발생일자 2015.04.10 

사건번호 1:15-cv-00307 

법원국가 UNITED STATES OF AMERICA 

관할법원명 D.C.Delaware(지방법원) 

침해권리 특허 

원고명 Janssen Products Lp/ Janssen Sciences Ireland Uc ( 아일랜드 / 외국기업 )  

피고명 Cipla Ltd./ Cipla Usa Inc. ( 인도 / 외국기업 )  

소송유형 침해금지 

[Janssen Products LP et al v. Cipla Ltd. et al] 사건번호 1:15-cv-00307에 따르면 원고 Janssen Products Lp/ Janssen Sciences Ireland Uc는 피고 Cipla Ltd./ Cipla Usa Inc.을 상대로 특허 US7126015|US7595408|US7700645|US8518987을 침해하였다는 이유로 미국 델라웨어 지방법원에 소를 제기하였다. 

분쟁결과 분쟁중 

산업분류 화학∙바이오 > 의약품 

계쟁제품 Generic versions of PREZISTA 800 mg darunavir tablets 

지재권번호/명칭

US7126015  Method for the preparation of hexahydro-furo-[2,3-b]furan-3-ol 

US7595408 Methods for the preparation of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol 

US7700645  Pseudopolymorphic forms of a HIV protease inhibitor 

US8518987  Pseudopolymorphic forms of a HIV protease inhibitor 

The present invention relates to a method for the preparation of hexahydro-furo[2,3-b]furan-3-ol as well as novel intermediates for use in said method. More in particular the invention relates to a stereoselective method for the preparation of hexahydro-furo[2,3-b]furan-3-ol, and to a method amenable to industrial scaling up. 

 1. A method for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7) starting from an intermediate of formula (1) wherein P.sup.1 and P.sup.2 represent each independently a hydrogen, a hydroxy-protecting group or may together form a vicinal-diol protecting group, ##STR00049## transforming said intermediate of formula (1) into a nitromethane derivative of formula (3) wherein R.sup.1 represents alkyl, aryl or aralkyl, R.sup.2 represents hydrogen or C(.dbd.O)OR.sup.3, R.sup.3 represents alkyl, aryl or aralkyl, or R.sup.3, if present, and R.sup.1 taken together with the atoms to which they are attached may form a 6 to 8-membered cyclic group which may be optionally substituted with alkyl, aralkyl, or aryl, ##STR00050## subsequently transforming said nitromethane derivative into a tetrahydrofuran derivative of formula (6) wherein OR.sup.4 represents an alcoholate, ##STR00051## and then transforming the intermediate of formula (6) into hexahydro-furo[2,3-b]furan-3-ol of formula (7) by way of an intramolecular cyclisation reaction ##STR00052## 

 2. A method according to claim 1 wherein the intermediate of formula (3) is transformed into an intermediate of formula (6) by making use of a Nef reaction. 

 3. A method according to claim 1 for the synthesis of hexahydro-furo[2,3-b]-furan-3-ol of formula (7), which comprises the steps of: a) condensing an intermediate of formula (1) ##STR00053## resulting in an .alpha.,.beta.-unsaturated ester of formula (2), ##STR00054## b) reacting said ester of formula (2) with nitromethane resulting in an intermediate of formula (3), ##STR00055## c) submitting said intermediate of formula (3) to a Nef reaction leading to intermediates of formula (4) and (4') ##STR00056## d) transforming said intermediates of formula (4) and (4') into an intermediate of formula (6) and, ##STR00057## e) converting intermediate of formula (6) to the compound of formula (7) by an intramolecular cyclisation reaction. 

 4. A method according to claim 1 for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7), which comprises the steps of: a) condensing an intermediate of formula (1) with CHR.sup.2R.sup.5--C(.dbd.O)--OR.sup.1 wherein R.sup.5 represents a hydrogen, a carboxylic ester, a phosphonium salt or a phosphonate ester, ##STR00058## resulting in an .alpha.,.beta.-unsaturated ester of formula (2) ##STR00059## b) reacting said ester of formula (2) with nitromethane resulting in an intermediate of formula (3), ##STR00060## c) submitting said intermediate of formula (3) to a Nef reaction by treating it with a base and subsequently with a strong acid resulting in a mixture of intermediates of formula (4) and (4'), ##STR00061## d) only in case R.sup.2 is different from hydrogen, decarboxylating the intermediates of formula (4) and (4') thus forming intermediates of formula (5) and (5') respectively, ##STR00062## e) reducing intermediates of formula (4) and (4'), or intermediates of formula (5) and (5') with a suitable reducing agent resulting in intermediate of formula (6) and, ##STR00063## f) converting intermediate of formula (6) to the compound of formula (7) by an intramolecular cyclisation reaction. 

 5. A method according to claim 1 for the synthesis of hexahydro-furo[2,3b]furan-3-ol of formula (7.1) starting from an intermediate of formula (1), wherein P.sup.1 and P.sup.2 taken together form an isopropylidene, ##STR00064## condensing said intermediate of formula (1) resulting in an intermediate of formula (2), wherein P.sup.1 and P.sup.2 taken together form an isopropylidene, R.sup.2 represents --C(.dbd.O)OR.sup.3, wherein R.sup.3 is methyl and R.sup.1 is methyl, ##STR00065## reacting said ester of formula (2) into a nitromethane derivative of formula (3) wherein P.sup.1 and P.sup.2 taken together form an isopropylidene, R.sup.2 represents --C(.dbd.O)OR.sup.3, wherein R.sup.3 is methyl, and R.sup.1 is methyl, ##STR00066## transforming said intermediate of formula (3) using a base and subsequently an acid to yield intermediates of formula (4) and (4'), wherein R.sup.2 represents --C(.dbd.O)OR.sup.3, wherein R.sup.3 is methyl, R.sup.1 is methyl and R.sup.4 is methyl, ##STR00067## decarboxylating intermediates of formula (4) leading to an intermediate of formula (5), wherein R.sup.4 is methyl, ##STR00068## reducing said intermediate of formula (5) with a suitable reducing agent resulting in an intermediate of formula (6), wherein R.sup.4 is methyl, ##STR00069## transforming the intermediate of formula (6) into compound 7.1 by way of intramolecular cyclization reaction ##STR00070## 

 6. A method according to claim 3 wherein intermediate of formula (3) is submitted to a Nef reaction using acidic quenching while keeping the temperature below -10.degree. C. during said quenching. 

 7. A method according to claim 4 wherein the decarboxylation of intermediates of formula (4) and (4') is performed in a buffered aqueous solution. 

 8. A method according to claim 3 wherein intermediate (6) is prepared via reduction of intermediates of formula (4) and (4') or intermediates of formula (5) and (5') using lithium borohydride in tetrahydrofuran or NaBH.sub.4 in the presence of LiCl. 

 9. A method according to claim 3 wherein the cyclisation of intermediate of formula (6) to the compound of formula (7) is performed by adding a strong acid to the reaction mixture containing intermediate of formula (6). 

 10. A method according to claim 9 wherein the cyclisation reaction is performed at a temperature lower then 5.degree. C. 

 11. A method according to claim 10 wherein the temperature of the reaction mixture while adding the strong acid to the reaction mixture remains lower than -5.degree. C. 

 12. A method according to claim 1 wherein an intermediate of formula (3) is prepared by a process comprising the steps of first condensing an intermediate of formula (1) with nitromethane, resulting in an intermediate of formula (8) and secondly, reacting said intermediate of formula (8) with CHR.sup.2R.sup.8--C(.dbd.O)--OR.sup.1 wherein R.sup.8 is hydrogen or a carboxylic ester ##STR00071## 

 13. A method according to claim 12 wherein the carboxylic ester is defined as C(.dbd.O)--OR.sup.1. 

 14. A method according to claim 1 wherein an intermediate of formula (6) is prepared by a process comprising the steps of first reducing intermediate of formula (3) wherein R.sup.2 is hydrogen with a suitable reducing agent, resulting in an intermediate of formula (9) and secondly submitting the obtained intermediate of formula (9) to a Nef reaction by treatment with a base and then with a strong acid ##STR00072## 

 15. A method according to claim 1 wherein hexahydro-furo[2,3-b]furan-3-ol of formula (7) is isolated by adding a small excess of a tertiary amine, followed by the removal of water and removal of formed salts. 

 16. A method according to claim 1 wherein R.sup.1 and R.sup.3 each independently are C.sub.1-6alkyl, aryl or arylC.sub.1-6alkyl or together with the atoms to which R.sup.1 and R.sup.3 are attached form a 6 to 8-membered cyclic group optionally substituted with C.sub.1-6alkyl, aryl or arylC.sub.1-6alkyl, and wherein R.sup.4 is C.sub.1-6alkyl. 

 17. A method according to claim 1 wherein R.sup.1, R.sup.3 and R.sup.4 each independently are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or pentyl. 

 18. A method according to claim 1 wherein P.sup.1 and P.sup.2 together form an acid labile vicinal-diol protecting group. 

 19. A method according to claim 1 wherein P.sup.1 and P.sup.2 is a dialkyl methylene radical. 

 20. A method according to claim 4 wherein R.sup.5 is hydrogen, R.sup.1O--C(.dbd.O)--, (R.sup.6).sub.3P=wherein R.sup.6 is alkyl, aryl or aralkyl, or (R.sup.7O).sub.2P(.dbd.O)-- wherein R.sup.7 is alkyl, aryl, aralkyl. 

 21. An intermediate having the formula (3), ##STR00073## wherein P.sup.1 and P.sup.2 represent each independently a hydrogen, a hydroxy-protecting group or may together form a vicinal-diol protecting group, R.sup.1 represents alkyl, aryl or aralkyl, R.sup.2 represents hydrogen or C(.dbd.O)OR.sup.3, R.sup.3 represents alkyl, aryl or aralkyl, or R.sup.3, if present, and R.sup.1 taken together with the atoms to which they are attached may form a 6 to 8-membered cyclic group which may be optionally substituted with alkyl, aralkyl, or aryl; provided that when R.sup.2 is hydrogen and P.sup.1 and P.sup.2 taken together form an isopropylidene, then R.sup.1 is other than methyl or ethyl. 

 22. An intermediate having the formula (4) or (4'), ##STR00074## wherein R.sup.1 represents alkyl, aryl or aralkyl; R.sup.2 represents hydrogen or C(.dbd.O)OR.sup.3; R.sup.3 represents alkyl, aryl or aralkyl, or R.sup.3, if present, and R.sup.1 taken together with the atoms to which they are attached may form a 6 to 8-membered cyclic group which may be optionally substituted with alkyl, aralkyl, or aryl; OR.sup.4 represents an alcoholate. 

 23. An intermediate having the formula (5) or (5'), ##STR00075## wherein OR.sup.4 represents an alcoholate. 

 24. An intermediate according to claim 23 wherein the intermediate has the formula (5a) ##STR00076## 

 25. An intermediate according to claim 24 in crystalline form. 

The present invention relates to methods for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol as well as a novel intermediate, (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one for use in said methods. More in particular the invention relates to a stereoselective method for the preparation of diastereomerically pure (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol, as well as methods for the crystallization of (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one and for the epimerization of (3aR,4R,6aS) 4-methoxy-tetrahydro-furo[3,4-b]-furan-2-one to (3aR,4S,6aS) 4-methoxy-tetrahydro-furo[3,4-b]furan-2-one. 

 1. A method for the synthesis of (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol having the structure of formula (6), ##STR00048## which method comprises the step of reducing the intermediate of formula .alpha.-(4): ##STR00049## 

 2. A method according to claim 1 which method further comprises crystallizing intermediate of formula .alpha.-(4) with a solvent prior to the reduction thereof. 

 3. A method according to claim 1 which method further comprises a) epimerizing with acid intermediate of formula .beta.-(4) into the intermediate of formula .alpha.-(4); and ##STR00050## b) crystallizing intermediate of formula .alpha.-(4) with a solvent prior to the reduction thereof. 

 4. A method according to claim 3 which method further comprises after crystallizing intermediate of formula .alpha.-(4), a) epimerizing with acid intermediate of formula .beta.-(4) in the mother liquor of said crystallization into the intermediate of formula .alpha.-(4); and ##STR00051## b) crystallizing intermediate of formula .alpha.-(4) with a solvent; prior to the reduction thereof. 

 5. A method according to claim 3 wherein the epimerization of compound of formula .beta.-(4) to compound of formula .alpha.-(4) and crystallization of compound of formula .alpha.-(4) occur simultaneously. 

 6. A method according to claim 5, wherein the simultaneous epimerization of compound of formula .beta.-(4) to compound of formula .alpha.-(4) and the crystallization of compound of formula .alpha.-(4) is performed in methanol in the presence of an acid by evaporation or partial evaporation of the methanol. 

 7. A method according to claim 1 which method comprises the steps of: a) treating compound of formula (3) with a base and subsequently with an acid in the presence of a non-methanolic solvent; and subsequently reacting with methanol under acidic conditions; ##STR00052## wherein P.sup.1 and P.sup.2 are each independently a hydrogen, a hydroxy-protecting group or may together form a vicinal-diol protecting group, R.sup.1 is alkyl, aryl or aralkyl; resulting in intermediates of formula (4); and ##STR00053## b) reducing intermediate of formula (4) with a reducing agent and applying an intramolecular cyclization reaction to obtain compound of formula (6) ##STR00054## 

 8. A method according to claim 7 wherein compounds of formula (3) are obtained by reacting compounds of formula (2) with nitromethane and a base ##STR00055## 

 9. A method according to claim 8 wherein compounds of formula (2) are obtained by condensing an intermediate of formula (1) or its hydrate, hemihydrate or a mixture thereof with phosphonates of the formula (R.sup.6O).sub.2P(.dbd.O)--CH.sub.2--C(.dbd.O)OR.sup.1, wherein P.sup.1 and P.sup.2 are as defined in claim 1, R.sup.1 is as defined in claim 1, R.sup.6 is alkyl, aryl or aralkyl, ##STR00056## 

 10. A method according to claim 7 wherein P.sup.1 and P.sup.2 together form a dialkyl methylene radical. 

 11. A method according to claim 8 wherein the base employed for the conversion of compounds of formula (2) into compounds of formula (3) is DBU or TMG or derivatives thereof. 

 12. A method according to claim 9 wherein the phosphonate of the formula (R.sup.6O).sub.2P(.dbd.O)--CH.sub.2--C(.dbd.O)OR.sup.1 is triethyl phosphonoacetate (TEPA). 

 13. A method according to claim 7 wherein the conversion of compounds of formula (3) into compounds of formula (4) is performed with a base selected from the group of sodium methoxide, lithium methoxide, DBU or TMG or mixtures thereof. 

 14. A method according to claim 8, wherein the conversion of compounds of formula (2) into compounds of formula (4) is performed by using DBU or TMG as the base in the conversion of compounds of formula (2) to compounds of formula (3), not isolating compounds of formula (3) and using sodium or lithium methoxide as additional base in the conversion of compounds of formula (3) to compounds of formula (4). 

 15. A method according to claim 7 wherein the acid employed in the conversion of compounds of formula (3) into compounds of formula (4) is concentrated sulphuric acid in an amount of 2.5 to 5 equivalents based on compound of formula (2) as a 20 to 80 wt % solution in methanol. 

 16. A method according to claim 2 wherein crystallization of compound of formula .alpha.-(4) is performed in an alcohol. 

 17. A method according to claim 16 wherein the alcohol is isopropanol, t-amyl alcohol or t-butanol. 

 18. A method for the conversion of compound of formula .beta.-(4) into the compound of formula .alpha.-(4) which comprises an epimerization with acid ##STR00057## 

 19. A method according to claim 3 wherein epimerization of compound of formula .beta.-(4) into compound of formula .alpha.-(4) is performed with 0.05 to 1.5 equivalents of MeSO.sub.3H in methanol. 

 20. A method according to claim 3 wherein the epimerization is performed at a temperature between 40.degree. C. and reflux temperature. 

New pseudopolymorphic forms of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sul- fonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate and processes for producing them are disclosed.

 1. An ethanolate solvate of the compound (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sul- fonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate, in which the ratio of compound to ethanol is about 1:1. 

 2. A solvate having the formula: ##STR00002## 

 3. A composition comprising an ethanolate solvate of the compound (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl(1S,2R)-3-[[(4-aminophenyl)sul- fonyl](isobutyl)amino]-1-benzyl-2-hydroxypropylcarbamate, in which the ratio of compound to ethanol is about 1:1, and an inert carrier. 

 4. The composition of claim 3 wherein the inert carrier is a pharmaceutically acceptable carrier. 

 5. The composition of claim 4 wherein the pharmaceutically acceptable carrier is a solid inert carrier. 

 6. A composition comprising a solvate having the formula: ##STR00003## and an inert carrier. 

 7. The composition of claim 6 wherein the inert carrier is a pharmaceutically acceptable earner. 

 8. The composition of claim 7 wherein the pharmaceutically acceptable carrier is a solid inert carrier.