenyl having 3 to 7 carbon atoms, which is optionally substituted by hydroxyl, or represents carboxyl, alkoxycarbonyl having up to 4 carbon atoms or a group of the formula -SiR21R22R23, -SnR21R22R23 or R24-CO-, in which R21, R22 and R23 have the abovementioned meaning Le A 28 841 - 42 -and R24 denotes hydrogen or straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, each of which is optionally substituted up to 3 times by phenyl or by the group of the formula -NH-CO-OR20, in which R20 has the abovementioned meaning, characterised in that carbamates of the general formula (II) (II), in which R1, R2, R10 and R11 have the abovementioned meaning, are first enantioselectively deprotonated in inert solvents, in the presence of a selective base and of a chelate-forming diamine (in the following designated by D) to give the carbanion complex compounds of the general formula (III) Le A 28 841 - 43 - (III), in which R1, R2, R10 and R11 have the abovementioned meaning, B represents a lithium, magnesium, titanium, zirconium or potassium atom, and D represents a chelate-forming diamine such as, for example, tetramethylethylenediamine (TMEDA) or (-)-sparteine, and then reacted with electrophiles of the general formulae (IV) and (V) A-M (IV) (V), in which A has the abovementioned meaning, Le A 28 841 - 44 -M represents halogen, C1-C4-alkoxy or another typical leaving group, and T and T' are identical or different and represent a chemically useful radical shown under the substituent A, or with CO2.

5. Carbamates of the general formula (II) (II), in which R1, R2, R10 and R11 have the meaning indicated in Claim 4.

6. Process for the preparation of carbamates of the general formula (II) according to Claim 4, characterised in that compounds of the general formula (VI) Le A 28 841 - 45 - (VI), in which R1 and R2 have the meaning indicated in Claim 4, are reacted with compounds of the general formula (VII) (VII), in which R10 and R11 have the meaning indicated in Claim 4 and Z represents halogen, in an inert solvent, in the presence of a base, at temperatures between 0°C and +130°C.

7. Use of the compounds of the general formula (I) Le A 28 841 - 46 -according to Claim 1 in the preparation of 1-hydroxy-substituted cycloalkyl compounds which can be employed for the synthesis of biologically active peptides and peptide mimetics.

Le A 28 841 - 47 -