EP1299394A1 - Verfahren zur herstellung von (+)-biotin - Google Patents

Verfahren zur herstellung von (+)-biotin

Info

Publication number
EP1299394A1
EP1299394A1 EP01984162A EP01984162A EP1299394A1 EP 1299394 A1 EP1299394 A1 EP 1299394A1 EP 01984162 A EP01984162 A EP 01984162A EP 01984162 A EP01984162 A EP 01984162A EP 1299394 A1 EP1299394 A1 EP 1299394A1
Authority
EP
European Patent Office
Prior art keywords
ring opening
furo
biotin
reaction
menthyloxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01984162A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ulrich Heywang
Thomas Koppe
Michael Schwarz
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Patent GmbH filed Critical Merck Patent GmbH
Publication of EP1299394A1 publication Critical patent/EP1299394A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a new process for the preparation of (+) - biotin using 5-hydroxy-2 (5H) -furanone as a starting material.
  • (+) - Biotin is known as vitamin H. However, it is also used as an active pharmaceutical ingredient for the treatment of dermatosis and as a feed additive with growth-enhancing effects for farm animals.
  • the improvement consists in the introduction of a carboxybutyl group in the 4-position of the dl-1,3-dibenzylhexahydrothieno [3,4-d] imidazole-2,4-dione. This dione is reacted with a 1,4-dihalomagnesium butane and then carboxylated with carbon dioxide.
  • a significant disadvantage for industrial use is the use of the expensive, optically active compounds cholesterol or ephedrine and the expensive alkali metal borohydrides. With the same disadvantage, namely the use of expensive opt. active compounds are affected by the processes of EP applications 0 161 580 and 0 173 185.
  • the problem is solved by a new process for the preparation of (+) - biotin using 5-hydroxy-2 (5H) -furanone as starting material. Furthermore, the problem is solved by a method in which 1-Chlorosulfonyl-1, 2,2a, 3,5,5a-hexa-hydro-3 - ((1 R) -menthyloxy -) - furo [3,4-b] azet-2-one is formed as an intermediate.
  • This product can then be converted to (+) - biotin in a known manner, possibly with the introduction of protective groups.
  • the ring opening can be induced by different nucleophiles.
  • nucleophiles which are preferably used according to the invention are azides, in particular sodium azide, ammonia and hydroxylamine.
  • the ring opening is induced by ammonia as the nucleophile and the ring opening product obtained is further converted analogously to a Hofmann degradation.
  • the ring opening is induced by hydroxylamine as the nucleophile and the ring opening product obtained is reacted further analogously to a Beckmann rearrangement. It is particularly preferred according to the invention if the ring opening is induced as an nucleophile by an azide, preferably sodium azide, and the ring opening product obtained is further reacted by increasing the temperature and subsequent reduction, preferably with disodium sulfite.
  • the 5-hydroxy-2 (5H) furanone is preferably acetalized with menthol first.
  • the 5-hydroxy-2 (5H) - furanone and (-) - menthol (R) -5 - ((1R) -mentyloxy -) - 2 (5H) -furanone are produced from it.
  • This synthesis step can be carried out by a method known from the literature (Feringa, B. L; Lange, B. de; Jong, J. C. de; J. Org. Chem. 1989, 54, 2471-2475).
  • the two starting materials furanone and menthol are mixed with one another in a molar ratio of 1: 1, 1 to 1: 1, 3, in particular 1: 1, 2, and at a temperature of 90 to 140 ° C., preferably to heated about 115 to 125 ° C.
  • the reaction i. H. after a reaction time of 65 to 80 hours, preferably of about 70 to 75 hours, the unreacted menthol is distilled off. The residue obtained is then purified, for example by crystallization.
  • the (R) -5 - ((1 R) -Mentyloxy) -2 (5H) -furanone obtained can preferably be analogous to one in the literature (Fliri, A .; Hohenlohe-Oehringen, K .; Chem. Ber. 1980, 113, 607-613; Hohenlohe-Oehringen, K. Fliri, A. [Hoffmann-LaRoche & Co AG] EP 0 022 446 (1980)) for the implementation of (2H) -chromes can be reacted with chlorosulfonyl isocyanate.
  • chlorosulfonyl isocyanate (CSI) is placed in a reaction flask and cooled to a temperature of about -70 to -50 ° C, preferably - 65 to - 55 ° C, in particular to -60 ° C. With further cooling and at a constant temperature, a solution of (R) -5 - ((1 R) -mentyloxy) -2 (5H) -furanone in absolute tetrahydrofuran is added dropwise with stirring. The reaction is then completed for a period of 12 to Stirred for 20 hours at -45 to - 25 ° C, especially at -35 ° C. To carry out this reaction, (R) -5 - ((1R) -Mentyloxy) -2 (5H) -furanone and chlorosulfonyl isocyanate are preferably used in equimolar amounts.
  • the 1-chlorosulfonyl-1, 2,2a, 3,5, 5a-hexahydro-3- ((1R) menthyloxy -) - furo [3,4-b] azet-2-one obtained by this reaction can advantageously without further Purification can be used for further reaction.
  • the amount of sodium azide is preferably dissolved in water, optionally cooled to a temperature of -10 to 0 ° C. and to the 1-chlorosulfonyl-1, 2.2a, 3.5 , 5a-hexahydro-3 - ((1R) menthyloxy -) - furo [3,4- b] azet-2-one-containing reaction solution, which is cooled to a temperature of - 10 to 0 ° C.
  • the pH is adjusted to a value between 6.5 and 7.5 by adding a mineral acid from the group consisting of hydrochloric acid, nitric acid, sulfuric acid or phosphoric acid set. Concentrated hydrochloric acid is preferably used for this purpose.
  • the bis-azide formed by the reaction with sodium azide is then extracted with an organic solvent from the group consisting of ether, ethyl acetate, dichloromethane, toluene or xylene, preferably with ethyl acetate.
  • the evolution of nitrogen sets in at a temperature of about 80 ° C.
  • the reaction solution is heated to a temperature of 75-95 ° C., preferably 85 ° C., with stirring for about 45 minutes to two hours.
  • the reaction product 1-azidosulfonyl-2,3,3a, 4,6,6a-hexahydro-4- ((1R) -menthoxy -) - 6-oxd-furo [3,4] imidazol-2-one falls out.
  • Hydrolysis to 2,3,3a, 4,6,6a-hexahydro-4 - ((1R) -menthyloxy -) - 6-oxo-furo [3,4-d] imidazol-2-one can preferably be done by cooking with Na 2 SC » 3 in water as a solvent. The product then precipitates out in crystalline form when the reaction solution is cooled. By concentrating the mother liquor under reduced pressure, the amount of product obtained can be increased, so that a yield of 90 to 95% can be obtained.
  • the menthyloxy group can now be split off using known methods (e.g. Jong, J.C. de; Feringa, B .; Tetrahedron Lett. 1989, 30, 7239-7240) and the lactone can be prepared by reducing the semi-acetal which forms as an intermediate.
  • the pH of the solution is preferably adjusted to a value between 1 and 2.
  • the hemiacetal obtained by cleavage of the menthyl radical is preferably reduced to 4-hydroxymethyl-2-oxo-2,3,4,5-tetrahydro-imidazole-5-carboxylic acid in the presence of NaBH.
  • the carboxylic acid cyclizes in an analogous manner, as described in US Pat. No.
  • the lactone is expediently dissolved in an aprotic solvent from the group consisting of dimethylformamide, dimethyl acetamide and N-methylpyrrolidone, preferably in dimethylformamide, and about 2 to 2.5 times the molar amount of benzyl chloride is added.
  • the reaction mixture cooled to a temperature between -15 to 5 ° C., preferably -10 to 0 ° C., is gradually mixed with the addition of small amounts of 2 to 2.5 times the molar amount of NaH.
  • the temperature should be maintained and if possible not rise above 0 ° C, but especially not above 5 ° C.
  • reaction mixture is then stirred at a temperature of 15 to 30 ° C, preferably at room temperature for 1.5 to 3 hours.
  • acetic acid is added in an amount of 0.1 to 0.3 mol per mol of NaH used.
  • the reaction solution is concentrated to a residue under reduced pressure.
  • the residue is taken up in water and extracted with a nonpolar aprotic solvent from the group of toluene, xylene, hexane and heptane, preferably with toluene.
  • the organic phase is concentrated again and the crude product obtained as a residue is recrystallized with an alcohol, preferably with ethanol.
  • the dibenzylated lactone can now in a known manner, such as. Example, described in US Pat. No. 3,740,416, via which thiolactone can be converted to (+) - biotin.
  • the ring-opening products obtained with the aid of other nucleophiles can, as shown in Reaction Scheme VIII, likewise to 2,3,3a, 4,5,5a-hexahydro-5-oxo-furo [3 , 4-d] imidazol-2-one as a biotin precursor.
  • the intermediate product is analogous to a Hofmann degradation (Donaruma, L G .; Heldt, WZ; Org. Reactions 11, 1 (1960)) implemented further.
  • the oxidation of the acid amide formed by nucleophilic ring opening with ammonia can be induced with Br 2 or C or, for example, with sodium hypobromite which is easier to handle.
  • the intermediate isocyanate then cyclizes with the azidosulfonyl function contained in the molecule.
  • the subsequent reduction to 2,3,3a, 4,5,5a-hexahydro-5-oxo-furo [3,4-d] imidazol-2-one can then be carried out as described above.
  • Another method variant which is also preferred according to the invention uses the reaction known as Beckmann rearrangement (Wallis, ES; Org. Reactions 3, 267 (1946)) to form the 2,3,3a, 4,5,5a-hexahydro-5-oxo furo [3,4-d] imidazol-2-one.
  • the intermediate oxime formed by nucleophilic ring opening with hydroxylamine also converts to an isocyanate.
  • the rearrangement can be induced by acids such as phosphoric acid, sulfuric acid or phosgene, phosphorus oxychloride, phosphorus pentachloride, phosphorus pentoxide.
  • the menthyl ether protective group is split off directly.
  • the isocyanate in turn cyclizes with the azidosulfonyl function contained in the molecule.
  • the subsequent reduction to 2,3,3a, 4,5,5a-hexahydro-5-oxo-furo [3,4-d] imidazol-2-one can also be carried out as already described above.
  • the toluene phase which contains the bis-azide, is slowly heated to approx. 85 ° C. From about 80 ° C nitrogen evolution begins. The mixture is heated for about 1 h with stirring until the reaction has ended and gas evolution no longer occurs. On cooling, 1-azidosulfonyl-2,3,3a, 4,6,6a-hexahydror4 - ((1 R) -menthyloxy -) - 6-oxo-furo [3,4-d] imidazol-2-one precipitates.
  • Example 2 The product from Example 2 is heated to boiling with 7 g of Na 2 S0 3 in 750 ml of water for 5 hours. After the reduction has taken place, crystalline 2,3,3a, 4,6,6a-hexahydro-4 - ((1 R) -menthyloxy -) - 6-oxo-furo [3,4-d] imidazol-2-one falls on cooling out. Further fractions are obtained by concentrating the mother liquor.
  • the lactone (50 mmol) (product from Example 4) is dissolved in DMF and benzyl chloride (110 mmol) is added. Then NaH (110 mmol) is added in small portions at -10 ° C to 0 ° C. After stirring at RT for 2 h, acetic acid (10 mmol) is added and the reaction solution is evaporated. The residue is taken up in water and extracted with toluene. The toluene solution is concentrated to the residue. The crude product is crystallized from ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP01984162A 2000-07-07 2001-06-20 Verfahren zur herstellung von (+)-biotin Withdrawn EP1299394A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10033284 2000-07-07
DE10033284A DE10033284A1 (de) 2000-07-07 2000-07-07 Verfahren zur Herstellung von (+)-Biotin
PCT/EP2001/006965 WO2002004460A1 (de) 2000-07-07 2001-06-20 Verfahren zur herstellung von (+)-biotin

Publications (1)

Publication Number Publication Date
EP1299394A1 true EP1299394A1 (de) 2003-04-09

Family

ID=7648275

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01984162A Withdrawn EP1299394A1 (de) 2000-07-07 2001-06-20 Verfahren zur herstellung von (+)-biotin

Country Status (8)

Country Link
US (1) US20030149278A1 (ko)
EP (1) EP1299394A1 (ko)
JP (1) JP2004502776A (ko)
KR (1) KR20030014424A (ko)
CN (1) CN1440413A (ko)
AU (1) AU2002218768A1 (ko)
DE (1) DE10033284A1 (ko)
WO (1) WO2002004460A1 (ko)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101215291B (zh) * 2008-01-10 2010-12-29 复旦大学 (+)-生物素及其衍生物的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2489232A (en) * 1949-11-22 Synthesis of biotin
BE759512A (fr) * 1969-11-29 1971-05-27 Hoffmann La Roche Lactone
CH671227A5 (ko) * 1986-12-02 1989-08-15 Lonza Ag

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0204460A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101215291B (zh) * 2008-01-10 2010-12-29 复旦大学 (+)-生物素及其衍生物的合成方法

Also Published As

Publication number Publication date
JP2004502776A (ja) 2004-01-29
DE10033284A1 (de) 2002-01-17
US20030149278A1 (en) 2003-08-07
CN1440413A (zh) 2003-09-03
AU2002218768A1 (en) 2002-01-21
KR20030014424A (ko) 2003-02-17
WO2002004460A1 (de) 2002-01-17

Similar Documents

Publication Publication Date Title
EP0380712B1 (de) Verfahren zur Herstellung von 2,6-Dichlordiphenylaminessigsäurederivaten
WO1988000592A1 (en) DIASTEROSELECTIVE STRECKER SYNTHESIS OF alpha-AMINOACIDS FROM GLYCOSYLAMINE DERIVATES
EP0252353B1 (de) 4-Benzyloxy-3-pyrrolin-2-on-1-yl-acetamid, dessen Herstellung und Verwendung
EP1299394A1 (de) Verfahren zur herstellung von (+)-biotin
WO1989009768A1 (en) Process for producing 5-member nitrogen-containing hetero-aromatic compounds
EP0216324A2 (de) 4-Alkoxy-3-pyrrolin-2-on-1-yl-essigsäurealkyl- bzw. -benzylester sowie deren Herstellung
DE3786770T2 (de) Stereokonvergentverfahren zur Herstellung von optisch aktiven Carbonsäuren.
EP0324336B2 (de) Verfahren zur Herstellung von 3-Cyano-4-aryl-pyrrolen
DE10019291C2 (de) 2-Alkoxy-5-methoxypyrimidine bzw. deren tautomere Formen sowie Verfahren zu deren Herstellung
EP1127879A1 (de) Herstellung der 2-Oxo-1,3-dibenzyl-cis-4,5-imidazolidindicarbonsäure bzw. ihres Anhydrids
DE3411203C1 (de) Verfahren zur Herstellung von N-Cyanimidoestern
DD209443A5 (de) Verfahren zur herstellung von acylaminoderivaten von 1-(aryl- oder subst.-aryl)amino-1-thioalkancarboxysaeuren
EP0811607A1 (de) Verfahren zur Nitrosierung von C-H-aciden Verbindungen
DE2628469A1 (de) Gamma-aminoalkohole und verfahren zu ihrer herstellung
DE19947953A1 (de) Verfahren zur selektiven Spaltung cyclischer Carbonsäureanhydride
DE2438462B2 (de) Verfahren zur herstellung von alpha- aethinylbenzhydrol und seinen ringsubstituierten derivaten sowie ringsubstituierte alpha-aethinylbenzhydrolderivate und solche enthaltende arzneimittel
EP1046638B1 (de) Verfahren zur Herstellung von Aminosäurederivaten
DE2813287A1 (de) Verfahren zur herstellung von 2-benzoyl- 3,3-dimethyl-7-oxo-alpha-(4-benzyloxyphenyl) -4-thia-2,6-diazabicyclo-eckige klammer auf 3.2.0 eckige klammer zu heptan-6-essigsaeurebenzylester
DE2613306C2 (ko)
DE3607993A1 (de) Verfahren zur herstellung von diaziridinen und produkte daraus
EP0757981A1 (de) Verfahren zur Herstellung von racemischen Amino-Derivaten
EP0492347A1 (de) Verfahren zur Herstellung von threo-4-Alkoxy-5-(arylhydroxymethyl)-2(5H)-furanonen
EP1223168A1 (de) Verfahren zur Herstellung von enantiomerenangereicherten Amino- und Hydroxyfuranonen
WO2005037817A2 (de) Verfahren zur herstellung von enantiomerenreinen, in 2-position substituierten chromanderivaten
DE19505934A1 (de) Verfahren zur Herstellung von Thietanaminen

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20021114

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Extension state: AL LT LV MK RO SI

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20040225