AU2008267515A1 - Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate - Google Patents
Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate Download PDFInfo
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- AU2008267515A1 AU2008267515A1 AU2008267515A AU2008267515A AU2008267515A1 AU 2008267515 A1 AU2008267515 A1 AU 2008267515A1 AU 2008267515 A AU2008267515 A AU 2008267515A AU 2008267515 A AU2008267515 A AU 2008267515A AU 2008267515 A1 AU2008267515 A1 AU 2008267515A1
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- 238000004519 manufacturing process Methods 0.000 title description 5
- BMWVCYQYUOAWEY-UHFFFAOYSA-N benzyl 2-(1,1,6,6,6-pentahydroxyhexylcarbamoyl)undecanoate Chemical compound CCCCCCCCCC(C(=O)NC(O)(O)CCCCC(O)(O)O)C(=O)OCC1=CC=CC=C1 BMWVCYQYUOAWEY-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 83
- 238000000034 method Methods 0.000 claims description 31
- -1 ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy Chemical group 0.000 claims description 30
- 238000002360 preparation method Methods 0.000 claims description 24
- SDOFMBGMRVAJNF-SLPGGIOYSA-N (2r,3r,4r,5s)-6-aminohexane-1,2,3,4,5-pentol Chemical compound NC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO SDOFMBGMRVAJNF-SLPGGIOYSA-N 0.000 claims description 17
- ZDTVBXVYNIHVNR-UHFFFAOYSA-M 12-oxo-12-phenylmethoxydodecanoate Chemical compound [O-]C(=O)CCCCCCCCCCC(=O)OCC1=CC=CC=C1 ZDTVBXVYNIHVNR-UHFFFAOYSA-M 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 229910052740 iodine Inorganic materials 0.000 claims description 12
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 235000013350 formula milk Nutrition 0.000 claims 55
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 5
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000000203 mixture Substances 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 14
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 14
- MIYPIGKJEJJRDD-UHFFFAOYSA-N 2-phenylmethoxycarbonyltridecanoic acid Chemical compound CCCCCCCCCCCC(C(O)=O)C(=O)OCC1=CC=CC=C1 MIYPIGKJEJJRDD-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- SZNYYWIUQFZLLT-UHFFFAOYSA-N 2-methyl-1-(2-methylpropoxy)propane Chemical compound CC(C)COCC(C)C SZNYYWIUQFZLLT-UHFFFAOYSA-N 0.000 description 10
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 9
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 7
- 238000002955 isolation Methods 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 5
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 5
- ZJDUVLTYGHTRFS-UHFFFAOYSA-N 1-o-benzyl 12-o-(2-methylpropoxycarbonyl) dodecanedioate Chemical compound CC(C)COC(=O)OC(=O)CCCCCCCCCCC(=O)OCC1=CC=CC=C1 ZJDUVLTYGHTRFS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- NRDQFWXVTPZZAZ-UHFFFAOYSA-N butyl carbonochloridate Chemical compound CCCCOC(Cl)=O NRDQFWXVTPZZAZ-UHFFFAOYSA-N 0.000 description 2
- TVIDDXQYHWJXFK-UHFFFAOYSA-L dodecanedioate(2-) Chemical compound [O-]C(=O)CCCCCCCCCCC([O-])=O TVIDDXQYHWJXFK-UHFFFAOYSA-L 0.000 description 2
- TVIDDXQYHWJXFK-UHFFFAOYSA-N dodecanedioic acid Chemical compound OC(=O)CCCCCCCCCCC(O)=O TVIDDXQYHWJXFK-UHFFFAOYSA-N 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 2
- 238000005897 peptide coupling reaction Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C68/00—Preparation of esters of carbonic or haloformic acids
- C07C68/02—Preparation of esters of carbonic or haloformic acids from phosgene or haloformates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/96—Esters of carbonic or haloformic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
WO 2009/000397 PCT/EP2008/004552 1 Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate The invention relates to an improved process for the preparation of benzyl pentahydroxyhexylcarbamoylundecanoate. 5 Benzyl pentahydroxyhexylcarbamoylundecanoate has the formula I 0 OHOH K-K-O N OH 0 H OHOH 10 This compound is an intermediate for the preparation of the compound of formula II 0 OH OH HO0 OH 0 H OHOH II 15 which, in turn, is an intermediate in the synthesis of the compound of formula III 0 OH N Fi r 0 H O OH OH O 0 H OHOH II 20 which is described in US 7,205,290. The compound of formula III can be used, for example, as an anticholesteremic. US 7,067,689 describes a process for the preparation of benzyl pentahydroxyhexylcarbamoyl undecanoate of formula I, where, in a first step, monobenzyl dodecanedioate is prepared from 25 dodecanedioic acid according to a process described in the literature (Prata, et al., J. Am. Chem. Soc. 126, 12196-12197 (2004)) and this ester is then reacted in a further step by WO 2009/000397 PCT/E P2008/004552 2 activation with 1 -hydroxybenzotriazole (HOBT) and N-(3-dimethylaminopropyl)-N' ethylcarbodiimide hydrochloride (EDC) with D-glucamine to give the compound of formula I. 5 The process has the disadvantage that a) the monobenzyl dodecanedioate has to be purified with the help of column chromatography. 10 b) 1-hydroxybenzotriazole (HOBt) is used as reagent and HOBt is known to be a potentially explosive substance. c) N-(3 -dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) is used which is known to be sensitizing and a trigger of allergies. 15 d) the costs of the individual steps and the availability of the reagents would significantly hinder economic production on an industrial scale. The object of the present invention was then to provide an improved process for the 20 preparation of the compound of formula I which does not have the aforementioned disadvantages. In particular, the improved process should also permit production of the compound of formula I in an industrial-scale production process. For this, the process should be able to be carried out under the most economical conditions possible, i.e. cost-effectively. 25 The object is achieved by preparation process A) 0 O OH + Hal RI 0 IV V 0 0 OHOH V O R1 + HN OH 0 OHOH 0 VN OH H OHOH WO 2009/000397 PCT/EP2008/004552 3 in which a) the monobenzyl dodecanedioate of formula IV is reacted with the compound of formula VI, in which RI is an alkyl radical having I to 18 carbon atoms, in which one or more CH 2 groups of the alkyl radical may be replaced by 5 -0-, -CO-, -CH=CH-, -C=C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V and then further b) the compound of formula V is reacted with D-glucamine to give the compound of 10 formula I. Preferred compounds of formula VI are alkyl acid halides and alkyl esters of haloformic acid, particularly preferably isobutyl chloroformate. 15 An alkyl radical is understood as meaning a straight-chain or branched hydrocarbon chain having one to eighteen carbon, such as, for example, methyl, ethyl, isopropyl, n-butyl, isobutyl, tert-butyl, hexyl, heptyl, octyl. Hal is understood as meaning a halogen radical which can have the meaning Br, Cl or I. 20 An aryl radical is understood as meaning a phenyl, naphthyl or biphenyl radical in which one or more CH groups may be replaced by 0, N or S. The aryl radicals may be substituted one or more times by suitable groups, such as, for example: F, Cl, Br, I, CF 3 , NO 2 , CN, COO(Ci-C 6 )alkyl, CON[(CI-C 6 )alkyl] 2 , cycloalkyl, (C 1 25 C Io)-alkyl, (C 2
-C
6 )-alkenyl, (C 2
-C
6 )-alkynyl, O-(C I-C 6 )-alkyl, 0-(C 2
-C
6 )-alkenyl, 0-(C 2
-C
6
)
alkynyl, O-CO-(CI-C 6 )-alkyl, O-CO-(Ci-C 6 )-aryl, O-CO-(Ci-C 6 )-heterocycle, SO 2 N[(Ci-C 6
)
alkyl] 2 , S-(CI-C 6 )-alkyl, N((Ci-C 6 )-alkyl) 2 . In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a 30 suitable base at -30 0 C to + 70 0 C, preferably at -10 C to +40'C, particularly preferably at -5*C to 0*C and over the course of 30 - 150 minutes, preferably 60-120 minutes, metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10 C to 30 C, preferably -10 C to 0*C. Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable WO 2009/000397 PCT/EP2008/004552 4 solvent, chilled to -10*C to 30*C, preferably -10*C to 0*C, can be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30*C to + 70'C, preferably at -1 0*C to +40*C, particularly preferably at -5'C to 0 0 C over the course of 30 - 150 minutes, preferably 60-120 minutes. 5 The reaction mixture is stirred at -10'C to 40*C, preferably at -10'C to 0 0 C, for 15 to 150 minutes, preferably 30 - 120 minutes. The reaction mixture can now either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo. Optionally, the reaction mixture is washed with water before the solvent is evaporated off. 10 Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine. 15 Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl 20 acetate. In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is added in portions to a solution of product V (prepared as described previously; either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally to 25 a suitable base in a suitable solvent at -10*C to 40*C, preferably -5'C to 0*C. Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine (NEM), tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably 30 triethylamine or ethyldiisopropylamine (HUnig base). Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N- WO 2009/000397 PCT/EP2008/004552 5 methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate. The reaction mixture is afterstirredfor 5 to 120 minutes, preferably 30 to 60 minutes, at -10*C 5 to 40 0 C, preferably at -5*C to 0*C, then for a further 5 to 20 hours, preferably 12 hours, at 0 to 30*C, preferably 15*C to 20C, and then extracted by washing with water at 10*C - 80*C, preferably at 50*C - 70 0 C. During subsequent cooling to 20*C, the product of formula I crystallizes. 10 A further aspect of this invention is an alternative preparation process B) OH + Hal I R1 O IV VI 0 0 0 Q O 0 R1 + 0 OH 000 + H2N O OH 0 VII 0 Y~ OHHOH 0 OH 0 H OHOH 15 in which a) the monobenzyl dodecanedioate of formula IV is reacted with the compound of formula VI, in which R1 is an alkyl radical having 1 to 18 carbon atoms, in which one or more CH 2 groups of the alkyl radical may be replaced by 20 -0-, -CO-, -CH=CH-, -C =C- or aryl, and the alkyl radical may be substituted one or more times by F, Cl, Br or I, to give the compound of formula V and then further b) the compound of formula V is reacted with further monobenzyl dodecanedioate of 25 formula IV to give the compound of formula VIII, and then WO 2009/000397 PCT/EP2008/004552 6 c) the compound of formula VIII is reacted with D-glucamine to give the compound of formula I. In step a), monobenzyl dodecanedioate is dissolved in a suitable solvent in the presence of a 5 suitable base at -30'C to + 70'C, preferably at -10'C to +40'C, particularly preferably at -5*C to 0 0 C and, over the course of 30 - 150 minutes, preferably 60-120 minutes, is metered into a solution of compound VI, particularly preferably isobutyl chloroformate, chilled to -10*C to 30 C, preferably -10*C to 0 0 C. Alternatively, a solution of compound VI, preferably butyl chloroformate, in a suitable 10 solvent chilled to -10*C to 30*C, preferably -10'C to 0 0 C, can also be initially introduced and then monobenzyl dodecanedioate and a suitable base in a suitable solvent can be metered in at -30'C to + 70'C, preferably at -I0 C to +40'C, particularly preferably at -5*C to 0*C over the course of 30 - 150 minutes, preferably 60-120 minutes. The reaction mixture is stirred at -10'C to 40'C, preferably at -10 0 C to 0*C for 15 to 150 15 minutes, preferably 30 - 120 minutes. The reaction mixture can then either be used directly in the subsequent reaction, or the formed product is isolated. Preferably, the reaction mixture is used directly. To isolate the compound of formula V, the solvent is evaporated off in vacuo. Optionally, the reaction mixture is washed with water before the solvent is evaporated off. 20 Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine. 25 Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate. 30 In step b), over the course of 5 to 60 minutes, preferably 15-30 minutes, nonobenzyl dodecanedioate of formula IV is metered in portions into a solution of product V (prepared as described previously; either reaction solution used directly or the isolated product dissolved in a suitable solvent) and optionally a suitable base in a suitable solvent at -10 C to 40'C, WO 2009/000397 PCT/EP2008/004552 7 preferably 0 0 C to 25*C. Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably 5 triethylamine or ethyldiisopropylamine. Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl 10 acetate. The reaction mixture is afterstirred for 5 to 240 minutes, preferably 60 to 150 minutes at -10*C to 40*C, preferably at 0*C to 25*C. The resulting precipitate is filtered off and dried, giving product of formula VIII. In step c), over the course of 5 to 60 minutes, preferably 15-30 minutes, D-glucamine is 15 metered in portions into a solution of product VIII and optionally a suitable base in a suitable solvent at -10*C to 40*C, preferably -5'C to 5'C. Suitable bases are, for example, tertiary amines, such as, for example, triethylamine, ethyldimethylamine, ethyldiisopropylamine, tributylamine, N-ethylmorpholine, 20 tetramethylethylenediamine, guanidine or alkylguanidines, particularly preferably triethylamine or ethyldiisopropylamine. Suitable solvents are, for example, customary aprotic organic solvents, such as, for example, toluene, chlorobenzene, dichloromethane, ethyl acetate, butyl acetate, diisobutyl ether, 25 diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylformamide, N methylpyrrolidone or methyl ethyl ketone, particularly preferably ethyl acetate or butyl acetate. The reaction mixture is afterstirred for I to 20 hours, preferably 10 to 18 hours at -10*C to 30 40'C, preferably at 10 C to 25*C and then extracted by washing with water at 10'C - 80*C, preferably at 50'C - 70'C. During subsequent cooling to 20*C, the product of formula I crystallizes. The compound of formula I obtained by process A) or B) is further reacted by WO 2009/000397 PCT/EP2008/004552 8 0 OHOH 0 OH 0 H OHOH H C 0 0 OHOH OH HO N 0 H + 0 H OH OH FN VII NH 2 O-CH3 OH N OH OH - N OH 0 H OH OH III 5 a) converting the compound of formula I to the compound of formula II by cleaving off the benzyl protective group, for example through saponification of the ester under alkaline conditions or through hydrogenation of the ester, and then b) reacting the compound of formula II with the amine of formula VII to give the [0 compound of formula III. This reaction of the compound of formula II with the amine of formula VII in the sense of a peptide coupling is carried out in accordance with customary methods. Suitable peptide coupling reagents and solvents or solvent mixtures are described, inter 5 alia, in, for example, A. Speicher et al., Journal fir Praktische Chemie/Chemiker-Zeitung (1998), 340, 581-583; Y. S. Klausner and M. Bodansky, Synthesis, (1972), 453 ff; K. Ishihara et al., J. Org. Chem., 61, 4196 (1996); M. Kunishima et al., Tetrahedron 55, 13159-13170 (1999) and also R.C. Larock: Comprehensive Organic Transformations; VCH, New York, 1989, page 981 ff. 20 The reaction of the compound of formula II with the amine of formula VII is described, for example, in WO 02/50027 or US 7,205,290.
WO 2009/000397 PCT/E P2008/004552 9 A further aspect of the invention is the novel compound of formula Va. 0 0 0 A Va 5 A further aspect of the invention is the novel compound of formula VIII. 0 0 NI 0 0 0 0 Vill 0 The examples given below serve to illustrate the invention without, however, limiting it. 10 Experimental section: 1. Preparation of benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va 15 1.5 g (4.7 mmol) of monobenzyl dodecanedioate are initially introduced into 15 ml of ethyl acetate and admixed with 0.8 ml (5.6 mmol) of triethylamine. The mixture is cooled to -5*C, and a solution of 0.7 ml (5.0 mmol) of isobutyl chloroformate is added. After 60 min, the precipitate is drawn off with suction under protective gas, washed twice with ethyl acetate and evaporated to dryness. A colorless oil in a yield of 96.4% is obtained. 20 1 H-NMR (600.13 MHz, ACN-d3), 6 7.35 (m, 5H), 5.06 (s, 2H), 4.01 (2H, d, J = 6.6 Hz), 2.46 (t, 2H, J = 7.4 Hz), 2.31 (t, 2H, J = 7.4 Hz), 1.97 (m, I H), 1.57 (m, 2H), 1.60 (m, 2H), 1.32 - 1.22 (m, 11 H), 1.31 (m, 1 H), 0.92 25 (d, 6H, J = 6.7 Hz) 13C-NMR (242.51 MHz, ACN-d3), 6 174.22 (C=O), 169.53 (C=O), 150.32 (C=O), 137.76 (C quaternary), 129.48 (CH), 129.00 3o (CH), 128.97 (CH), 76.15 (CH 2 ), 66.56 (CH 2 ), 34.76 (CH 2 ), 34.66 (CH 2 ), 30.05 (CH 2 ), 30.01 WO 2009/000397 PCT/EP2008/004552 10
(CH
2 ), 29.89 (CH 2 ), 29.79 (CH 2 ), 29.71 (CH 2 ), 29.38 (CH 2 ), 28.45 (CH), 25.71 (CH 2 ), 24.94
(CH
2 ), 18.92 (CH 3 ) MW: 420.55; MS: 438.29 (M+NH 4 +) 5 HR-MS: C 24
H
3 6 0 6 + NH 4 * calculated 438.2856 found 438.2860 2. Preparation of benzyl ll-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) undecanoate I starting from benzyl 12-isobutoxycarbonyloxy-12-oxo 10 dodecanoate Va The benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate prepared as in 1. is dissolved with 15 ml of ethyl acetate and admixed at 0*C with 0.9 g (5.2 mmol) of 2R,3R,4R,5S-6-amino hexane- 1,2,3,4,5-pentanol (D-glucamine). The mixture is stirred for one hour at 0 0 C, heated 15 to 20'C and left to stand overnight. The resulting white suspension is extracted at 65'C by shaking three times with 20 ml of water at the same temperature. The organic phase is then evaporated to dryness. A colorless solid in a yield of 92.9% is obtained. Melting point: 129 - 132'C 20 1 H-NMR (400.13 MHz, DMSO-d6), 5 7.67 (t, I H), 7.39 - 7.30 (m, 5H), 5.08 (s, 2H), 4.72 (d, I H, J = 4.5 Hz), 4.43 (d, 1 H, J = 5.6 Hz), 4.36 (d, I H, J = 5.9 Hz), 4.31 (t, I H, 5.7 Hz), 4.24 (d, I H, J = 6.3 Hz), 3.61 - 3.54 (m, 25 3H), 3.50 - 3.44 (m, I H), 3.42 - 3.35 (m, 3H), 3.30 - 3.22 (m, I H), 3.04 - 2.98 (m, 1 H), 2.34 (t, 2H, J = 7.4 Hz), 2.06 Hz (t, 2H, J = 7.5 Hz), 1.55 - 1.44 (m, 4H), 1.22 (im, 12 H) MW: 483.61; MS: 484.30 (M+H*) 0 3. Preparation of the monobenzyl dodecanedioate anhydride VIII starting from the benzyl 12-isobutoxycarbonyloxy-12-oxododecanoate Va The benzyl 12-isobutoxycarbonyloxy- 12-oxododecanoate prepared as in 1. is admixed with 20 ml of ethyl acetate and admixed at 20'C with 1.9 g (4.2 mmol) of monobenzyl WO 2009/000397 PCT/EP2008/004552 11 dodecanedioate. The mixture is stirred for 2.5 hours, and the resulting precipitate is drawn off with suction and dried. A colorless solid in a yield of 55.0% is obtained. Melting point: 67 - 70'C 5 1 H-NMR (400.13 MHz, DMSO-d6), 5 7.33 - 7.35 (in, 5H), 5.07 (s, 2H), 2.44 (t, 2H, J = 7.4 Hz), 2.32 (t, 2H, J = 7.4 Hz), 1.58 (m, 2H), 1.57 (m, 2H), 1.33 - 1.26 (m, 11H), 1.31 (m, IH) 10 13C-NMR (161.69 MHz, ACN-d3), 6 174.25 (C=O), 170.96 (C=O), 137.75 (C quaternary, 129.48 (CH), 129.00 (CH), 128.97 (CH), 66.57 (CH2), 35.77 (CH2), 34.76 (CH2), 30.06 (CH2), 30.02 (CH2), 29.89 (CH2), 29.83 I5 (CH2), 29.71 (CH2), 29.45 (CH2), 25.71 (CH2), 24.95 (CH2) HR-MS: C 38
H
54 0 7 calculated 623.3948 found 623.3950 4. Preparation of benzyl 1-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) 0 undecanoate I starting from the monobenzyl dodecanedioate anhydride VIII 0.50 g (0.80 mmol) of monobenzyl dodecanedioate anhydride are initially introduced into 10 ml of ethyl acetate and admixed with 0.14 ml (0.96 mmol) of triethylamine and cooled to 0 0 C. A suspension of 0.16 g (0.88 mmol) of 2R,3R,4R,5S-6-aminohexane- 1,2,3,4,5-pentanol 5 (D-glucamine) in 6 ml of ethyl acetate is added and the mixture is stirred for 18 h at room temperature. The mixture is heated to 70'C and extracted by shaking three times with 20 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 72% is obtained. 0 Melting point: 129 - 132'C 5. Preparation of benzyl 1-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) undecanoate I starting from the monobenzyl dodecanedioate IVa without isolation of the intermediates WO 2009/000397 PCT/EP2008/004552 12 17 kg of isobutyl chloroformate are initially introduced into 150 1 of ethyl acetate and cooled to -5'C. Over the course of 2 hours, a solution of 37.3 kg of monobenzyl dodecanedioate and 14.2 kg of triethylamine in 100 1 of ethyl acetate, chilled to -5*C, is metered into this solution. 5 When the metered addition is complete, the mixture is afterstirred for 2 hours at -5'C. Then, at -5*C, over the course of 30 minutes, 23.2 kg of D-glucamine arc metered in in portions, and when the metered addition is complete the mixture is afterstirred for a further 1 hour at -5'C and then for 12 hours at 20*C. The reaction mixture is added to 200 1 of ethyl acetate and 300 1 of water, the mixture is heated to 65'C and the phases are separated from one another. 10 The organic phase is washed with a further 80 1 of water at 60*C, then the organic phase is cooled to 20'C over the course of 60 minutes. Following afterstirring for 1 hour, the precipitated solid is filtered off and dried. Yield: 44.7 kg (80%). 6. Preparation of benzyl 1-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) 15 undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.53 ml (16.8 mmol) of benzyl chloroformate are initially introduced into 20 ml of ethyl acetate and cooled to -5'C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of 20 monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of ethyl acetate are metered in. The mixture is afterstirred for 2 hours at 0*C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentano (D-glucamine) are added in portions and the mixture is further stirred initially for I h at 0 0 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 25 65'C and stirred for a further I h. Following phase separation, extraction is carried out by shaking again with 10 ml of water at the same temperature. The organic phase is allowed to cool to room temperature, and the resulting precipitate is filtered off and dried. A colorless solid in a yield of 2.68 g (36%; purity HPLC 76.7 area%) is obtained. 30 7. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl WO 2009/000397 PCT/EP2008/004552 13 acetate and cooled to -5'C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylamine in 13.4 ml of butyl acetate are metered in. The resulting thick suspension is diluted with a further 10 ml of butyl acetate. The mixture is afterstirred for 2 hours at 0 0 C, then, over the course of 20 5 minutes, 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D glucamine) and a further 10 ml of butyl acetate are added in portions and the mixture is then stirred further firstly for I h at -5 0 C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 80'C and stirred for a further 2 h. The phase mixture is allowed to cool to room temperature, and the resulting precipitate is filtered off, 10 afterwashed with 20 ml of water and dried. A colorless solid in a yield of 6.11 g (81%; purity HPLC 99.4 area%) is obtained. 8. Preparation of benzyl ll-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without 15 isolation of the intermediates 2.11 ml (16.8 mmol) of isobutyl chloroformate are initially introduced into 20 ml of butyl acetate and cooled to -5'C. Then, over the course of 15 minutes, 5 g (15.6 mmol) of monobenzyl dodecanedicarboxylate and 2.41 ml (18.7 mmol) of N-ethylmorpholine in 20 13.4 ml of butyl acetate are metered in. The mixture is afterstirred for 2 hours at 0*C, then, over the course of 20 minutes, a suspension of 3.11 g (17.2 mmol) of 2R,3R,4R,5S-6-amino hexane-1,2,3,4,5-pentanol (D-glucamine) in 50 ml of butyl acetate is added and the mixture is stirred further firstly for 1 h at -5'C, then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 65'C and stirred for a further 5 h. Following phase 25 separation, the organic phase is also washed with 10 ml of water, the organic phase is cooled to room temperature and the precipitate is filtered off and dried. A colorless solid in a yield of 2.53 g (34%; purity HPLC 92.5 area%) is obtained. 9. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) 30 undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 2.19 ml (16.9 mmol) of isobutyl chloroformate are initially introduced into 20 ml of dichloromethane and cooled to -5'C. Then, over the course of 20 minutes, 5 g (15.6 mmol) of WO 2009/000397 PCT/EP2008/004552 14 monobenzyl dodecanedicarboxylate and 2.63 ml (18.7 mmol) of triethylanine in 13.4 ml of dichloromethane are metered in. The mixture is afterstirred for 2 hours at 0 0 C, then, over the course of 20 minutes, 3.11 g (17.2 mmol) of 2R,3 R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for I h at -5*C, 5 then for 20 h at room temperature. The mixture is admixed with 40 ml of water, heated to 40'C and stirred for a further 2 h. After cooling to room temperature, the precipitate is filtered off, washed with 20 ml of water and dried. A colorless solid in a yield of 6.57 g (87%; purity HPLC 90.5 area%) is obtained. 10 10. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyliexylcarbamoyl) undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.28 ml (25.3 mmol) of isobutyl chloroformate are initially introduced into 30 ml of toluene 15 and cooled to -5'C. Then, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 4.65 ml (28.1 mmol) of ethyldiisopropylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours at 0 0 C, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-1,2,3,4,5-pentanol (D glucamine) are added and the mixture is stirred further firstly for I h at -5*C, then is heated to 0 70'C and afterstirred for 3 hours at this temperature, followed by 20 h at room temperature. The mixture is admixed with 60 ml of water, heated to 70'C and stirred for a further 3 h. After cooling to room temperature, the precipitate is filtered off. A colorless solid in a yield of 7.65 g (68%; purity HPLC 86.8 area%) is obtained. 5 11. Preparation of benzyl 11-(2S,3R,4R,5R-2,3,4,5,6-pentahydroxyhexylcarbamoyl) undecanoate I starting from the monobenzyl dodecanedicarboxylate IVa without isolation of the intermediates 3.14 ml (25.3 mmol) of pivaloyl chloride are initially introduced into 30 ml of toluene at room 0 temperature and, over the course of 15 minutes, 7.5 g (23.4 mmol) of monobenzyl dodecanedicarboxylate and 3.94 ml (28.1 mmol) of triethylamine in 20 ml of toluene are metered in. The mixture is afterstirred for 2 hours, then, over the course of 20 minutes, 4.67 g (25.8 mmol) of 2R,3R,4R,5S-6-aminohexane-l,2,3,4,5-pentanol (D-glucamine) are added in portions and the mixture is stirred further firstly for 73 h at room temperature. The mixture is WO 2009/000397 PCT/E P2008/004552 15 admixed with 60 ml of water, heated to II I 0 C and stirred for a further 4 h. It is filtered hot, the filtrate is cooled to room temperature and the resulting precipitate is diluted with 20 ml of toluene and filtered off. A colorless solid in a yield of 10.9 g (96%; purity H PLC 87.4 area%) is obtained.
Claims (24)
1. A process for the preparation of the compound of formula I 5 0 OHOH O 0H 0 H OHOH which comprises reacting 10 a) the compound of formula IV 0 o >OH 0 IV with a compound of formula VI 0 Hal R1 VI 15 in which Hal can have the meaning Br, Cl or I and in which R I is an alkyl radical having I to 18 carbon atoms, in which one or more CH 2 groups of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, 20 to give the compound of formula V O110 A O R1 0 V and then, in a second step, b) reacting the compound of formula V with D-glucamine to give the compound of 5 formula I.
2. The process as claimed in claim 1, wherein Hal in the compound of formula VI has the WO 2009/000397 PCT/EP2008/004552 17 meaning Cl.
3. The process as claimed in claim 1 or 2, wherein RI in the compound of formula VI has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, 5 ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy.
4. The process as claimed in claim 1, 2 or 3, wherein R I in the compound of formula VI has the meaning isobutyloxy. 10
5. A process for the preparation of the compound of formula I n_ 0 OHOH 0 H OHOH which comprises reacting 15 a) the compound of formula IV - 0 0 OH 0 1 V with a compound of formula VI 0 Hal R1 20 VI in which Hal can have the meaning Br, Cl or I and in which RI is an alkyl radical having I to 18 carbon atoms, in which one or more CH 2 groups of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl and the alkyl radical may be substituted 5 one or more times by F, Cl, Br or I, to give the compound of formula V WO 2009/000397 PCT/EP2008/004552 18 -~ 0 0 V and then, in a second step, b) reacting the compound of formula V with further monobenzyl dodecanedioate of 5 formula IV to give the compound of formula VIII -~ 0 0 0 0 Viii 0 and then, in a third step, 10 c) reacting the compound of formula VIII with D-glucamine to give the compound of formula I.
6. The process as claimed in claim 5, wherein Hal in the compound of formula VI has the 15 meaning Cl.
7. The process as claimed in claim 5 or 6, wherein R1 in the compound of formula VI has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy. 20
8. The process as claimed in claim 5, 6 or 7, wherein RI in the compound of formula VI has the meaning isobutyloxy.
9. The process as claimed in any one of claims 1 to 8, wherein the compound of formula 25 I is converted in a further step to the compound of formula II 0 OH OH HO N OH 0 H OHOH II WO 2009/000397 PCT/EP2008/004552 19
10. The process as claimed in claim 9, wherein the compound of formula II is converted in a further step through reaction with the compound of formula VII 5 H C 0 OH F N 0 VI C NH2 to the compound of formula III 0 OH N.N FHO OH OH NN OH 10 0 H OH OH III.
11. A compound of formula Va 0 0 00 0 Va 15
12. A process for the preparation of the compound of formula Va 0 0 O O AO 0 Va which comprises reacting the compound of formula IV WO 2009/000397 PCT/EP2008/004552 20 0 O OH 0 I with a compound of formula VIa 0 Hal 0 VIa 5 in which Hal can have the meaning Br, Cl or I.
13. A process for the preparation of the compound of formula 0 OHOH o H OHOH 10 I which comprises reacting the compound of formula Va ~0 0 0 O Ok0 0 Va with D-glucamine to give the compound of formula I. 15
14. A compound of formula VIII 0 0O 0 ViII 0
15. A process for the preparation of the compound of formula VIII 511 00 0 0 0 0 ' 20 0 Vili 0 which comprises reacting WO 2009/000397 PCT/EP2008/004552 21 a) the compound of formula IV 0 ON OH O IV with a compound of formula VIa 0 Hal 0 5 VIa in which Hal can have the meaning Br, Cl or I to give the compound of formula Va 0 0 0 O O 00 Va and then, in a second step, 10 b) reacting the compound of formula Va with the compound of formula IV to give the compound of formula VIII.
16. A process for the preparation of the compound of formula I 5 0 OHOH 0 N OH O H- OH OH I which comprises reacting the compound of formula VIII ~0 0 0 0 0 >~ 0 ViII 0 0 with D-glucamine to give the compound of formula I.
17. A process for the preparation of the compound of formula I WO 2009/000397 PCT/E P2008/004552 22 0 OHOH N OH 0 H OHOH which comprises reacting 5 a) the compound of formula IV 0 0 OH 0 IV with a compound of formula VI 0 Hal R1 VI 10 in which Hal can have the meaning Br, Cl or I and in which RI is an alkyl radical having 1 to 18 carbon atoms, in which one or more carbon atoms of the alkyl radical may be replaced by -0-, -CO-, -CH=CH-, -C=C- or aryl and the alkyl radical may be substituted one or more times by F, Cl, Br or I, 15 to give the compound of formula V ~0 0 0 O RI 0 V and then, in a second step, b) reacting the compound of form ula V with D-glucamine to give the compound of 20 fonnula I.
18. The process as claimed in claim 17, wherein Hal in the compound of formula VI has the meaning Cl. 25
19. The process as claimed in claim 17 or 18, wherein R 1 in the compound of formula VI has the meaning methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, methyloxy, WO 2009/000397 PCT/EP2008/004552 23 ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy or benzyloxy. tert-butyl, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert butyloxy or benzyloxy. 5
20. The process as claimed in claim 17, 18 or 19, wherein RI in the compound of formula VI has the meaning isobutyloxy.
21. The process as claimed in claim 17, 18 or 19, wherein RI in the compound of formula VI has the meaning benzyloxy. 10
22. The process as claimed in claim 17, 18 or 19, wherein RI in the compound of formula VI has the meaning tert-butyloxy.
23. The process as claimed in any one of claims 17 to 22, wherein the compound of 15 formula I is converted in a further step to the compound of formula II 0 OH OH HO N 0H 0 H OHOH II 20
24. The process as claimed in claim 23, wherein the compound of formula II is converted in a further step through reaction with the compound of formula VII H 3 OH F N O ?5 V1 NH 2 to the compound of formula III WO 2009/000397 PCT/EP2008/004552 24 0 OH F N , H 0 OH OH N / N OH 0 H OH OH III
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11/767,298 | 2007-06-22 | ||
| US11/767,284 US20080319218A1 (en) | 2007-06-22 | 2007-06-22 | Processes for Making and Using Benzyl Pentahydroxyhexylcarbamoylundecanoate |
| US11/767,284 | 2007-06-22 | ||
| US11/767,298 US20080319221A1 (en) | 2007-06-22 | 2007-06-22 | Esters of Pentahydroxyhexylcarbamoyl Alkanoic Acids |
| DE102007029612.8 | 2007-06-27 | ||
| DE102007029612A DE102007029612A1 (en) | 2007-06-27 | 2007-06-27 | Preparing pentahydroxy-pentylcarbamoyl-undecanoic acid benzyl ester, useful to prepare tetrahydroxy-hexylcarbamoyl-undecanoic acid, comprises reacting dodecanedioic acid monobenzyl ester with halo-carbonyl compound and then with glucamine |
| PCT/EP2008/004552 WO2009000397A1 (en) | 2007-06-22 | 2008-06-07 | Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2008267515A1 true AU2008267515A1 (en) | 2008-12-31 |
Family
ID=39695874
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008267515A Abandoned AU2008267515A1 (en) | 2007-06-22 | 2008-06-07 | Process for preparing benzyl pentahydroxyhexylcarbamoylundecanoate |
Country Status (12)
| Country | Link |
|---|---|
| KR (1) | KR20100023886A (en) |
| CN (1) | CN101687769A (en) |
| AR (1) | AR068977A1 (en) |
| AU (1) | AU2008267515A1 (en) |
| BR (1) | BRPI0813120A2 (en) |
| CA (1) | CA2691065A1 (en) |
| CL (1) | CL2008001857A1 (en) |
| IL (1) | IL202824A0 (en) |
| MX (1) | MX2009012727A (en) |
| TW (1) | TW200914406A (en) |
| UY (1) | UY31165A1 (en) |
| WO (1) | WO2009000397A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3857338B2 (en) * | 1995-10-25 | 2006-12-13 | 株式会社Ｌｔｔバイオファーマ | Lecithinized superoxide dismutase and medicine containing the same as an active ingredient |
| US7067689B1 (en) * | 2005-07-08 | 2006-06-27 | Microbia, Inc. | Process for production of pentahydroxyhexylcarbamoyl alkanoic acids |
-
2008
- 2008-06-07 BR BRPI0813120A patent/BRPI0813120A2/en not_active Application Discontinuation
- 2008-06-07 CN CN200880021496A patent/CN101687769A/en active Pending
- 2008-06-07 AU AU2008267515A patent/AU2008267515A1/en not_active Abandoned
- 2008-06-07 KR KR1020097026689A patent/KR20100023886A/en not_active Application Discontinuation
- 2008-06-07 MX MX2009012727A patent/MX2009012727A/en not_active Application Discontinuation
- 2008-06-07 WO PCT/EP2008/004552 patent/WO2009000397A1/en active Application Filing
- 2008-06-07 CA CA2691065A patent/CA2691065A1/en not_active Abandoned
- 2008-06-19 AR ARP080102606A patent/AR068977A1/en unknown
- 2008-06-19 TW TW097122784A patent/TW200914406A/en unknown
- 2008-06-20 CL CL200801857A patent/CL2008001857A1/en unknown
- 2008-06-20 UY UY31165A patent/UY31165A1/en unknown
-
2009
- 2009-12-17 IL IL202824A patent/IL202824A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| KR20100023886A (en) | 2010-03-04 |
| BRPI0813120A2 (en) | 2019-09-10 |
| WO2009000397A1 (en) | 2008-12-31 |
| CN101687769A (en) | 2010-03-31 |
| CA2691065A1 (en) | 2008-12-31 |
| CL2008001857A1 (en) | 2008-10-10 |
| AR068977A1 (en) | 2009-12-23 |
| MX2009012727A (en) | 2009-12-08 |
| UY31165A1 (en) | 2009-01-30 |
| IL202824A0 (en) | 2010-06-30 |
| TW200914406A (en) | 2009-04-01 |
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