CA2568510C - One-pot processes for preparing prednisolone derivatives - Google Patents
One-pot processes for preparing prednisolone derivatives Download PDFInfo
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- 150000003116 prednisolone derivatives Chemical class 0.000 title claims abstract description 14
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 45
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 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 abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 32
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 239000003377 acid catalyst Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 7
- 125000000304 alkynyl group Chemical group 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 3
- 239000003495 polar organic solvent Substances 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000376 reactant Substances 0.000 description 12
- -1 cyclohexylmethylene Chemical group 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- GUSVXFPRNUPMFZ-ZEVBYOGFSA-N 16a-Hydroxyprednisolone Chemical compound C[C@]12C[C@@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@]34C)[C@@H]1C[C@H](O)[C@]2(O)CC(O)=O GUSVXFPRNUPMFZ-ZEVBYOGFSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- KVFDZFBHBWTVID-UHFFFAOYSA-N cyclohexanecarbaldehyde Chemical compound O=CC1CCCCC1 KVFDZFBHBWTVID-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 150000008064 anhydrides Chemical class 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- FGLBSLMDCBOPQK-UHFFFAOYSA-N 2-nitropropane Chemical compound CC(C)[N+]([O-])=O FGLBSLMDCBOPQK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 208000002205 allergic conjunctivitis Diseases 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000009151 chronic rhinitis Diseases 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 150000003117 prednisolones Chemical class 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
Abstract
Disclosed is a one-pot process for the preparation of a prednisolone derivative of formula I, comprising reacting the compound of formula II with the compound of formula III and the compound of formula IV The process does not need to separate and purify the intermediate formed, and therefore the process reduces the reaction time and increases the yield of the product compared to the prior art (see formula II) (see formula III) (see formula IV) (see formula I).
Description
ONE-POT PROCESSES FOR PREPARING PREDNISOLONE DERIVATIVES
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention [00011 The present invention relates to a process for preparing a prednisolone derivative of formula 1, especially to a one-pot process for the preparation of prednisolone derivatives using 16a-hydroxyprednisolone, an anhydride and an aldehyde as starting materials.
O
O~
C ) H
'Ri CH3 H uiu0 ~ = =
H H
O
BACKGROUND OF THE INVENTION
1. Technical Field of the Invention [00011 The present invention relates to a process for preparing a prednisolone derivative of formula 1, especially to a one-pot process for the preparation of prednisolone derivatives using 16a-hydroxyprednisolone, an anhydride and an aldehyde as starting materials.
O
O~
C ) H
'Ri CH3 H uiu0 ~ = =
H H
O
2. Description of Prior Art [0002] Many prednisolone derivatives have been known to be of anti-inflammatory activities; and used for the treatment of skin diseases, respiratory diseases, inflammatory diseases, of intestinal tract, allergic rhinitis, conjunctivitis and the like.
[0003] Ciclesonide, a compound with the chemical name (22,R)-pregna-1,4-diene-3,20-dione-16a,17-[(cyclohexylmethylene)-dioxy]-11(3-hydroxy-21-(2-methyl-l-oxo-acetone), is an important prednisolone derivative clinically used for treating asthma, chronic obstructive pulmonary disease and rhinitis.
[0004] DE 4,129,535 discloses a process for preparing pregna-1,4-diene-3,20-dione-16a,17-acetal-2l-esters having a butyl, isopropyl, sec-butyl, cyclohexyl or phenyl radical on the cyclic acetal ring, and whose C21-hydroxyl group is acylated by an acetyl or isobytyryl radical, comprising reacting 16a-hydroxyprednisolone with an anhydride to produce a C-16, C-17 and C-21 esterified intermediate, separating, purifying and then reacting the intennediate with an aldehyde to give the desired product.
[0005] In the international application WO 02/38584, a process for preparing a 16a,17-[(cyclohexylmethylene)-bis(oxy)]-110,21-dihydroxy-pregna-1,4-diene-3,20-dione-21-isobutyrate is disclosed, which comprises reacting a C-21 esterified ketal with cyclohexyl formaldehyde.
[0006] The above-mentioned processes are multi-step methods comprising preparing an intermediate from the starting prednisolone, separating, purifying and reacting the intermediate with other reactants to produce the desire product. The methods in the art are less cost-effective for the reason that they need several steps and a long reaction period, and each step for, separating or. purifying is complicated and may probably cause a loss of the product. In addition, in DE
4,129,535 the yield of the C22-R epimer (the desired prednisolone derivative) in the product is relatively low, and consequently it is difficult to obtain a pure C22-R epimer suitable for pharmaceutical applications.
[00071 US patent No. 5,733,901 discloses a process. for preparing a 16a,17-(22R.,S)-[(cyclohexylmethylene)-bis(oxy)]-11(3,21-dihydroxy-pregna-l,4-diene-3,20-dione, comprising reacting 16a-hydroxyprednisolone with cyclohexyl formaldehyde.
[0009] According to an aspect of the present invention, there is provided a one-pot process for the preparation of a prednisolone derivative of formula I, il ~C-RZ
O
O~
C~
H
R
,uw11Q t H
O ~ I
in which Ri represents alkyl, alkenyl, alkynyl, cycloalkyl or aryl; and R2 represents alkyl, alkenyl or alkynyl, comprising reacting the compound of formula II;
.OH
C
H2CI,, O
H ,,~u-~OH
HO
.,,1uUGH
H
O ~ II
with a compound of forrnula III, il RZ C
RZ C/
O III
in which R2 is as previously defined, and a compound of formula IV, RI-C-H IV
in which Rl is as previously defined.
[0010] In a preferred embodiment of the invention, Rl represents Cl-C8 alkyl, alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C20 aryl.
[0011] In a further preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl.
[0012] In another preferred embodiment of the invention, R2 represents CI-Cg alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0013] In a further preferred embodiment of the invention, R2 is methyl or isopropyl.
[0014] The process of the invention can be carried out with or without a solvent. Preferably, the process is carried out in a polar organic solvent.
[0015] In some preferred embodiments of the invention, the process is carried out at the presence of a protonic acid catalyst. Preferably, a molar ratio of the catalyst used to the compound of formula II is in the range of 1-10:1, and more preferably in the range of 1-4:1.
[0016] In other preferred embodiments of the invention, the process is carried out at the temperature of 0-50 C.
[0017] In the process of the invention, it is unnecessary to separate and purify intermediates formed, and therefore the process is simplified, and the loss of the product, the reaction period and the cost are greatly reduced.
According to another aspect of the present invention, there is provided a one-pot process for the preparation of a prednisolone derivative of formula I, II
O
O.Z~ C~
HO
,cr~0000*
~ = =
H
o wherein Ri is n-butyl, isobutyl, cyclohexyl or phenyl; and R2 is methyl or isopropyl, comprising reacting the compound of fonmula II, OH
I
HZC~
HO, -11inpH
H
o ~ II
4a with a compound of formula III, RZ C
O
RZ-C/
o` III
wherein R2 is as previously defined, and a compound of formula IV, RI-C-H IV
wherein Rl is as previously defined, at the presence of dioxaneand a catalyst of.60-70% perchloric acid, and at the temperature of 20r30 C, and wherein a molar ratio of the, compound of formula II, the compound of formula III and the compound of formula IV is 1:4-8:2-6,.and a molar ratio of the catalyst to the compound of formula II is 1-4:1.
4b DETAILED DESCRIPTION OF THE INVENTION
[0018) As described above, the present invention provides a one-pot process for the preparation of a prednisolone derivative of formula I, ~C=R2 O~
C~
H
H3C ",aik0 HO 'u1iiR
, ~ = =
H H
in which Rt represents alkyl, alkenyl, alkynyl,cycloalkyl or aryl; and R2 represents a114y1, alkenyl or alkynyl, comprising reacting the compound of formula iI, OH
, . I
HZC~ /O
C
HO
CH3 H -1nt1OH
~
~ = =_ =
H
O ~ II
with a compound of formula III, Rz-C
O
R2-C~
(I
O III
in which R2 is as previously defined, and a compound of formula IV, RI-C-H IV
in which Rl is as previously defined.
[0019] The term "alkyl", as used herein, generally refers to a linear or branched saturated aliphatic radical, preferably refers to C1-C8 alkyl, and more preferably refers to C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.
[0020] The term "alkenyl", as used herein, generally refers to a linear or branched unsaturated aliphatic radical having one or more C=C double bonds, preferably refers to C2-C8 alkenyl, and more preferably refers to C2-C6 alkenyl, such as vinyl, propenyl, allyl, 1-butenyl, 2-butenyl and the like.
[0021] The term "alkynyl", as used herein, generally refers to a linear or branched unsaturated aliphatic radical having one or more C=C triple bonds, preferably refers to C2-C8 alkynyl, and more preferably refers to C2-C6 alkynyl, such as ethynyl, 1-propinyl, 2-butynyl, 3-butynyl and the like.
[0022] The term "cycloalkyl", as used herein, generally refers to a saturated alicyclic radical, preferably refers to C3-C8 cycloalkyl, and more preferably refers to C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0023] The term "acyl", as used herein, generally refers to a univalent radical derived from an aromatic hydrocarbon, preferably refers to C5-C20 acyl, such as phenyl, naphthyl and the like, and more preferably refers to phenyl.
[0024] The term "one-pot process", as used herein, generally refers to a process for preparing a desired product, comprising simultaneously or successively adding all reactants into a reactor to have them react together, in which no separation and/or purification of the intermediate formed is needed before the product is produced.
[0025] The term "intermediate(s)", as used herein, refers to a resultant of the reaction between any two of the three compounds of formulae II, III and IV, which then reacts with the unreacted compound to form a compound of formula I, or a resultant of the reaction of the three compounds of formulae II, III and IV, which then can be converted into a compound of formula I.
[0026] In a particular embodiment of the invention, the intermediate comprises C-16, C-17 and/or C-21 esterified derivatives of prednisolone.
[0027] In a preferred embodiment of the invention, Rl represents Cj-C8 alkyl, Cz-Cg alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C20 aryl.
[0028] In another preferred embodiment of the invention, R2 represents CI-Cg alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0029] In a further preferred embodiment of the invention, R, represents C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C2o aryl, and R2 represents C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0030] In a still further preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl.
[0031] In some preferred embodiments of the invention, the reactants of the process, i.e. the compounds of formula II, III and IV, are added simultaneously.
[0032] In other preferred embodiments of the invention, the reactants of the process are added successively, in which there is no specific requirement for the sequence of addition of the reactants. For example, the reactants can be added in the sequence of II-->III-->IV (i.e. the compound of formula II followed by the compound of formula III, and then the compound of formula IV), II--IV--III, IV->II->III, IV-*III-*II, IIhII-+IV or III->IV--*II.
More preferably, the compound of formula III and the compound of formula IV are added successively into a solution of the compound of formula I.
[0033] Preferably, a molar ratio of the three reactants used is in the range of formula II:
formula III: formula IV=1:1-15:1-10, and more preferably is in the range of 1:4-8:2-6. Most preferably the molar ratio of the reactants is about 1:6:4.
[0034] In a particularly preferred embodiment of the invention, the reactants are added in the sequence of formula Ihformula III->formula IV, and the molar ratio of the reactants is in the range of formula II: formula III: formula IV=1:4-8:2-6.
[0035] In a preferred embodiment of the invention, the process of the invention is carried out without an additional solvent. In this case, it should be appreciated that at least one of the reactants, such as the anhydride or the aldehyde, also serves as a solvent.
[0036] In another preferred embodiment of the invention, the process of the invention is carried out at the presence of a polar organic solvent including, but not limited to, ethers, such as ethyl ether, dioxane, dipropyl ether and dibutyl ether; esters, such as ethyl acetate and methyl acetate; halogenated hydrocarbons, such as methylene chloride and chloroform;
nitrated hydrocarbons, such as nitromethane, 2-nitropropane and 1-nitropropane.
[0037] In a further preferred embodiment of the invention, the solvent used may be selected from the group consisting of dioxane, methylene chloride, chloroform, nitromethane and ethyl acetate, and more preferably the solvent is dioxane.
[0038] In some preferred embodiments of the invention, the process is carried out at the presence of a protonic acid catalyst including, but not limited to, hydrochloric acid, sulfuric acid, perchloric acid, methanesulfonic acid, toluene-p-sulfonic acid and tetrafluoroboric acid.
Preferably, a molar ratio of the catalyst used to the compound of formula II
is in the range of 1-10:1, and more preferably in the range of 1-4:1. Most preferably, the molar ratio of the catalyst to the compound of formula II is about 3.8:1.
4,129,535 the yield of the C22-R epimer (the desired prednisolone derivative) in the product is relatively low, and consequently it is difficult to obtain a pure C22-R epimer suitable for pharmaceutical applications.
[00071 US patent No. 5,733,901 discloses a process. for preparing a 16a,17-(22R.,S)-[(cyclohexylmethylene)-bis(oxy)]-11(3,21-dihydroxy-pregna-l,4-diene-3,20-dione, comprising reacting 16a-hydroxyprednisolone with cyclohexyl formaldehyde.
[0009] According to an aspect of the present invention, there is provided a one-pot process for the preparation of a prednisolone derivative of formula I, il ~C-RZ
O
O~
C~
H
R
,uw11Q t H
O ~ I
in which Ri represents alkyl, alkenyl, alkynyl, cycloalkyl or aryl; and R2 represents alkyl, alkenyl or alkynyl, comprising reacting the compound of formula II;
.OH
C
H2CI,, O
H ,,~u-~OH
HO
.,,1uUGH
H
O ~ II
with a compound of forrnula III, il RZ C
RZ C/
O III
in which R2 is as previously defined, and a compound of formula IV, RI-C-H IV
in which Rl is as previously defined.
[0010] In a preferred embodiment of the invention, Rl represents Cl-C8 alkyl, alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C20 aryl.
[0011] In a further preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl.
[0012] In another preferred embodiment of the invention, R2 represents CI-Cg alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0013] In a further preferred embodiment of the invention, R2 is methyl or isopropyl.
[0014] The process of the invention can be carried out with or without a solvent. Preferably, the process is carried out in a polar organic solvent.
[0015] In some preferred embodiments of the invention, the process is carried out at the presence of a protonic acid catalyst. Preferably, a molar ratio of the catalyst used to the compound of formula II is in the range of 1-10:1, and more preferably in the range of 1-4:1.
[0016] In other preferred embodiments of the invention, the process is carried out at the temperature of 0-50 C.
[0017] In the process of the invention, it is unnecessary to separate and purify intermediates formed, and therefore the process is simplified, and the loss of the product, the reaction period and the cost are greatly reduced.
According to another aspect of the present invention, there is provided a one-pot process for the preparation of a prednisolone derivative of formula I, II
O
O.Z~ C~
HO
,cr~0000*
~ = =
H
o wherein Ri is n-butyl, isobutyl, cyclohexyl or phenyl; and R2 is methyl or isopropyl, comprising reacting the compound of fonmula II, OH
I
HZC~
HO, -11inpH
H
o ~ II
4a with a compound of formula III, RZ C
O
RZ-C/
o` III
wherein R2 is as previously defined, and a compound of formula IV, RI-C-H IV
wherein Rl is as previously defined, at the presence of dioxaneand a catalyst of.60-70% perchloric acid, and at the temperature of 20r30 C, and wherein a molar ratio of the, compound of formula II, the compound of formula III and the compound of formula IV is 1:4-8:2-6,.and a molar ratio of the catalyst to the compound of formula II is 1-4:1.
4b DETAILED DESCRIPTION OF THE INVENTION
[0018) As described above, the present invention provides a one-pot process for the preparation of a prednisolone derivative of formula I, ~C=R2 O~
C~
H
H3C ",aik0 HO 'u1iiR
, ~ = =
H H
in which Rt represents alkyl, alkenyl, alkynyl,cycloalkyl or aryl; and R2 represents a114y1, alkenyl or alkynyl, comprising reacting the compound of formula iI, OH
, . I
HZC~ /O
C
HO
CH3 H -1nt1OH
~
~ = =_ =
H
O ~ II
with a compound of formula III, Rz-C
O
R2-C~
(I
O III
in which R2 is as previously defined, and a compound of formula IV, RI-C-H IV
in which Rl is as previously defined.
[0019] The term "alkyl", as used herein, generally refers to a linear or branched saturated aliphatic radical, preferably refers to C1-C8 alkyl, and more preferably refers to C1-C6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl and the like.
[0020] The term "alkenyl", as used herein, generally refers to a linear or branched unsaturated aliphatic radical having one or more C=C double bonds, preferably refers to C2-C8 alkenyl, and more preferably refers to C2-C6 alkenyl, such as vinyl, propenyl, allyl, 1-butenyl, 2-butenyl and the like.
[0021] The term "alkynyl", as used herein, generally refers to a linear or branched unsaturated aliphatic radical having one or more C=C triple bonds, preferably refers to C2-C8 alkynyl, and more preferably refers to C2-C6 alkynyl, such as ethynyl, 1-propinyl, 2-butynyl, 3-butynyl and the like.
[0022] The term "cycloalkyl", as used herein, generally refers to a saturated alicyclic radical, preferably refers to C3-C8 cycloalkyl, and more preferably refers to C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0023] The term "acyl", as used herein, generally refers to a univalent radical derived from an aromatic hydrocarbon, preferably refers to C5-C20 acyl, such as phenyl, naphthyl and the like, and more preferably refers to phenyl.
[0024] The term "one-pot process", as used herein, generally refers to a process for preparing a desired product, comprising simultaneously or successively adding all reactants into a reactor to have them react together, in which no separation and/or purification of the intermediate formed is needed before the product is produced.
[0025] The term "intermediate(s)", as used herein, refers to a resultant of the reaction between any two of the three compounds of formulae II, III and IV, which then reacts with the unreacted compound to form a compound of formula I, or a resultant of the reaction of the three compounds of formulae II, III and IV, which then can be converted into a compound of formula I.
[0026] In a particular embodiment of the invention, the intermediate comprises C-16, C-17 and/or C-21 esterified derivatives of prednisolone.
[0027] In a preferred embodiment of the invention, Rl represents Cj-C8 alkyl, Cz-Cg alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C20 aryl.
[0028] In another preferred embodiment of the invention, R2 represents CI-Cg alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0029] In a further preferred embodiment of the invention, R, represents C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C2o aryl, and R2 represents C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
[0030] In a still further preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl.
[0031] In some preferred embodiments of the invention, the reactants of the process, i.e. the compounds of formula II, III and IV, are added simultaneously.
[0032] In other preferred embodiments of the invention, the reactants of the process are added successively, in which there is no specific requirement for the sequence of addition of the reactants. For example, the reactants can be added in the sequence of II-->III-->IV (i.e. the compound of formula II followed by the compound of formula III, and then the compound of formula IV), II--IV--III, IV->II->III, IV-*III-*II, IIhII-+IV or III->IV--*II.
More preferably, the compound of formula III and the compound of formula IV are added successively into a solution of the compound of formula I.
[0033] Preferably, a molar ratio of the three reactants used is in the range of formula II:
formula III: formula IV=1:1-15:1-10, and more preferably is in the range of 1:4-8:2-6. Most preferably the molar ratio of the reactants is about 1:6:4.
[0034] In a particularly preferred embodiment of the invention, the reactants are added in the sequence of formula Ihformula III->formula IV, and the molar ratio of the reactants is in the range of formula II: formula III: formula IV=1:4-8:2-6.
[0035] In a preferred embodiment of the invention, the process of the invention is carried out without an additional solvent. In this case, it should be appreciated that at least one of the reactants, such as the anhydride or the aldehyde, also serves as a solvent.
[0036] In another preferred embodiment of the invention, the process of the invention is carried out at the presence of a polar organic solvent including, but not limited to, ethers, such as ethyl ether, dioxane, dipropyl ether and dibutyl ether; esters, such as ethyl acetate and methyl acetate; halogenated hydrocarbons, such as methylene chloride and chloroform;
nitrated hydrocarbons, such as nitromethane, 2-nitropropane and 1-nitropropane.
[0037] In a further preferred embodiment of the invention, the solvent used may be selected from the group consisting of dioxane, methylene chloride, chloroform, nitromethane and ethyl acetate, and more preferably the solvent is dioxane.
[0038] In some preferred embodiments of the invention, the process is carried out at the presence of a protonic acid catalyst including, but not limited to, hydrochloric acid, sulfuric acid, perchloric acid, methanesulfonic acid, toluene-p-sulfonic acid and tetrafluoroboric acid.
Preferably, a molar ratio of the catalyst used to the compound of formula II
is in the range of 1-10:1, and more preferably in the range of 1-4:1. Most preferably, the molar ratio of the catalyst to the compound of formula II is about 3.8:1.
[0039] In a further preferred embodiment of the invention, the catalyst used may be selected from the group consisting of hydrochloric acid, tetrafluoroboric acid, methanesulfonic acid and perchloric acid. More preferably, the catalyst is a 35-70% perchloric acid, and further more preferably the catalyst is a 60-70% perchloric acid. Most preferably, the catalyst is a 70%
perchloric acid.
[0040] In another preferred embodiment of the invention, the process is carried out at a temperature in the range of 0-50 C, more preferably in the range of 0-30 C, and further more preferably in the range of 20-30 C. In the process of the invention, if the reaction temperature is too low (such as lower than 0 C), the dissolution of the reactants and the intermediated formed will be deteriorated. And if the reaction temperature is too high (such as higher than 50 C), the C-21 ester of the compound of formula I will be decomposed, which will cause a reduction of the yield of the desired product.
[0041] In a particularly preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl, and the process is carried out at the presence of dioxane and a catalyst of 60-70% perchloric acid, and at the temperature of 20-30 C, in which the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is 1:4-8:2-6, and the molar ratio of the catalyst to the compound of formula II is 1-4:1.
[0042] In a most preferred embodiment of the invention, R, is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl, and the process is carried out at the presence of dioxane and a catalyst of 70% perchloric acid, and at the temperature of 20-30 C, in which the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is about 1:6:4, and the molar ratio of the catalyst to the compound of formula II
is about 3.8:1.
[0043] In a preferred embodiment of the invention, the process is carried out for about 2-10 hours, and more preferably for about 5-8 hours.
[0044] In a preferred embodiment of the invention, the process further comprises the steps for separating and purifying the desired product. The steps may be performed using conventional separating and purifying techniques, such as preparative High Performance Liquid Chromatography (HPLC) and fractional crystallization.
perchloric acid.
[0040] In another preferred embodiment of the invention, the process is carried out at a temperature in the range of 0-50 C, more preferably in the range of 0-30 C, and further more preferably in the range of 20-30 C. In the process of the invention, if the reaction temperature is too low (such as lower than 0 C), the dissolution of the reactants and the intermediated formed will be deteriorated. And if the reaction temperature is too high (such as higher than 50 C), the C-21 ester of the compound of formula I will be decomposed, which will cause a reduction of the yield of the desired product.
[0041] In a particularly preferred embodiment of the invention, Rl is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl, and the process is carried out at the presence of dioxane and a catalyst of 60-70% perchloric acid, and at the temperature of 20-30 C, in which the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is 1:4-8:2-6, and the molar ratio of the catalyst to the compound of formula II is 1-4:1.
[0042] In a most preferred embodiment of the invention, R, is n-butyl, isobutyl, cyclohexyl or phenyl and R2 is methyl or isopropyl, and the process is carried out at the presence of dioxane and a catalyst of 70% perchloric acid, and at the temperature of 20-30 C, in which the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is about 1:6:4, and the molar ratio of the catalyst to the compound of formula II
is about 3.8:1.
[0043] In a preferred embodiment of the invention, the process is carried out for about 2-10 hours, and more preferably for about 5-8 hours.
[0044] In a preferred embodiment of the invention, the process further comprises the steps for separating and purifying the desired product. The steps may be performed using conventional separating and purifying techniques, such as preparative High Performance Liquid Chromatography (HPLC) and fractional crystallization.
[0045] Besides the benefits of shortening the reaction period and reducing the production cost, the process of the invention has an advantage that the ratio of the C22-R epimer (the desired prednisolone derivative) to the C22-S epimer in the product is increased to R/S>95/5.
[0046] Hereinafter, the invention will be illustrated more in detail by the following examples which show various aspects and advantages of the invention. However, it should be understood that the examples below are non-limiting and are only illustrative of some of the embodiments of the present invention.
EXAMPLES
Example 1 [0047] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8m1 of 70% perchloric acid (102.4mmol) under stirring.
26.5m1 of isobutyric anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 12.8ml of cyclohexyl formaldehyde (106.4mmo1) for 10 minutes. The resultant was stirred under room temperature for 5 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 11.8g of the product, yield 82% and R/S=96.5/3.5.
Example 2 [0048] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8ml of 70% perchloric acid (102.4mmol) under stirring.
15.1ml of acetic anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 12.8m1 of cyclohexyl formaldehyde (106.4mmol) for 10 minutes. The resultant was stirred under room temperature for 7 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 11.1 g of the product, R/S=96.8/3.2.
Example 3 [0049] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8m1 of 70% perchloric acid (102.4mmo1) under stirring.
15.1ml of acetic anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 6.Oml of acetaldehyde (106.4mmol) for 10 minutes. The resultant was stirred under room temperature for 6 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 9.8g of the product, R/S=96.0/4Ø
[0050] It should be understood that although the present invention has been specifically disclosed by preferred embodiments and descriptions, modifications and variations to the present invention, without departing from the spirit of the invention, may be made by one of ordinary skill in the art, and that such modifications and variations will fall within the scope of the invention.
ti
[0046] Hereinafter, the invention will be illustrated more in detail by the following examples which show various aspects and advantages of the invention. However, it should be understood that the examples below are non-limiting and are only illustrative of some of the embodiments of the present invention.
EXAMPLES
Example 1 [0047] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8m1 of 70% perchloric acid (102.4mmol) under stirring.
26.5m1 of isobutyric anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 12.8ml of cyclohexyl formaldehyde (106.4mmo1) for 10 minutes. The resultant was stirred under room temperature for 5 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 11.8g of the product, yield 82% and R/S=96.5/3.5.
Example 2 [0048] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8ml of 70% perchloric acid (102.4mmol) under stirring.
15.1ml of acetic anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 12.8m1 of cyclohexyl formaldehyde (106.4mmol) for 10 minutes. The resultant was stirred under room temperature for 7 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 11.1 g of the product, R/S=96.8/3.2.
Example 3 [0049] To a suspension of 10.0g of 16a-hydroxyprednisolone (26.6mmol) in 100m1 of dioxane, was added 8.8m1 of 70% perchloric acid (102.4mmo1) under stirring.
15.1ml of acetic anhydride (159.6mmol) was then added dropwise within 10 minutes, followed by 6.Oml of acetaldehyde (106.4mmol) for 10 minutes. The resultant was stirred under room temperature for 6 hours, neutralized with an aqueous solution of sodium carbonate, and then extracted with ethyl acetate. The organic phase was separated, washed with water, dried in sodium sulfate, and concentrated under vacuum. The residue was recrystallized in ether/petroleum ether to give 9.8g of the product, R/S=96.0/4Ø
[0050] It should be understood that although the present invention has been specifically disclosed by preferred embodiments and descriptions, modifications and variations to the present invention, without departing from the spirit of the invention, may be made by one of ordinary skill in the art, and that such modifications and variations will fall within the scope of the invention.
ti
Claims (18)
1. A one-pot process for the preparation of a prednisolone derivative of formula I, wherein R1 represents alkyl, alkenyl, alkynyl, cycloalkyl or aryl; and R2 represents alkyl, alkenyl or alkynyl, comprising reacting the compound of formula II, with a compound of formula III, wherein R2 is as previously defined, and a compound of formula IV, wherein R1 is as previously defined.
2. The process according to claim 1, wherein R1 represents C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl or C5-C20 aryl.
3. The process according to claim 1, wherein R1 is n-butyl, isobutyl, cyclohexyl or phenyl.
4. The process according to any one of claims 1 to 3, wherein R2 represents C1-C8 alkyl, C2-C8 alkenyl or C2-C8 alkynyl.
5. The process according to any one of claims 1 to 3, wherein R2 is methyl or isopropyl.
6. The process according to any one of claims 1 to 5, wherein a molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is 1:1-15:1-10.
7. The process according to claim 6, wherein the molar ratio is 1:4-8:2-6.
8. The process according to any one of claims 1 to 7, wherein the process is carried out at a temperature of 0-50°C.
9. The process according to any one of claims 1 to 7, wherein the process is carried out at a temperature of 20-30°C.
10. The process according to any one of claims 1 to 9, wherein the process is carried out in presence of a protonic acid catalyst.
11. The process according to claim 10, wherein the protonic acid catalyst is selected from the group consisting of hydrochloric acid, sulfuric acid, perchloric acid, methanesulfonic acid, toluene-p-sulfonic acid and tetrafluoroboric acid.
12. The process according to claim 11, wherein the protonic acid catalyst is 35-70% perchloric acid.
13. The process according to claim 11, wherein the protonic acid catalyst is 60-70% perchloric acid.
14. The process according to any one of claims 10 to 13, wherein a molar ratio of the protonic acid catalyst to the compound of formula II is 1-10:1.
15. The process according to any one of claims 10 to 13, wherein the molar ratio of the protonic acid catalyst to the compound of formula II is 1-4:1.
16. The process according to any one of claims 1 to 15, wherein the process is carried out at the presence of a polar organic solvent selected from the group consisting of dioxane, methylene chloride, chloroform, nitromethane and ethyl acetate.
17. A one-pot process for the preparation of a prednisolone derivative of formula I, wherein R1 is n-butyl, isobutyl, cyclohexyl or phenyl; and R2 is methyl or isopropyl, comprising reacting the compound of formula II, with a compound of formula III, wherein R2 is as previously defined, and a compound of formula IV, wherein R1 is as previously defined, at the presence of dioxane and a catalyst of 60-70% perchloric acid, and at.
the temperature of 20-30°C, and wherein a molar ratio of the compound of formula II, the compound-of formula III and the compound of formula IV is 1:4-8:2-6, and a molar ratio of the catalyst to the compound of formula II is 1-4:1.
the temperature of 20-30°C, and wherein a molar ratio of the compound of formula II, the compound-of formula III and the compound of formula IV is 1:4-8:2-6, and a molar ratio of the catalyst to the compound of formula II is 1-4:1.
18. The process according to claim 17, wherein the. catalyst is a 70%
perchloric acid, and the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is about 1:6:4, and the molar ratio of the catalyst to the compound of formula II is about 3.8:1.
perchloric acid, and the molar ratio of the compound of formula II, the compound of formula III and the compound of formula IV is about 1:6:4, and the molar ratio of the catalyst to the compound of formula II is about 3.8:1.
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