GB2108501A - Process for the preparation of DELTA 2,3 and DELTA 3,4 prostaglandins - Google Patents
Process for the preparation of DELTA 2,3 and DELTA 3,4 prostaglandins Download PDFInfo
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- GB2108501A GB2108501A GB08231152A GB8231152A GB2108501A GB 2108501 A GB2108501 A GB 2108501A GB 08231152 A GB08231152 A GB 08231152A GB 8231152 A GB8231152 A GB 8231152A GB 2108501 A GB2108501 A GB 2108501A
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- 150000003180 prostaglandins Chemical class 0.000 title claims abstract description 22
- 229940094443 oxytocics prostaglandins Drugs 0.000 title claims abstract description 20
- 238000000034 method Methods 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- -1 trialkyl silyl enol ether Chemical class 0.000 claims abstract description 24
- 239000002253 acid Substances 0.000 claims abstract description 12
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000001408 amides Chemical class 0.000 claims abstract description 11
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 11
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 8
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 claims abstract description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000005864 Sulphur Substances 0.000 claims abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 229910052711 selenium Inorganic materials 0.000 claims abstract description 6
- 239000011669 selenium Substances 0.000 claims abstract description 6
- 150000002576 ketones Chemical class 0.000 claims abstract description 5
- 230000001590 oxidative effect Effects 0.000 claims abstract description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 3
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- UYYCVBASZNFFRX-UHFFFAOYSA-N n-propan-2-ylcyclohexanamine Chemical compound CC(C)NC1CCCCC1 UYYCVBASZNFFRX-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- UPRXAOPZPSAYHF-UHFFFAOYSA-N lithium;cyclohexyl(propan-2-yl)azanide Chemical compound CC(C)N([Li])C1CCCCC1 UPRXAOPZPSAYHF-UHFFFAOYSA-N 0.000 description 1
- XVDBWWRIXBMVJV-UHFFFAOYSA-N n-[bis(dimethylamino)phosphanyl]-n-methylmethanamine Chemical compound CN(C)P(N(C)C)N(C)C XVDBWWRIXBMVJV-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WJCXADMLESSGRI-UHFFFAOYSA-N phenyl selenohypochlorite Chemical compound Cl[Se]C1=CC=CC=C1 WJCXADMLESSGRI-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 150000003814 prostanoids Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/22—Tin compounds
- C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for the preparation of E type DELTA 2,3 or DELTA 3,4 prostaglandins which comprises: (a) preparing a trialkyl silyl enol ether of a prostaglandin C-9 ketone; (b) treating the trialkyl silyl enol ether with a lithium dialkyl amide, followed by a selenium or sulphur reagent; (c) oxidizing the product of (b); and if DELTA 2,3 compounds are required, (d) hydrolyzing the product of (c) using a weak acid to yield the desired DELTA 2,3 prostaglandins; or, if DELTA 3,4 compounds are required, (d) treating the product of (c) with a lithium dialkyl amide; (e) treating the product of (d) with a proton source; and (f) hydrolyzing the product of (e) using a weak acid to produce the desired DELTA 3,4 prostaglandins is disclosed. Examples prepare (I) methyl 11 alpha ,16(RS)-dehydroxy-16-methyl-9- oxoprosta-2EZ,5Z,13E-trienoate and the corresponding 3EZ,5Z,13E-trienoate.
Description
SPECIFICATION
Process for the preparation of A 2,3 and A 3,4 prostaglandins
This invention relates to a process for the preparation of A 2,3 and A 3,4 prostaglandins; more particularly, it relates to a method of introducing a double bond at the 2,3 or 3,4 position of E type prostaglandins.
The present invention is particularly applicable to E type prostaglandins corresponding to the following general formulae (I), (II) and (Ill):
For examples of specific compounds, reference may be made to "Prostaglandin Synthesis", J.S. Bendra and
R Bendra,Academic Press (1977),forexample. In particularthe present process maybe used to prepare useful compounds of the type described in U.S. Patent No. 4,312,994. The present process is particularly useful in that it decreases the number of steps and increases the yield over previous processes for producing valuable A 2,3 and A 3,4 E type prostaglandins. Prostaglandin compounds of the E series are known to have a variety of therapeutic applications. (See, for example, E.W.Horton in "Chemistry, Biochemistry and
Pharmacological Activity of Prostanoids" Pergamon Press (1979).)
In one embodiment, the present invention relates to a process for the preparation of E type A 2,3 prostaglandins which comprises:
(a) preparing a higher trialkyl silyl enol ether of a C-9 ketone;
(b) treating the higher trialkyl silyl enol ether with a lithium dialkyl amide, followed by a selenium or sulphur reagent;
(c) oxidizing the product of (b); and
(d) hydrolyzing the product of (c) using a weak acid to produce the desired A 2,3 prostaglandins.
In another embodiment, the present invention relates to a process for the preparation of A 3,4 E type prostaglandins which comprises:
(a) preparing a highertrialkyl silyl enol ether of a C-9 ketone;
(b) treating the higher trialkyl silyl enol ether with a lithium dialkyl amide, followed by a selenium or sulphur reagent;
(c) oxidizing the product of (b);
(d) treating the product of (c) with a lithium dialkyl amide;
(e) treating the product of (d) with a proton source; and
(f) hydrolyzing the product of (e) using a weak acid to produce the desired A 3,4 prostaglandins.
Accordingly, the present invention provides a process for the preparation of E type A 2,3 or A 3,4 prostaglandins which comprises:
(a) preparing a higher trialkyl silyl enol ether of a C-9 ketone;
(b) treating the higher trialkyl silyl enol ether with a lithium dialkyl amide, followed by a selenium or sulphur reagent;
(c) oxidizing the product of (b); and, if A 2,3 compounds are required,
(d) hydrolyzing the product of (c) using a weak acid to yield the desired A 2,3 prostaglandins; or, if A 3,4 compounds are required,
(d) treating the product of (c) with a lithium dialkyl amide;
(e) treating the product of (d) with a proton source; and
(f) hydrolyzing the product of (e) using a weak acid to produce the desired A 3,4 prostaglandins.
For example, one A 3,4 prostaglandins.
For example, one A 3,4 compound which it is preferred to prepare in accordance with the present invention is (+) methyl 11a, 16(RS)-dihydrnxy-16-methyl-9-oxoprnsta-3EZ,SZ, 13E-trienoate.
The higher trialkyl silyl enol ether will vary depending on the compound being prepared. In general, this process is a competition reaction with the possibility of protons being pulled from a number of sites, and thus a consequential wide variety of potential end products exists. the trialkyl silyl enol ether used must be such that it protects other sites from deprotonation. There is in general no formula for determing the relative size based on any constant factors, but, for example, in preparing (+) methyl 11 a, 1 6(RS)-dihydroxy-1 6- methyl-9-oxoprosta-3EZ, 5Z. 1 3E-trienoate, the dimethyl t-butyl silyl enol ether will work successfully in producing this compound. However, relatively smaller or less branched trialkyl silyl enol ethers will not work.Examples of ineffective compounds for this example are trimethylsilyl, triethylsilyl (which has the same molecular weight as the dimethyl-t-butyl) or even dimethyl butyl which is a straight-chain isomer. It appears, therefore, that some degree of branched side chain is necessary to achieve the desired results; the exact degree may be determined on a compound by compound basis.
The general schematic of the present invention as applied to compounds of the above mentioned U.S.
Patent No. 4,312,994 is illustrated in the following:
(A) O OR2 R4, - 1. Cuprate (n) 2. Higher tri alkyl silyl CI Hexamethyl phosphoric iamide (HMPT) Si (Alkyl)3 0 COOR2 R3 R " + (]CI) ,SI(Alkyl)j 1. LDA 2. Ph2Se2 Si (Alkyl)3 d Kbw zCOOR2 R4 < 3 cxm, OSi (Alkyl)j s r agent agent eg H2 2 Si (Alkyl)3 0 eCooR2 R ,- L A (v) OSi (Alkyl )3
(B) Si (Aikyl)3 bcCOOR2 N X,/ (:ar) R3 R4 l OSi (Alkyl )3 1. LDA-60 O 2. AcO6O' K rCOOR2 R3 HO OH Si (Alkyl )3 t < oCOOR2 -",,R3 (sxm) l OSi(Alkyi)3 /t p%,COOR2 3 (1XX[P) HO' OH The ether compound (XI), wherein R4 represents -O-tetrahydropyranyl or -O-silyl trialkyl and R2 and R3 represent hydrogen or alkyl, is reacted with the appropriate cuprate and then with a higher trialkylchlorosilane in the presence of HMPT. The resulting compound (XII) is then treated with a lithium dialkyl amide, such as lithium diisopropyl amide or lithium isopropyl cyclohexyl amide, and quenched with a selenium or sulphur reagent, such as diphenyl diselenide, phenyl selenium chloride or diphenyl disulphide, with diphenyl diselenide being preferred, to give a compound (XIII).The compound (XIII) is then oxidized, for example using hydrogen peroxide or sodium periodate, to yield the (XIV) or (XXI) compound. The (XXI) compound may be hydrolyzed using a weak acid, such as acetic acid, to yield the (XXII) compound according to the present invention. Alternatively, the (XXII) compound may be treated with a lithium dialkyl amide and then quenched with a proton source, such as a weak acid or alcohol, with acetic acid being preferred, to yield the (XXIII) compounds according to the present invention. The (XXIII) compounds may be hydrolyzed using a weak acid, such as acetic acid, to yield the (XXIV) compounds. The following Examples illustrated the present invention.
EXAMPLE 1
Methyl 7-(3rRS)-tetrahydropyran-2-yloxy-5-oxo-cyclopent-1-ene)hept-5Z-enoate.
To a solution of 2.88 g of methyl 7-(3(RS)-hydroxy-5-oxocyclopent-1 -ene)hept-5Z-enoate and 35 ml of ether is added 50 mg of p-toluene sulphonic acid and 1.1 g of dihydropyran. The reaction mixture is allowed to stand at room temperature for about 24 hours, then is diluted with ether, washed successively with 5 percent aqueous potassium carbonate and water, dried over an hydros sodium sulphate and stripped of solvent under reduced pressure. The residue is chromatographed on silica gel using 25 percent ethyl acetate in hexane as eluent to produce the title compound.
EXAMPLE 2 E- ?-(tri-n-butyl-stannyl)-4-methyl-4-trimethylsilyoxy-1 -octene
2.12 grams of 4(RS)-trimethylsiloxy-4-methyl-l -octyne and 3.0 grams of tri-n-butyl tin hydride are mixed and irradiated using a sunlamp under a sunlamp under argon at 0 C for 2 hours and then at 55"C for 2 hours.
The resulting title compound is used directly in Example 3.
EXAMPLE 3
Racemic methyl 7-[3a-tetrah ydrop yranyloxy-2(3(4(RS)-4-trimeth ylsllyloxy-4-meth yl- lE-octen yl)-5-t- butyldimethylsilyloxy-cyclopent- 1-(5)-enej- 1a-hept-5Z-enoate.
The title compound of Example 2, 11.5 grams, is dissolved in dry THF (30 ml) and cooled to -600C under argon. n-butyl lithium (14.5 ml of a 1.55 M solution) is added. This solution is stirred for about 45 minutes. In a separate flask, 3.0 g of copper 1-pentynilide and 7.4 g of hexamethyl phosphorous triamide are dissolved with stirring in 30 ml of ether. This solution is then added to the reaction mixture. The resulting mixture is stirred for 10 minutes at -60"C then a solution of the product from Example 1(3.7 grams) in 30 mls of ether is added.The reaction mixture is stirred at -60 C for about 1 hour and then treated successively with 40 ml of hexamethylphosphorictriamide and 5 grams of t-butyldimethylchlorosilane dissolved in 10 ml of ether. The temperature of the reaction mixture is allowed to rise to -200C and then is maintained for about 1 hour. The reaction mixture is poured over a mixture of 1 N HCI and ether. The ether layer is separated and washed twice with water, filtered and dried over sodium sulphate and stripped.The residue is chromatographed in a 2 percent ethyl acetate and hexane solvent system to give the pure title product
EXAMPLE 4
Racemic methyl 7-[3a-tetrahydropyranyloxy-2ss-[4gRS)-4-trimethylsilyloxy-4methyl- lE-octenyl)-5-t- butyldimethylsilyloxy cyclopent- 1 (5)-ene]- 1a-hept-2-phenylselenyl-5Z-enoate A solution of 550 mg of cyclohexyl isopropyl amine in 15 ml of dry THF is cooled to about -30"C under argon and treated with 2.31 ml of a 1.55 M solution of n-butyl lithium. After stirring for about 1.5 hours at from -30 to -200C the solution is cooled to -600C and treated dropwise with a solution of 2.1 g of the enol ether product from Example 3 in 20 ml of THF.After the addition is complete, a solution of 1 gram of diphenyldiselenide in 10 ml of THF is added dropwise. The reaction mixture is diluted with ether and washed twice with water, dried and stripped. The residue is chromatographed in a 2 percent ethyl acetate and hexane solvent system to give the desired product.
EXAMPLES
Racemic methyl 7-[3a-tetrahydropyranyloxy-2ss-[4FRS)-4-trimethylsilyloxy-4methyl- 1E-octeny/)t- butyldim ethylsilyloxy-cyclop en t- 1(5)-en ej- la-h ept-2E, 5Z-dienoa te.
A solution of 1 gram of the product from Example 4 in 50 mls of methylene chloride containing 500 mg of pyridine is treated with a solution of 5 g of 30 percent hydrogen peroxide in 5 ml of water and this diphasic system is vigorously stirred for about 4 hours at room temperature. The solution is poured into ether and washed once with 1 N hydrochloric acid and twice with water, then dried over sodium sulphate and stripped of solvent. The residue is chromatographed with a 2 percent ethyl acetate and hexane solvent system to give the title product.
EXAMPLE 6
Racemic methyl 7-[3a-tetrahydropyranyloxy-2ss-[4rRS)-4-trimethylsilyloxy-4methyl-1E-octenyl)-5-t- butyidimethylsilyloxy-cyclopent- 165)-ene]- 1 a-hep t-3EZ, 5Z-dien oa te.
A solution of 165 mg of cyclohexyl isopropyl amine and 4 ml of dried THF is cooled to -30"C under argon and treated with 0.75 mls of a 1.55 M solution of n-butyl lithium. This solution is stirred at from -30 to -200C for 1 hour and then is cooled to -600C. A solution of 230 mg of hexamethyl phosphoric triamide in 1 ml of
THF is added. A solution of 630 mg of the product from Example 5 in 6 ml of dry THF is added dropwise over a 1 hour period. After the addition is complete, a THF solution (1 ml) of 90 mg of acetic acid is added. The reaction mixture is poured into ether and water. The organic layer is washed with water, dried over sodium sulphate and stripped. The residue is used directly in Example 7.
EXAMPLE 7 (+) methyl 1 lea, 16{RS)-dEhydroxy- 16-methyl-9-oxoprosta-3EZ, 5Z, 13E-trienoate
The product from Example 6 (630 mg) is dissolved by stirring in 10 mls of a 3:1:1 mixture of acidic acid, water and THF. Stirring is continued until the mixture becomes homogeneous. The solution is then allowed to stand at room temperature for from 24 to 48 hours. The solution is diluted with ether, washed four times with water, dried over sodium sulphate and stripped of solvent. The residue is chromatographed in 70 percent ethyl acetate and 30 percent hexane to give the title compound.
EXAMPLE 8
A higher molecular weight trialkyl silyl chloride may be substituted in Example 3 and the product thereof carried through Examples 4 to 7 to yield the title product of Example 7.
EXAMPLE 9
The processes of Examples 2 to 7 are used except a triethylsilyl group at the C-1 1 position is used in place of the tetrahydropyranyl group to yield the title compound of Example 7.
EXAMPLE 10 (*) methyl 1 la, 16(RS)-dihydroxy- 16-methyl-9-oxo prosta-2E, 5Z, 13E-trienoate
The title product of Example 5 is substituted into the process of Example 7 to yield the title compound.
Claims (3)
1. A process for the preparation of E type A 2,3 or A 3,4 prostaglandins which comprises:
(a) preparing a highertrialkyl silyl enol ether of a C-9 ketone;
(b) treating the higher trialkyl silyl enol ether with a lithium dialkyl amide, followed by a selenium or sulphur reagent;
(c) oxidizing the product of (b); and if A 2,3 compounds are required,
(d) hydrolyzing the product of (c) using a weak acid to yield the desired A 2,3 prostaglandins; or, if A 3,4 compounds are required,
(d) treating the product of (c) with a lithium dialkyl amide;
(e) treating the product of (d) with a proton source; and
(f) hydrolyzing the product of (e) using a weak acid to produce the desired A 3,4 prostaglandins.
2. A process as claimed in claim 1 for the preparation of A 3,4 compounds wherein (+) methyl 11 a, 1 6(RS)-dihydroxy-1 6-methyl-9-oxoprosta-3EZ, SZ,13E-trienoate is obtained.
3. A process as claimed in claim 1 substantially as herein described with particular reference to the
Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US31765481A | 1981-11-02 | 1981-11-02 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2108501A true GB2108501A (en) | 1983-05-18 |
| GB2108501B GB2108501B (en) | 1985-07-17 |
Family
ID=23234673
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08231152A Expired GB2108501B (en) | 1981-11-02 | 1982-11-01 | Process for the preparation of 2,3 and 3,4 prostaglandins |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPS5888355A (en) |
| CA (1) | CA1215975A (en) |
| DE (1) | DE3240488A1 (en) |
| FR (1) | FR2515643B1 (en) |
| GB (1) | GB2108501B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4905063A (en) * | 1988-06-21 | 1990-02-27 | American Telephone And Telegraph Company, At&T Bell Laboratories | Floating gate memories |
| JP4648340B2 (en) * | 2006-02-07 | 2011-03-09 | 株式会社アールテック・ウエノ | Method for producing 15-keto prostaglandin E derivative |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6036422B2 (en) * | 1979-01-29 | 1985-08-20 | 小野薬品工業株式会社 | Prostaglandin-like compounds and their production methods |
| US4312994A (en) * | 1981-03-25 | 1982-01-26 | G. D. Searle & Co. | α Chain dienic prostanoic acid derivatives |
-
1982
- 1982-11-01 CA CA000414633A patent/CA1215975A/en not_active Expired
- 1982-11-01 GB GB08231152A patent/GB2108501B/en not_active Expired
- 1982-11-02 DE DE19823240488 patent/DE3240488A1/en not_active Withdrawn
- 1982-11-02 JP JP57193291A patent/JPS5888355A/en active Pending
- 1982-11-02 FR FR8218350A patent/FR2515643B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR2515643A1 (en) | 1983-05-06 |
| DE3240488A1 (en) | 1983-05-11 |
| CA1215975A (en) | 1986-12-30 |
| FR2515643B1 (en) | 1986-02-21 |
| JPS5888355A (en) | 1983-05-26 |
| GB2108501B (en) | 1985-07-17 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |