NZ753956B2 - Processes of making and crystalline forms of a mdm2 inhibitor - Google Patents
Processes of making and crystalline forms of a mdm2 inhibitor Download PDFInfo
- Publication number
- NZ753956B2 NZ753956B2 NZ753956A NZ75395614A NZ753956B2 NZ 753956 B2 NZ753956 B2 NZ 753956B2 NZ 753956 A NZ753956 A NZ 753956A NZ 75395614 A NZ75395614 A NZ 75395614A NZ 753956 B2 NZ753956 B2 NZ 753956B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- chlorophenyl
- mixture
- added
- compound
- water
- Prior art date
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- 238000000034 method Methods 0.000 title abstract description 55
- 230000002401 inhibitory effect Effects 0.000 title description 15
- 101700032565 MDM2 Proteins 0.000 title description 13
- 239000003112 inhibitor Substances 0.000 title description 13
- 102000001309 Proto-Oncogene Proteins c-mdm2 Human genes 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 188
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 44
- 238000002441 X-ray diffraction Methods 0.000 claims description 10
- 239000000543 intermediate Substances 0.000 abstract description 18
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- 150000002596 lactones Chemical class 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M laurate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 238000011068 load Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-L maleate(2-) Chemical compound [O-]C(=O)\C=C/C([O-])=O VZCYOOQTPOCHFL-UPHRSURJSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- LXNFVVDCCWUUKC-UHFFFAOYSA-N methyl 4-chlorobenzoate Chemical compound COC(=O)C1=CC=C(Cl)C=C1 LXNFVVDCCWUUKC-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000000394 mitotic Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000000051 modifying Effects 0.000 description 1
- 238000001565 modulated differential scanning calorimetry Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000003793 myelodysplastic syndrome Diseases 0.000 description 1
- 125000005487 naphthalate group Chemical group 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- GBWFYBZWCZOBLI-UHFFFAOYSA-N naphthalene-1-sulfonic acid;dihydrate Chemical compound O.O.C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 GBWFYBZWCZOBLI-UHFFFAOYSA-N 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000003472 neutralizing Effects 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 150000002829 nitrogen Chemical group 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 102000025475 oncoproteins Human genes 0.000 description 1
- 108091008124 oncoproteins Proteins 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-L oxalate Chemical compound [O-]C(=O)C([O-])=O MUBZPKHOEPUJKR-UHFFFAOYSA-L 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 230000001590 oxidative Effects 0.000 description 1
- BHIIWXJHALLFBD-UHFFFAOYSA-N oxolane;propan-2-ol Chemical compound CC(C)O.C1CCOC1 BHIIWXJHALLFBD-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M palmitate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N palmityl stearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 238000001907 polarising light microscopy Methods 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- CBMSDILKECEMOT-UHFFFAOYSA-N potassium;2-methylpropan-1-olate Chemical compound [K+].CC(C)C[O-] CBMSDILKECEMOT-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000000861 pro-apoptotic Effects 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- YWVYZMVYXAVAKS-UHFFFAOYSA-N pyridin-1-ium;trifluoromethanesulfonate Chemical compound C1=CC=[NH+]C=C1.[O-]S(=O)(=O)C(F)(F)F YWVYZMVYXAVAKS-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 230000001603 reducing Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 201000010208 seminoma Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- JUFGMKFPFVIKOY-UHFFFAOYSA-N sodium;tri(butan-2-yl)boranuide Chemical compound [Na+].CCC(C)[BH-](C(C)CC)C(C)CC JUFGMKFPFVIKOY-UHFFFAOYSA-N 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940086735 succinate Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002411 thermogravimetry Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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- 238000004448 titration Methods 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
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- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000001131 transforming Effects 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 210000004881 tumor cells Anatomy 0.000 description 1
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- 238000004450 types of analysis Methods 0.000 description 1
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Abstract
The present invention provides processes for making 2-((3R,5R,6S)-5-(3- chlorophenyl)-6-(4-chlorophenyl)-l-((S)-l-(isopropylsulfonyl)-3-methylbutan-2-yl)-3- methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates. of the compound and the intermediates.
Description
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PROCESSES OF MAKING AND CRYSTALLINE
FORMS OF A MDM2 INHIBITOR
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of New Zealand 714821, which claims
the benefit of U.S. Provisional Application No. 61/833,196 filed June 10, 2013 and which
are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
Described herein are processes for making 2-((3R,5R,6S)(3-chlorophenyl)
(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methyl
oxopiperidinyl)acetic acid (“Compound A” herein). The present invention provides
intermediates, processes for making the intermediates, and crystalline forms of the
intermediates.
BACKGROUND OF THE INVENTION
p53 is a tumor suppressor and transcription factor that responds to cellular stress
by activating the transcription of numerous genes involved in cell cycle arrest, apoptosis,
senescence, and DNA repair. Unlike normal cells, which have infrequent cause for p53
activation, tumor cells are under constant cellular stress from various insults including
hypoxia and pro-apoptotic oncogene activation. Thus, there is a strong selective
advantage for inactivation of the p53 pathway in tumors, and it has been proposed that
eliminating p53 function may be a prerequisite for tumor survival. In support of this
notion, three groups of investigators have used mouse models to demonstrate that
absence of p53 function is a continuous requirement for the maintenance of established
tumors. When the investigators restored p53 function to tumors with inactivated p53, the
tumors regressed.
p53 is inactivated by mutation and/or loss in 50% of solid tumors and 10% of
liquid tumors. Other key members of the p53 pathway are also genetically or
epigenetically altered in cancer. MDM2, an oncoprotein, inhibits p53 function, and it is
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activated by gene amplification at incidence rates that are reported to be as high as 10%.
MDM2, in turn, is inhibited by another tumor suppressor, p14ARF. It has been suggested
that alterations downstream of p53 may be responsible for at least partially inactivating
WT WT
the p53 pathway in p53 tumors (p53 wildtype). In support of this concept, some p53
tumors appear to exhibit reduced apoptotic capacity, although their capacity to undergo
cell cycle arrest remains intact. One cancer treatment strategy involves the use of small
molecules that bind MDM2 and neutralize its interaction with p53. MDM2 inhibits p53
activity by three mechanisms: 1) acting as an E3 ubiquitin ligase to promote p53
degradation; 2) binding to and blocking the p53 transcriptional activation domain; and 3)
exporting p53 from the nucleus to the cytoplasm. All three of these mechanisms would
be blocked by neutralizing the MDM2-p53 interaction. In particular, this therapeutic
strategy could be applied to tumors that are p53 , and studies with small molecule
MDM2 inhibitors have yielded promising reductions in tumor growth both in vitro and in
vivo. Further, in patients with p53-inactivated tumors, stabilization of wildtype p53 in
normal tissues by MDM2 inhibition might allow selective protection of normal tissues
from mitotic poisons.
Described herein is a compound capable of inhibiting the interaction between p53
and MDM2 and activating p53 downstream effector genes, and/or providing the public
with a useful choice. As such, the compound described herein would be useful in the
treatment of cancers, bacterial infections, viral infections, ulcers and inflammation. In
particular, the compound described herein is useful to treat solid tumors such as: breast,
colon, lung and prostate tumors; and liquid tumors such as lymphomas and leukemias. As
used herein, MDM2 means a human MDM2 protein and p53 means a human p53 protein.
It is noted that human MDM2 can also be referred to as HDM2 or hMDM2.
The compound, 2-((3R,5R,6S)(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methyloxopiperidinyl)acetic acid,
having the chemical structure below
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is disclosed in published PCT Application No. ,509 (Example No. 362)
This compound, a MDM2 inhibitor, is being investigated in human clinical trials for the
treatment of various cancers. Described herein are processes for making the compound.
The present invention provides intermediates, processes for making the intermediates,
and crystalline forms of the intermediates.
SUMMARY OF THE INVENTION
Described herein is crystalline
Also described is crystalline anhydrous
.
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Also described is crystalline anhydrous
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle
2 theta degrees at approximately 11.6, 12.4, 18.6, 19.0, 21.6 and 23.6.
Also described is crystalline anhydrous
characterized by the powder X-ray diffraction pattern as described above, having the X-
ray diffraction pattern substantially as shown in Figure 1.
Also described is pharmaceutical compositions comprising: crystalline
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as described above; and a pharmaceutically acceptable excipient.
Also described herein are methods of treating bladder cancer, breast cancer, colon
cancer, rectal cancer, kidney cancer, liver cancer, small cell lung cancer, non-small-cell
lung cancer, esophagus cancer, gall-bladder cancer, ovarian cancer , pancreatic cancer,
stomach cancer, cervix cancer, thyroid cancer, prostate cancer, squamous cell carcinoma,
melanoma, acute lymphocytic leukemia, chronic myelogenous leukemia, acute
lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-
Hodgkin's lymphoma, hairy cell lymphoma, Burkett's lymphoma, acute myelogenous
leukemia, chronic myelogenous leukemia, endometrial cancer, head and neck cancer,
glioblastoma, osteosarcoma, or rhabdomyosarcoma, the methods comprising
administering to a patient in need thereof, a therapeutically acceptable amount of a
pharmaceutical composition comprising crystalline
as described above..
In embodiment 1, the present invention provides the compound
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In embodiment 2, the present invention provides the compound
In embodiment 3, the present invention provides the compound of embodiment 2,
which is in crystalline form.
In embodiment 4, the present invention provides the compound of embodiment 3
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle
2 theta degrees at approximately 8.7, 18.5, 22.6 and 26.6.
In embodiment 5, the present invention provides the compound of embodiment 4
having the X-ray diffraction pattern substantially shown in Figure 3.
Also described is the compound
.
In embodiment 6, the present invention provides a process for making
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the process comprising:
reacting
under dehydrating conditions with
to form
In embodiment 7, the present invention provides the process of embodiment 6
wherein the dehydrating conditions are azeotropic distillation with toluene.
In embodiment 8, the present invention provides a process of making
, the process comprising:
reacting
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with to form
wherein X is CF SO or .
In embodiment 9, the present invention provides a process of making
, the process comprising:
reacting with toluene to form .
Also described is a process of making
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, the process comprising:
reacting
with lutidine and to form
Also described is a process of making
, the process comprising reacting
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with
to form
, which is oxidized to , which
is further converted to
In some embodiments, the oxidation is accomplished using ozone.
In some embodiments, the oxidation is accomplished using ozone followed by
Pinnick oxidation.
In some embodiments the conversion of
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to is
accomplished using methanol and water.
In some embodiments the oxidation is accomplished using ozone followed by
Pinnick oxidation, and the conversion of
to is
accomplished using methanol and water.
Also described is a process of making
, the process comprising reacting
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with to form ,
oxidizing to form which is
further converted to
In some embodiments the
and are reacted in the presence of a base.
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In some embodiments the base is sodium tert-butoxide.
In some embodiments the oxidation is accomplished using RuCl and NaIO .
In some embodiments the conversion of
to is
accomplished using methanol and water.
In some embodiments the
and are reacted in the presence of a base;
the oxidation is accomplished using RuCl and NaIO ; and
the conversion of
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to is
accomplished using methanol and water.
Also described is the compound
ethanolate.
Also described is crystalline
ethanolate.
Also described is crystalline
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ethanolate
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle
2 theta degrees at approximately 10.5, 18.2, 20.3, 21, 21.9 and 24.2.
Also described is crystalline
ethanolate
characterized by the powder X-ray diffraction pattern as described above, having the X-
ray diffraction pattern substantially shown in Figure 6.
Also described herein is the compound
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Also described herein is crystalline
Also described herein is crystalline
characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle
2 theta degrees at approximately 11.5, 14.3, 15.8, 17.7, 19.5 and 20.7.
Also described herein is crystalline
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characterized by the powder X-ray diffraction pattern as described above, having the X-
ray diffraction pattern substantially shown in Figure 12.
Also described herein is a process of making
, the process comprising reacting
with an oxidizing agent and DABCO to form
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and reacting
with an acid to form
In some embodiments the oxidizing agent is ozone and the acid is hydrochloric
acid.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. XRPD Pattern of Compound A Crystalline Anhydrous
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Figure 2. XRPD Pattern of Compound A Amorphous
Figure 3. XRPD Pattern of Crystalline (3S, 5S, 6R, 8S)allyl(3-chlorophenyl)(4-
chlorophenyl)isopropylmethyl-2, 3,5,6,7, 8-hexahydrooxazolo
[3,2-a]pyridinium naphthalenesulfonate, hemi-toluene solvate
Figure 4. XRPD Pattern of Compound A Crystalline Form 1
Figure 5. XRPD Pattern of Compound A Crystalline Form 2
Figure 6. XRPD Pattern of Compound A Ethanolate (ethanol solvate)
Figure 7. XRPD Pattern of Compound A Propanol Solvate
Figure 8. DSC Curve of Compound A Crystalline Anhydrous
Figure 9. DSC Curve of Compound A Amorphous
Figure 10. DSC Curve of Crystalline (3S, 5S, 6R, 8S)allyl(3-chlorophenyl)(4-
chlorophenyl)isopropylmethyl-2, 3,5,6,7, 8-hexahydrooxazolo
[3,2-a]pyridinium naphthalenesulfonate, hemi-toluene solvate
Figure 11. DSC Curve of Compound A Ethanolate
Figure 12. XRPD Patten of Compound A DABCO Salt
Figure 13. DSC Curve of Compound A DABCO Salt.
DETAILED DESCRIPTION OF THE INVENTION
Described herein are processes for making 2-((3R,5R,6S)(3-chlorophenyl)
(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methyl
oxopiperidinyl)acetic acid (“Compound A” herein). The present invention provides
intermediates and processes for making the intermediates, and crystalline forms of the
intermediates.
The term "comprising" is meant to be open ended, including the indicated
component but not excluding other elements. That is to say, the term “comprising” as
used in this specification and claims means “consisting at least in part of”. When
interpreting statements in this specification and claims which include the term
“comprising”, other features besides the features prefaced by this term in each statement
can also be present. Related terms such as “comprise” and “comprised” are to be
interpreted in a similar manner.
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The term "therapeutically effective amount" means an amount of a compound or
combination of therapeutically active compounds that ameliorates, attenuates or
eliminates one or more symptoms of a particular disease or condition, or prevents or
delays the onset of one of more symptoms of a particular disease or condition.
The terms "patient" and “subject” may be used interchangeably and mean
animals, such as dogs, cats, cows, horses, sheep and humans. Particular patients are
mammals. The term patient includes males and females.
The term "pharmaceutically acceptable" means that the referenced substance,
such as a compound described herein, or a salt of the compound, or a formulation
containing the compound, or a particular excipient, are suitable for administration to a
patient.
The terms "treating", "treat" or "treatment" and the like include preventative (e.g.,
prophylactic) and palliative treatment.
The term “excipient” means any pharmaceutically acceptable additive, carrier,
diluent, adjuvant, or other ingredient, other than the active pharmaceutical ingredient
(API), which is typically included for formulation and/or administration to a patient.
The compound described herein can be administered to a patient in a
therapeutically effective amount. The compound can be administered alone or as part of a
pharmaceutically acceptable composition or formulation. In addition, the compound or
compositions can be administered all at once, as for example, by a bolus injection,
multiple times, such as by a series of tablets, or delivered substantially uniformly over a
period of time, as for example, using transdermal delivery. It is also noted that the dose of
the compound can be varied over time.
The compound described herein, or the pharmaceutically acceptable salts thereof,
may also be administered in combination with one or more additional pharmaceutically
active compounds/agents. It is noted that the additional pharmaceutically active
compounds/agents may be a traditional small organic chemical molecules or can be
macromolecules such as a proteins, antibodies, peptibodies, DNA, RNA or fragments of
such macromolecules.
When a patient is to receive or is receiving multiple pharmaceutically active
compounds, the compounds can be administered simultaneously, or sequentially. For
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example, in the case of tablets, the active compounds may be found in one tablet or in
separate tablets, which can be administered at once or sequentially in any order. In
addition, it should be recognized that the compositions may be different forms. For
example, one or more compound may be delivered via a tablet, while another is
administered via injection or orally as a syrup. All combinations, delivery methods and
administration sequences are contemplated.
The term "cancer" means a physiological condition in mammals that is
characterized by unregulated cell growth. General classes of cancers include carcinomas,
lymphomas, sarcomas, and blastomas.
The compound described herein can be used to treat cancer. The methods of
treating a cancer comprise administering to a patient in need thereof a therapeutically
effective amount of the compound, or a pharmaceutically acceptable salt thereof.
The compound described herein can be used to treat tumors. The methods of
treating a tumor comprise administering to a patient in need thereof a therapeutically
effective amount of the compound, or a pharmaceutically acceptable salt thereof.
Cancers which may be treated with compounds described herein include, without
limitation, carcinomas such as cancer of the bladder, breast, colon, rectum, kidney, liver,
lung (small cell lung cancer, and non-small-cell lung cancer), esophagus, gall-bladder,
ovary, pancreas, stomach, cervix, thyroid, prostate, and skin (including squamous cell
carcinoma); hematopoietic tumors of lymphoid lineage (including leukemia, acute
lymphocytic leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, B-
cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors of myeloid lineage
(including acute and chronic myelogenous leukemias, myelodysplastic syndrome and
promyelocytic leukemia); tumors of mesenchymal origin (including fibrosarcoma and
rhabdomyosarcoma, and other sarcomas, e.g., soft tissue and bone); tumors of the central
and peripheral nervous system (including astrocytoma, neuroblastoma, glioma and
schwannomas); and other tumors (including melanoma, seminoma, teratocarcinoma,
osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and
Kaposi's sarcoma). Other cancers that can be treated with the compound described herein
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include endometrial cancer, head and neck cancer, glioblastoma, malignant ascites, and
hematopoietic cancers.
Particular cancers that can be treated by the compound described herein include
soft tissue sarcomas, bone cancers such as osteosarcoma, breast tumors, bladder cancer,
Li-Fraumeni syndrome, brain tumors, rhabdomyosarcoma, adrenocortical carcinoma,
colorectal cancer, non-small cell lung cancer, and acute myeleogenous leukemia (AML).
In a particular embodiment that relates to the treatment of cancers, the cancer is
identified as p53wildtype (p53 ). In another particular embodiment, the cancer is
identified as p53 and CDKN2A mutant. Also described herein is a diagnostic for
determining which patients should be administereda compound described herein. For
example, a sample of a patient’s cancer cells may be taken and analyzed to determine the
status of the cancer cells with respect to p53 and/or CDKN2A. In one embodiment, a
patient having a cancer that is p53 will be selected for treatment over patients having a
cancer that is mutated with respect to p53. In another embodiment, a patient having a
cancer that is both p53 and has a mutant CDNK2A protein is selected over a patient
that does not have these characteristics. The taking of a cancer cells for analyses is well
known to those skilled in the art. The term “p53 ” means a protein encoded by genomic
DNA sequence no. NC_000017 version 9 (7512445..7531642)(GenBank); a protein
encoded by cDNA sequence no. NM_000546 (GenBank); or a protein having the
GenBank sequence no. NP_000537.3. The term “CDNK2A mutant” means a CDNK2A
protein that is not wildtype. The term “CDKN2A wildtype” means a protein encoded by
genomic DNA sequence no. 9:21957751-21984490 (Ensembl ID); a protein encoded by
cDNA sequence no. NM_000077 (GenBank) or NM_058195 9GenBank) or; or a protein
having the GenBank sequence no. NP_000068 or NP_478102.
Also described is the use of Compound A in combination with one or more
pharmaceutical agent that is an inhibitor of a protein in the phosphatidylinositol 3-kinase
(PI3K) pathway. Combinations of Compound A along with inhibitors of proteins in the
PI3K pathway have shown synergy in cancer cell growth assays, including enhanced
apoptosis and cell killing. Examples of proteins in the PI3K pathway include PI3K,
mTOR and PKB (also known as Akt). The PI3K protein exists in several isoforms
including α, β, δ, or γ. It is contemplated that a PI3K inhibitor that can be used in
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combination with Compound A can be selective for one or more isoform. By selective it
is meant that the compounds inhibit one or more isoform more than other isoforms.
Selectivity is a concept well known to those in the art and can be measured with well
known activity in in vitro or cell-based assays. Preferred selectivity includes greater than
2-fold, preferably 10-fold, or more preferably 100-fold greater selectivity for one or more
isoform over the other isoforms. In one aspect, the PI3K inhibitors that can be used in
combination with Compound A is a PI3K α selective inhibitor. In another aspect the
compound is a PI3K δ selective inhibitor.
Examples of PI3K inhibitors that can be used in combination include those
disclosed in the following: PCT published application no. WO2010/151791; PCT
published application no. WO2010/151737; PCT published application
no.WO2010/151735; PCT published application no. WO2010151740; PCT published
application no. WO2008/118455; PCT published application no. WO2008/118454; PCT
published application no. WO2008/118468; U.S. published application no.
US20100331293; U.S. published application no. US20100331306; U.S. published
application no. US20090023761; U.S. published application no. US20090030002; U.S.
published application no. US20090137581;U.S. published application no.
US2009/0054405; U.S. published application no. U.S. 2009/0163489; U.S. published
application no. US 2010/0273764; U.S. published application no. U.S. 2011/0092504; or
PCT published application no. WO2010/108074.
Compounds that inhibit both PI3K and mTOR (dual inhibitors) are known. In
still another embodiment, the combination of dual PI3K and mTOR inhibitors for use
with Compound A is described.
mTOR is a protein in the PI3K pathwayIn one embodiment, an mTOR inhibitor
may be used in combination withCompound A. mTOR inhibitors that can be used in
combination include those disclosed in the following documents: PCT published
application no. WO2010/132598 or PCT published application no. WO2010/096314.
PKB (Akt) is also a protein in the PI3K pathway. In another embodiment, an
mTOR inhibitor may be used in combination with Compond A. PKB inhibitors that can
be used in combination include those disclosed in the following documents: U.S. patent
no. 7,354,944; U.S. patent no. 7,700,636; U.S. patent no. 7,919,514; U.S. patent no.
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7,514,566; U.S. patent application publication no. US 2009/0270445 A1; U.S. patent no.
7,919,504; U.S. patent no. 7,897,619; or PCT published application no.
The combinations described herein may also be used in conjunction with radiation
therapy, hormone therapy, surgery and immunotherapy, which therapies are well known
to those skilled in the art.
Since one embodiment contemplates the treatment of the disease/conditions with
a combination of pharmaceutically active compounds that may be administered
separately, separate pharmaceutical compositions in kit form may be combined. The kit
comprises two separate pharmaceutical compositions: the compound described herein,
and a second pharmaceutical compound. The kit comprises a container for containing the
separate compositions such as a divided bottle or a divided foil packet. Additional
examples of containers include syringes, boxes and bags. Typically, the kit comprises
directions for the use of the separate components. The kit form is particularly
advantageous when the separate components are preferably administered in different
dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is desired by the
prescribing physician or veterinarian.
An example of such a kit is a so-called blister pack. Blister packs are well known
in the packaging industry and are being widely used for the packaging of pharmaceutical
unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a
sheet of relatively stiff material covered with a foil of a preferably transparent plastic
material. During the packaging process recesses are formed in the plastic foil. The
recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets
or capsules are placed in the recesses and the sheet of relatively stiff material is sealed
against the plastic foil at the face of the foil which is opposite from the direction in which
the recesses were formed. As a result, the tablets or capsules are sealed in the recesses
between the plastic foil and the sheet. Preferably the strength of the sheet is such that the
tablets or capsules can be removed from the blister pack by manually applying pressure
on the recesses whereby an opening is formed in the sheet at the place of the recess. The
tablet or capsule can then be removed via said opening.
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It may be desirable to provide a memory aid on the kit, e.g., in the form of
numbers next to the tablets or capsules whereby the numbers correspond with the days of
the regimen which the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card, e.g., as follows "First
Week, Monday, Tuesday,. . . etc . . . Second Week, Monday, Tuesday, . . . " etc. Other
variations of memory aids will be readily apparent. A "daily dose" can be a single tablet
or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a
compound described herein can consist of one tablet or capsule, while a daily dose of the
second compound can consist of several tablets or capsules and vice versa. The memory
aid should reflect this and aid in correct administration of the active agents.
In another specific embodiment, a dispenser designed to dispense the daily doses one at a
time in the order of their intended use is described. Preferably, the dispenser is equipped
with a memory-aid, so as to further facilitate compliance with the regimen. An example
of such a memory-aid is a mechanical counter which indicates the number of daily doses
that has been dispensed. Another example of such a memory-aid is a battery-powered
micro-chip memory coupled with a liquid crystal readout, or audible reminder signal
which, for example, reads out the date that the last daily dose has been taken and/or
reminds one when the next dose is to be taken.
The compound described herein and other pharmaceutically active compounds, if
desired, can be administered to a patient either orally, rectally, parenterally, (for example,
intravenously, intramuscularly, or subcutaneously) intracisternally, intravaginally,
intraperitoneally, intravesically, locally (for example, powders, ointments or drops), or as
a buccal or nasal spray. All methods that are used by those skilled in the art to administer
a pharmaceutically active agent are contemplated.
Compositions suitable for parenteral injection may comprise physiologically
acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or
emulsions, and sterile powders for reconstitution into sterile injectable solutions or
dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or
vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol,
and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the
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use of a coating such as lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preserving, wetting,
emulsifying, and dispersing agents. Microorganism contamination can be prevented by
adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol,
phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for
example, sugars, sodium chloride, and the like. Prolonged absorption of injectable
pharmaceutical compositions can be brought about by the use of agents delaying
absorption, for example, aluminum monostearate and gelatin.
Solid dosage forms for oral administration include capsules, tablets, powders, and
granules. In such solid dosage forms, the active compound is admixed with at least one
inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a)
fillers or extenders, as for example, starches, lactose, sucrose, mannitol, and silicic acid;
(b) binders, as for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d)
disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca
starch, alginic acid, certain complex silicates, and sodium carbonate; (a) solution
retarders, as for example, paraffin; (f) absorption accelerators, as for example, quaternary
ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol
monostearate; (h) adsorbents, as for example, kaolin and bentonite; and (i) lubricants, as
for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols,
sodium lauryl sulfate, or mixtures thereof. In the case of capsules, and tablets, the dosage
forms may also comprise buffering agents. Solid compositions of a similar type may also
be used as fillers in soft and hard filled gelatin capsules using such excipients as lactose
or milk sugar, as well as high molecular weight polyethylene glycols, and the like.
Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be
prepared with coatings and shells, such as enteric coatings and others well known in the
art. They may also contain opacifying agents, and can also be of such composition that
they release the active compound or compounds in a certain part of the intestinal tract in a
delayed manner. Examples of embedding compositions that can be used are polymeric
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substances and waxes. The active compound can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active
compounds, the liquid dosage form may contain inert diluents commonly used in the art,
such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl
benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular,
cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame seed oil,
glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of
sorbitan, or mixtures of these substances, and the like.
Besides such inert diluents, the composition can also include adjuvants, such as
wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming
agents. Suspensions, in addition to the active compound, may contain suspending agents,
as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan
esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and
tragacanth, or mixtures of these substances, and the like.
Compositions for rectal administration are preferably suppositories, which can be
prepared by mixing the compounds described herein with suitable non-irritating
excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax,
which are solid at ordinary room temperature, but liquid at body temperature, and
therefore, melt in the rectum or vaginal cavity and release the active component.
Dosage forms for topical administration of the compound described herein
include ointments, powders, sprays and inhalants. The active compound or compounds
are admixed under sterile condition with a physiologically acceptable carrier, and any
preservatives, buffers, or propellants that may be required. Opthalmic formulations, eye
ointments, powders, and solutions are also contemplated as being within the scope
described herein.
The compound described herein can be administered to a patient at dosage levels
in the range of about 0.1 to about 3,000 mg per day. For a normal adult human having a
body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per
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kilogram body weight is typically sufficient. The specific dosage and dosage range that
can be used depends on a number of factors, including the requirements of the patient, the
severity of the condition or disease being treated, and the pharmacological activity of the
compound being administered. The determination of dosage ranges and optimal dosages
for a particular patient is within the ordinary skill in the art.
The compound described herein can be administered as pharmaceutically
acceptable salts, esters, amides or prodrugs. The term "salts" refers to inorganic and
organic salts of compounds described herein. The salts can be prepared in situ during the
final isolation and purification of a compound, or by separately reacting a purified
compound in its free base or acid form with a suitable organic or inorganic base or acid
and isolating the salt thus formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate,
borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate,
tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts,
and the like. The salts may include cations based on the alkali and alkaline earth metals,
such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-
toxic ammonium, quaternary ammonium, and amine cations including, but not limited to,
ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,
trimethylamine, triethylamine, ethylamine, and the like. See, for example, S. M. Berge, et
al., "Pharmaceutical Salts," J Pharm Sci, 66: 1-19 (1977).
Examples of pharmaceutically acceptable esters of the compound described
herein include C -C alkyl esters. Acceptable esters also include C -C cycloalkyl esters,
1 8 5 7
as well as arylalkyl esters such as benzyl. C -C alkyl esters are commonly used. Esters
of compounds described herein may be prepared according to methods that are well
known in the art.
Examples of pharmaceutically acceptable amides of the compound described
herein include amides derived from ammonia, primary C -C alkyl amines, and secondary
C -C dialkyl amines. In the case of secondary amines, the amine may also be in the form
of a 5 or 6 membered heterocycloalkyl group containing at least one nitrogen atom.
Amides derived from ammonia, C -C primary alkyl amines and C -C dialkyl secondary
1 3 1 2
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amines are commonly used. Amides of the compound described herein may be prepared
according to methods well known to those skilled in the art.
The term "prodrug" means compounds that are transformed in vivo to yield a
compound described herein. The transformation may occur by various mechanisms, such
as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T.
Higuchi and W. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the A.C.S.
Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987.
To illustrate, because the compound described herein contains a carboxylic acid
functional group, a prodrug can comprise an ester formed by the replacement of the
hydrogen atom of the carboxylic acid group with a group such as (C -C alkyl, (C -
1 8 2
C1 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-
methyl(alkanoyloxy)ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl
having from 4 to 7 carbon atoms, 1-methyl(alkoxycarbonyloxy)ethyl having from 5 to
8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-
crotonolactonyl, gamma-butyrolactonyl, di-N,N-(C -C )alkylamino(C -C )alkyl (such
1 2 2 3
as β-dimethylaminoethyl), carbamoyl-(C -C )alkyl, N,N-di(C -C )alkylcarbamoyl-(C -
1 2 1 2 1
C )alkyl and piperidino-, pyrrolidino- or morpholino(C - )alkyl.
2 2 3
The compound described herein may contain asymmetric or chiral centers, and
therefore, exist in different stereoisomeric forms. It is contemplated that all
stereoisomeric forms of the compound as well as mixtures thereof, including racemic
mixtures, form part of the present invention. In addition, the present invention
contemplates all geometric and positional isomers. For example, if the compound
contains a double bond, both the cis and trans forms (designated as Z and E,
respectively), as well as mixtures, are contemplated.
Mixture of stereoisomers, such as diastereomeric mixtures, can be separated into
their individual stereochemical components on the basis of their physical chemical
differences by known methods such as chromatography and/or fractional crystallization.
Enantiomers can also be separated by converting the enantiomeric mixture into a
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diastereomeric mixture by reaction with an appropriate optically active compound (e.g.,
an alcohol), separating the diastereomers and converting (e.g., hydrolyzing) the
individual diastereomers to the corresponding pure enantiomers. Also, some compounds
may be atropisomers (e.g., substituted biaryls).
The compound described herein may exist in unsolvated as well as solvated forms
with pharmaceutically acceptable solvents such as water (hydrate), ethanol, and the like.
The present invention contemplates and encompasses both the solvated and unsolvated
forms as set forth herein.
It is also possible that the compound described herein may exist in different
tautomeric forms. All tautomers of the compound described herein are contemplated. For
example, all of the tautomeric forms of the tetrazole moiety are included. Also, for
example, all keto-enol or imine-enamine forms of the compounds are included.
Those skilled in the art will recognize that the compound names and structures
contained herein may be based on a particular tautomer of a compound. While the name
or structure for only a particular tautomer may be used, it is intended that all tautomers
are encompassed by the present invention, unless stated otherwise.
It is also intended that the present description encompass compounds that are
synthesized in vitro using laboratory techniques, such as those well known to synthetic
chemists; or synthesized using in vivo techniques, such as through metabolism,
fermentation, digestion, and the like. It is also contemplated that the compounds
described herein may be synthesized using a combination of in vitro and in vivo
techniques.
The present description also includes isotopically-labelled compounds, which are
identical to those recited herein, but for the fact that one or more atoms are replaced by an
atom having an atomic mass or mass number different from the atomic mass or mass
number usually found in nature. Examples of isotopes that can be incorporated into
compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen,
2 3 13 14 15 16 17 18 31 32
phosphorous, fluorine and chlorine, such as H, H, C, C, N, O, O, O, P, P,
18 36
S, F, and Cl. In one embodiment, one or more hydrogen atom can be replaced with
deuterium ( H) atoms.
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The compound described herein that contains the aforementioned isotopes and/or
other isotopes of other atoms are described. Certain isotopically-labelled compounds
3 14
described herein, for example those into which radioactive isotopes such as H and C
are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated,
3 14
i.e., H, and carbon-14, i.e., C, isotopes are particularly preferred for their ease of
preparation and detection. Further, substitution with heavier isotopes such as deuterium,
i.e., H, can afford certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced dosage requirements and,
hence, may be preferred in some circumstances. Isotopically labeled compounds
described herein can generally be prepared by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent.
The compound described herein may exist in various solid states including
crystalline states and as an amorphous state. The different crystalline states, also called
polymorphs, and the amorphous states of the present compounds are contemplated as part
of this invention as set forth herein.
In synthesizing the compound described herein, it may be desirable to use certain
leaving groups. The term “leaving groups” (“LG”) generally refer to groups that are
displaceable by a nucleophile. Such leaving groups are known in the art. Examples of
leaving groups include, but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g.,
mesylate, tosylate), sulfides (e.g., SCH ), N-hydroxsuccinimide, N-hydroxybenzotriazole,
and the like. Examples of nucleophiles include, but are not limited to, amines, thiols,
alcohols, Grignard reagents, anionic species (e.g., alkoxides, amides, carbanions) and the
like.
All patents, published patent applications and other publications recited herein are
hereby incorporated by reference.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission
that such documents, or such sources of information, in any jurisdiction, are prior art, or
form part of the common general knowledge in the art.
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The specific experimental examples presented in this application illustrate
specific embodiments of the present invention. These examples are meant to be
representative and are not intended to limit the scope of the claims in any manner.
H-NMR spectra were typically acquired on a Bruker Avance III 500
spectrometer system (Bruker, Billerica, MA) operating at a H frequency of 500.13 MHz,
equipped with a Bruker 5 mm PABBI probe with a z-axis gradient; or on a Bruker
Avance II or Avance III 400 spectrometer operating at a H frequency of 400.23 MHz,
equipped with a Bruker 5 mm PABBO probe with a z-axis gradient. Samples were
typically dissolved in 500 µL of either DMSO-d or CD OD for NMR analysis. H
chemical shifts are referenced to the residual solvent signals from DMSO-d at δ 2.50 and
CD OD at δ 3.30.
Significant peaks are tabulated and typically include: number of protons,
multiplicity (s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m,
multiplet; br s, broad singlet) and coupling constant(s) in Hertz. Electron Ionization (EI)
mass spectra were typically recorded on an Agilent Technologies 6140 Quadrupole
LC/MS mass spectrometer (Agilent Technologies, Englewood, CO). Mass spectrometry
results are reported as the ratio of mass over charge, sometimes followed by the relative
abundance of each ion (in parentheses). Starting materials in the Examples below are
typically either available from commercial sources such as Sigma-Aldrich, St. Louis,
MO, or via literature procedures.
X-Ray powder diffraction data (XRPD) were obtained using a PANalytical X’Pert
PRO diffractometer (PANalytical, Almelo, The Netherlands) fitted with a real time
multiple strip (RTMS) detector. The radiation used was CuK α(1.54 Å) and the voltage
and current were set at 45 kV and 40 mA, respectively. Data were collected at room
temperature from 5 to 45 degrees 2-theta with a step size of 0.0334 degrees. Samples
were prepared on a low background sample holder and placed on the sample stage which
was rotated with a 2 second revolution time.
Alternatively, XRPD data were obtained using a PANalytical X’Pert PRO
diffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMS detector. The
radiation used was CuK α(1.54 Å) and the voltage and current were set at 45 kV and 40
mA, respectively. Data were collected at room temperature from 5 to 40, degrees 2-theta
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with a step size of either 0.0334 degrees. Samples were prepared on a low background
sample holder and placed on the sample stage which was rotated with a 2 second
revolution time.
Alternatively, XRPD data were obtained using a PANalytical X’Pert PRO
diffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMS detector. The
radiation used was CuK α(1.54 Å) and the voltage and current were set at 45 kV and 40
mA, respectively. Data were collected at room temperature from 5 to 40, degrees 2-theta
with a step size of either 0.0167 degrees. Samples were prepared on a low background
sample holder and placed on the sample stage which was rotated with a 2 second
revolution time.
Alternatively, XRPD data were obtained using a PANalytical X’Pert Pro
diffractometer (PANalytical, Almelo, The Netherlands) fitted with a RTMS detector. The
radiation used was CuKa(1.54 Å) and the voltage and current were set at 45 kV and 40
mA, respectively. Data were collected at room temperature from 3 to 40, degrees 2-theta
with a step size of 0.008 degrees. Samples were prepared on a low background sample
holder and placed on the sample stage with a 2 second revolution time.
Alternatively, XRPD data were obtained using a Bruker D8 Discover X-ray
diffraction system (Bruker, Billerica, MA) fitted with a motorized xyz sample stage and a
GADDS area detector. The radiation used was CuK α(1.54 Å) and the voltage and current
were set at 45 kV and 40 mA, respectively. The solid samples on a flat glass plate were
mapped and for each sample an area of 1 mm was scanned in an oscillating mode for 3
minutes from 5 to 48 degrees 2-theta.
Differential Scanning Calorimetry (DSC) data was collected using standard DSC
mode (DSC Q200, TA Instruments, New Castle, DE). A heating rate of 10 °C/min was
employed over a temperature range from 40 °C to 300 °C. Analysis was run under
nitrogen and samples were loaded in standard, hermetically-sealed aluminum pans.
Indium was used as a calibration standard.
Alternatively, DSC data were collected using temperature-modulated DSC mode
(DSC Q200, TA Instruments, New Castle, DE). After sample equilibration at 20 °C for
five minutes, the heating rate of 3 °C/min was employed with a modulation of +/-
0.75 °C/min over a temperature range from 20 °C to 200 °C. Analysis was run under
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nitrogen and samples were loaded in standard, uncrimped aluminum pans. Indium was
used as a calibration standard.
The following abbreviations may be used herein.
~ about
+ve or pos. ion positive ion
∆ heat
Ac acetyl
ACN acetonitrile
AcO acetic anhydride
aq aqueous
AcOH acetic acid
Bn benzyl
Boc tert-butyloxycarbonyl
BSA bovine serum albumin
Bu butyl
Bz benzoyl
Calcd or Calc’d calculated
Ca(OH) calcium hydroxide
CHOK potassium methoxide
CHONa sodium methoxide
Conc. concentrated
d day(s)
DABCO 1,4-diazabicyclo[2.2.2]octane
DCE dichloroethane
DCM dichloromethane
DEA diethylamine
Dess-Martin periodinane;
1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol(1H)-one
Dess-Martin reagent
DIEA or DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
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DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide
dr or DR diastereomeric ratio
DSC differential scanning calorimetry
DTT dithiothreitol
DVB divinylbenzene
EDC N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide
ee or e.e. enantiomeric excess
eq equivalent
ESI or ES electrospray ionization
Et ethyl
Et O diethyl ether
EtN triethylamine
EtOAc ethyl acetate
EtOH ethyl alcohol
g gram(s)
h hour(s)
O-(7-azabenzotriazolyl)-N,N,N’,N’-
HATU
tetramethyluronium hexafluorophosphate
O-benzotriazole-N,N,N’,N’-tetramethyl-uronium-
HBTU
hexafluorophosphate
Hex hexanes
HMPA hexamethylphosphoramide
HOAt 1-hydroxyazabenzotriazole
HOBt hydroxybenzotriazole
HPLC high pressure liquid chromatography
IPAc or IPAC isopropyl acetate
IPA or iPrOH isopropyl alcohol
iPr isopropyl
Jones reagent solution of chromium(IV)oxide and sulfuric acid in water
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KHMDS potassium hexamethyldisilazide
KOAc potassium acetate
LCMS, LC-MS or LC/MS liquid chromatography mass spectrometry
LDA lithium diisopropylamide
LHMDS or LiHMDS lithium hexamethyldisilazide
lithium tri-sec-butylborohydride (Sigma-Aldrich, St.
L-Selectride
Louis)
M molar (mol L )
mCPBA m-chloroperoxybenzoic acid
mDSC modulated differential scanning calorimetry
Me methyl
MeCN acetonitrile
MeI iodomethane
MEK methyl ethyl ketone
MeOH methyl alcohol
mg milligram(s)
min minute(s)
mL milliliter(s)
M mole(s)
MS mass spectrometry
MsCl methanesulfonyl chloride
MTBE or MtBE methyl tert-butyl ether
m/z mass-to-charge ratio
NaHMDS sodium hexamethyldisilazide
NaOtBu sodium tert-butoxide
NBS N-bromosuccinimide
nBuLi n-butyl lithium
NMO N-methylmorpholine-N-oxide
NMP 1-methylpyrrolidinone
NMR nuclear magnetic resonance
N-Selectride sodium tri-sec-butylborohydride (Sigma-Aldrich, St.
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Louis)
PBS phosphate buffered saline
PMB paramethoxybenzyl
Ph phenyl
Pr propyl
ppm parts per million
PTFE polytetrafluoroethylene
p-tol para-toluoyl
rac racemic
RP-HPLC or RPHPLC reversed phase high pressure liquid chromatography
RT or rt or r.t. room temperature
sat. or sat’d or satd saturated
SFC supercritical fluid chromatography
TBAF tetrabutylammonium fluoride
TBDMS tert-butyldimethylsilyl
TBDMS-Cl tert-butyldimethylsilyl chloride
TBDPS tert-butyldiphenylsilyl
TEMPO (2,2,6,6-tetramethylpiperidinyl)oxidanyl
tert or t tertiary
TFA trifluoroacetic acid
TGA thermogravimetric analysis
THF tetrahydrofuran
TIPS triisopropylsilyl
TLC thin layer chromatography
TMS trimethylsilyl or trimethylsilane
TPAP tetrapropylammonium perruthenate
t retention time
TRIS 2-aminohydroxymethyl-propane-1,3-diol
TfOH trifluoroacetic acid
TfO trifluoroacetate
TfO trifluoroacetic acid anhydride
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TsOH or PTSA p-toluenesulfonic acid
TsO p-toluenesulfonate
TsO p-toluenesulfonic acid anhydride
tBuOH tert-butyl alcohol
XRD X-ray diffraction
XRPD or PXRD X-ray powder diffraction
v/v volume per volume
Procedures to Make Certain Intermediates and Starting Materials
Method for making
, and .
Step A. 2-(3-Chlorophenyl)(4-chlorophenyl)ethanone
Sodium bis(trimethylsilyl)amide (1 M in tetrahydrofuran, 117 mL) was slowly
added to a -78 °C solution of 2-(3-chlorophenyl) acetic acid (10 g, 58.6 mmol) in
tetrahydrofuran (58 mL) over 1 hour. After stirring at -78 °C for 40 minutes, a solution of
methyl 4-chlorobenzoate (10 g, 58.6 mmol) in tetrahydrofuran (35 mL) was added over a
period of 10 minutes. The reaction was stirred at -78 °C for 3 hours then allowed to
warm to 25 °C. After two hours at 25 °C, the reaction was quenched with saturated
aqueous ammonium chloride solution, and most of the tetrahydrofuran was removed
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under reduced pressure. The residue was extracted with ethyl acetate (2 × 100 mL). The
combined organic layers were washed with saturated sodium chloride solution, dried over
sodium sulfate, filtered and the filtrate was concentrated. The product was recrystallized
from ether/pentane to provide the title compound as a white solid.
Alternative Procedure
To a mixture of chlorobenzene (170 L, 1684 mol), 3-chlorophenylacetic acid (50
Kg, 293 mol), and dimethylformamide (0.7 L, 9 mol) at 0 °C was added thionyl chloride
(39.1 Kg, 329 mol) over the course of 30 min. The mixture was warmed to 15 °C and
agitated for 6 h. The mixture was cooled to 0 °C and aluminum chloride (43 Kg, 322
mol) was added over the course of 1.5 h. The mixture was warmed to 20 °C and agitated
for 15 h. Water (200 L) and ethanol (200 L) were added to the mixture and the biphasic
mixture was agitated for 2 h. The phases were separated and the organic phase was
washed twice with aqueous ethylenediaminetetraacetic acid tetrasodium salt (3 wt%, 200
L), and once with water (200 L). Heptane (1600 L) was added to the organic phases over
the course of 15 minutes. The suspension was agitated for 30 minutes, cooled to −5 °C,
and filtered. The filtered material was dried at 40 °C for 20 h. 2-(3-Chlorophenyl)(4-
chlorophenyl)ethanone was isolated in 83.6% yield (67.4 Kg).
H NMR (500 MHz, DMSO-d , δ ppm): 8.05 (m, 2H), 7.62 (m, 2H), 7.33 (m, 3H), 7.21
(br d, J = 7.3 Hz, 1H), 4.45 (s, 2H). MS (ESI) = 265.1 [M + H] .
Step B: Methyl 4-(3-chlorophenyl)(4-chlorophenyl)methyloxopentanoate
Methyl methacrylate (12.65 mL, 119 mmol) was added to a solution of 2-(3-
chlorophenyl)(4-chlorophenyl)ethanone (30 g, 113 mmol) in tetrahydrofuran (283
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mL). Potassium tert-butoxide (1.27 g, 11.3 mmol) was then added and the reaction was
stirred at room temperature for 2 days. The solvent was removed under a vacuum and
replaced with 300 mL of ethyl acetate. The organic phase was washed with brine (50
mL), water (3 x 50 mL), and brine (50 mL). The organic phase was dried over
magnesium sulfate, filtered and concentrated under a vacuum to afford methyl 4-(3-
chlorophenyl)(4-chlorophenyl)methyloxopentanoate as an approximately 1:1
mixture of diastereomers.
H NMR (400 MHz, CDCl , δ ppm): 7.87 (m, 2H), 7.38 (m, 2H), 7.27-7.14 (series of m,
4H), 4.61 (m, 1H), 3.69 (s, 1.5H), 3.60 (s, 1.5 H), 2.45 (m, 1H), 2.34 (m, 1H), 2.10 (ddd,
J = 13.9, 9.4, 5.5 Hz, 0.5H), 1.96 (ddd, J = 13.7, 9.0, 4.3 Hz, 0.5H), 1.22 (d, J = 7.0 Hz,
1.5H), 1.16 (d, J = 7.0, 1.5 H). MS (ESI) = 387.0 [M + 23] .
Step C: (3S, 5R,6R)(3-Chlorophenyl)(4-chlorophenyl)methyltetrahydro-2H-
pyranone and (3R, 5R,6R)(3-chlorophenyl)(4-chlorophenyl)methyltetrahydro-
2H-pyranone
Methyl 4-(3-chlorophenyl)(4-chlorophenyl)methyloxopentanoate (40 g, 104.0
mmol) was dissolved in 200 mL of anhydrous toluene and concentrated under a vacuum.
The residue was placed under high vacuum for 2 hours before use. The compound was
split into 2 x 20 g batches and processed as follows: methyl 4-(3-chlorophenyl)(4-
chlorophenyl)methyloxopentanoate (20 g, 52.0 mmol) in anhydrous 2-propanol
(104 mL) was treated with potassium tert-butoxide (2.33 g, 20.8 mmol) in a 250 mL glass
hydrogenation vessel. RuCl (S-xylbinap)(S-DAIPEN) (0.191 g, 0.156 mmol, Strem
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Chemicals, Inc., Newburyport, MA) in 3.8 mL of toluene was added. After 1.5 hours, the
vessel was pressurized to 50 psi (344.7 kPa) and purged with hydrogen five times and
allowed to stir at room temperature. The reaction was recharged with additional
hydrogen as needed. After 3 days, the reactions were combined and partitioned between
50% saturated ammonium chloride solution and ethyl acetate. The aqueous layer was
extracted with ethyl acetate. The combined organic phases were washed with brine, dried
over magnesium sulfate, filtered, and concentrated.
The crude product (predominantly, (4R,5R)-isopropyl 4-(3-chlorophenyl)(4-
chlorophenyl)hydroxymethylpentanoate) was dissolved in tetrahydrofuran (450
mL) and methanol (150 mL). Lithium hydroxide (1.4 M, 149 mL, 208 mmol) was added,
and the solution was stirred at room temperature for 24 hours. The mixture was
concentrated under a vacuum and the residue was redissolved in ethyl acetate. Aqueous
1N hydrochloric acid was added with stirring until the aqueous layer had a pH of about 1.
The layers were separated and the organic phase was washed with brine, dried over
magnesium sulfate, filtered and concentrated. The material was dissolved in 200 mL of
anhydrous toluene and treated with pyridinium p-toluenesulfonate (PPTS, 0.784 g, 3.12
mmol). The reaction was heated to reflux under Dean-Stark conditions until the seco-
acid was consumed (about 2 hours). The reaction was cooled to room temperature and
washed with saturated sodium bicarbonate (50 mL) and brine (50 mL). The solution was
dried over sodium sulfate, filtered and concentrated. The crude material was purified by
flash chromatography on silica gel (120 g column; eluting with 100% dichloromethane).
The title compounds were obtained as a white solid with an approximate 94:6
enantiomeric ratio and a 7:3 mixture of methyl diastereomers.
H NMR (400 MHz, CDCl , δ ppm): 7.22-6.98 (series of m, 5H), 6.91 (dt, J = 7.4, 1.2
Hz, 0.3H), 6.81 (m, 2H), 6.73 (dt, J = 7.6, 1.4 Hz, 0.7H), 5.76 (d, J = 4.1 Hz, 0.3 H), 5.69
(d, J = 4.7 Hz, 0.7H), 3.67 (dt, J = 6.6, 4.3 Hz, 0.3H), 3.55 (td, J = 7.8, 4.7 Hz, 0.7 H),
2.96 (d of quintets, J = 13.5, 6.7 Hz, 0.7 H), 2.81 (m, 0.3 H), 2.56 (dt, J = 14.3, 8.0 Hz,
0.7 H), 2.32 (dt, J = 13.69, 7.0 Hz, 0.3 H), 2.06 (ddd, J = 13.7, 8.4, 4.1, 0.3 H), 1.85 (ddd,
J = 14.1, 12.5, 7.4, 0.7 H), 1.42 (d, J = 7.0 Hz, 0.9 H), 1.41 (d, J = 6.7 Hz, 2.1H). MS
(ESI) = 357.0 [M + 23] . [ α]D (22 °C, c = 1.0, CH2Cl2) = -31.9°; m.p. 98–99 °C.
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Step D. (3S,5R,6R)Allyl(3-chlorophenyl)(4-chlorophenyl)methyltetrahydro-
2H-pyranone
A solution of (3S, 5R,6R)(3-chlorophenyl)(4-chlorophenyl)
methyltetrahydro-2H-pyranone and (3R,5S,6S)(3-chlorophenyl)(4-
chlorophenyl)methyltetrahydro-2H-pyranone (4.5 g, 13.4 mmol) and allyl bromide
(3.48 mL, 40.3 mmol) in tetrahydrofuran (22 mL) at -35 °C (acetonitrile/dry ice bath)
was treated with a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M,
17.45 mL, 17.45 mmol). The reaction was allowed to warm to -5 °C over 1 hour and
then was quenched with 50% saturated ammonium chloride. The reaction was diluted
with 100 mL of ethyl acetate and the layers were separated. The organic phase was
washed with brine, dried over magnesium sulfate, filtered and concentrated under a
vacuum to afford the title compound as a white solid upon standing under a vacuum.
Chiral SFC (92% CO , 8% methanol (20 mM ammonia), 5 mL/min, Phenomenex Lux-2
column (Phenomenex, Torrance, CA), 100 bar (10,000 kPa), 40 °C, 5 minute method)
was used to determine that the compound had an enantiomeric ratio of 96:4. (Major
enantiomer: title compound, retention time = 2.45 minutes, 96%; minor enantiomer
(structure not shown, retention time = 2.12 min, 4%). The title compound was
recrystallized by adding to heptane (4.7 g slurried in 40 mL) at reflux and 1.5 mL of
toluene was added dropwise to solubilize. The solution was cooled to 0 °C. The white
solid was filtered and rinsed with 20 mL of cold heptanes to afford a white powder.
Chiral SFC (92% CO , 8% methanol, Phenomenex Lux-2 column, same method as
above) indicated an enantiomeric ratio of 99.2:0.8. (major enantiomer, 2.45 min, 99.2%;
minor enantiomer: 2.12 min, 0.8%)
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H NMR (400 MHz, CDCl , δ ppm): 7.24 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 7.20–7.15
(series of m, 3H), 6.91 (t, J = 2.0 Hz, 1H), 6.78 (br d, J = 7.6 Hz, 1H), 6.60 (m, 2H), 5.84
(ddt, J = 17.6, 10.2, 7.4 Hz, 1H), 5.70 (d, J = 5.3 Hz, 1H), 5.21–5.13 (series of m, 2H),
3.82 (dt, J = 11.7, 4.5 Hz, 1H), 2.62 (ABX J = 13.7 Hz, J = 7.6 Hz, 1H), 2.53 (ABX,
AB AX
J = 13.9 Hz, J = 7.2 Hz, 1H). 1.99 (dd, J = 14.1, 11.9 Hz, 1H), 1.92 (ddd, J = 13.9,
AB BX
3.9, 1.2 Hz, 1H). C NMR (CDCl , 100 MHz, δ ppm): 175.9, 140.2, 134.5, 134.3, 134.0,
132.2, 129.8, 128.6, 128.0, 127.9, 127.8, 126.4, 119.9, 83.9, 44.5, 42.4, 40.7, 31.8, 26.1.
+ -1
MS (ESI) = 375.2 [M + H] . IR = 1730 cm . [ α] (24 °C, c = 1.0, CH Cl ) = -191°.
D 2 2
m.p. 111–114 °C.
Alternative route to make (3S,5R,6R)allyl(3-chlorophenyl)(4-
chlorophenyl)methyltetrahydro-2H-pyranone
Step 1: Isopropyl 4-(3-chlorophenyl)(4-chlorophenyl)methyloxopentanoate
A solution of 2-(3-chlorophenyl)(4-chlorophenyl)ethanone (Step A) (67.4 Kg,
255 mol) in THF (325 L) was dried azeotropically to achieve a water content by Karl
Fisher of 0.05 wt%. Methyl methacrylate (25.8 Kg, 257 mol) was added to the solution
and the mixture was heated to 45 °C. A solution of potassium tert-butoxide (20 wt% in
THF, 14.3 Kg, 25 mol) was added over the course of 30 minutes and the mixture was
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agitated for 6 h. The mixture was cooled to 10 °C and an aqueous solution of citric acid
monohydrate (20 wt%, 35 L) was added in less than 5 minutes. Isopropyl acetate (400 L)
and an aqueous sodium chloride solution (20 wt%, 300 L) were added. The mixture was
agitated for 15 minutes and the phases were separated. The organic phase was distilled
under reduced pressure to generate a distillate volume of 560 L while simultaneously
adding isopropanol (350 L) and producing a solution of methyl 4-(3-chlorophenyl)(4-
chlorophenyl)methyloxopentanoate in isopropanol (54 wt%, 140 kg total solution
mass). The solution had a water content of 0.01 wt% by Karl Fisher. Additional
isopropanol (420 L) and sulfuric acid (53 Kg, 535 mol) were added to the solution. The
mixture was warmed to reflux and agitated for 12 h, during which time 200 L of solvent
were distilled and 200 L of fresh isopropanol were added to the mixture. The mixture
was cooled to 20 °C and water (180 L) was added over the course of 30 minutes.
Isopropyl acetate (270 L) was added and the mixture was agitated for 30 minutes. The
phases were separated and the aqueous phase was extracted using isopropyl acetate (100
L). The combined organic phases were washed with water (200 L) four times. The
organic phase was distilled under reduced pressure to generate a distillate volume of 500
L while simultaneously adding isopropanol (50 L) and producing a solution of isopropyl
4-(3-chlorophenyl)(4-chlorophenyl)methyloxopentanoate in isopropanol (60
wt%, 134 kg total solution mass). The solution had a water content of 0.02 wt% by Karl
Fisher. The title material was obtained in 81% overall yield as a roughly 1:1 mixture if
diastereoisomers.
H NMR (400 MHz, CDCl , δ ppm): 7.70-7.80 (m, 2H), 7.22-7.28 (m, 2H), 7.00-7.18
(series of m, 4H), 4.78-4.96 (m, 1H), 4.42-4.50 (m, 1H), 2.02-2.30 (m, 2H), 1.80-1.95 (m,
1H), 0.99-1.19 (m, 15H).
Step 2. (3S,5R,6R)Allyl(3-chlorophenyl)(4-chlorophenyl)methyltetrahydro-
2H-pyranone
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To a degassed solution of isopropyl 4-(3-chlorophenyl)(4-chlorophenyl)
methyloxopentanoate in isopropanol (60 wt%, 252 kg total solution mass, 151 Kg of
isopropyl ester starting material, 385 mol) was added degassed isopropanol (900 L) and
potassium tert-butoxide (13 Kg, 116 mol). A separately prepared degassed solution of
(S)-RUCY -XylBINAP (also known as RuCl[(S)-diapena][(S)-xylbinap] (230 g, 0.2 mol,
catalyst, Takasago International Corporation, Rockleigh, NJ) in isopropanol (25 L). The
mixture was purged four times with hydrogen at 5 bars (500 kPa) and agitated at 20 °C
for 5.5 h. The hydrogen pressurization was discontinued and the mixture was degassed
with nitrogen. Tetrahydrofuran (460 L) was added to the mixture. A solution of lithium
hydroxide (24 Kg, 576 mol) in water (305 L) was added to the reaction mixture over the
course of 40 minutes and the resultant mixture was agitated at 20 °C for 24 h. A solution
of concentrated hydrochloric acid (79.3 Kg, 11.4 M, 740 mol) in water (690 L) was
added to the mixture over the course of 2 h. Toluene (580 L) was added, the mixture was
agitated for 30 minutes, and the phases were separated. The aqueous was extracted using
toluene (700 L). The combined organic layers were washed with an aqueous solution of
sodium chloride (25 wt%, 700 Kg). The organic phase was distilled at atmospheric
pressure and 100 °C to generate a distillate volume of 2700 L while simultaneously
adding toluene (800 L). Less than 0.05 wt% isopropanol or water (by Karl Fisher) were
left in the mixture after this solvent exchange. Carbonyl diimidazole (59 Kg, 365 mol)
was added to the toluene solution over the course of 2 h and the mixture was agitated at
°C for two additional hours. The mixture was cooled to 10 °C and a solution of
orthophosphoric acid (72 Kg, 545 mol) in water (400 L) was added over the course of 1
h, while maintaining the temperature of the mixture below 20 °C. The mixture was
agitated for 30 minutes, the phases were separated and the organic layer was washed with
an aqueous solution of sodium chloride (25 wt%, 484 Kg). Toluene (400 L) was distilled
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at atmospheric pressure and 110 °C. After cooling of the solution to 20 °C,
tetrahydrofuran (500 L) was added and the water content by Karl Fisher was measured to
be 0.03 wt%. The product solution was cooled to −10 °C and a solution allyl bromide
(66.8 Kg, 552 mol) in tetrahydrofuran (50 L) was added. A lithium hexamethyldisilazide
solution in toluene (255 Kg, 26 wt%, 492 mol) was added over the course of 6 h and the
mixture was stirred at −10 °C for 1 h. The mixture was warmed to 0 °C and an aqueous
solution of orthophosphoric acid (40 wt%, 400 mol) was added over the course of 3 h.
The mixture was warmed to 20 °C. Water (200 L) and dichloromethane (400 L) were
added. The mixture was agitated for 15 minutes and the phases were separated. The
solution was distilled at atmospheric pressure and 100 °C to generate a distillate volume
of 1350 L and the residual toluene in the mixture was measured to be 9.8 wt%. The
mixture was cooled to 70 °C. Diisopropyl ether (85 L), water (26 L), and isopropanol (65
L) were added. The mixture was cooled to 35 °C, agitated for 9 h, cooled to 30 °C, and
filtered. The filtered material was washed three times with heptane (80 L). The solids
were dried at 55 °C for 48 hours to provide 90.1 Kg of (3S,5R,6R)allyl(3-
chlorophenyl)(4-chlorophenyl)methyltetrahydro-2H-pyranone in 63% overall
yield. Chiral HPLC indicated an enantiomeric ratio of 99.95:0.05.
Step E. (S)((2R,3R)(3-Chlorophenyl)(4-chlorophenyl)hydroxypropyl)-N-((S)-
1-hydroxymethylbutanyl)methylpentenamide
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(3S,5R,6R)Allyl(3-chlorophenyl)(4-chlorophenyl)methyltetrahydro-
2H-pyranone (113 g, 300.0 mmol) was combined with (S)aminomethyllbutan
ol (93 g, 900.0 mmol) and the suspension was heated at 100 °C for 5 hours. The reaction
mixture was cooled to room temperature, diluted with ethyl acetate (1000 mL) and
washed with 1N hydrochloric acid (2X), water, and brine. The organic layer was dried
over magnesium sulfate and concentrated under a vacuum to give the title compound as
white solid which was used in next step without further purification.
Step F. (3S,5S,6R,8S)allyl(3-chlorophenyl)(4-chlorophenyl)isopropyl
methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium trifluoromethanesulfonate
Trifluoromethanesulfonic anhydride (57 mL, 339 mmol) was added dropwise
over 60 minutes via addition funnel to a solution of (S)((2R,3R)(3-chlorophenyl)
(4-chlorophenyl)hydroxypropyl)-N-((S)hydroxymethylbutanyl)
methylpentenamide (73.7 g, 154 mmol) and 2,6-dimethylpyridine (78 mL, 678 mmol)
in dichloromethane (700 mL) at -50 °C. The reaction mixture was stirred at -50 °C for
one additional hour and concentrated under a vacuum to provide the title compound as a
reddish solid which was used in next step without further purification.
Step G. (3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylthio)methylbutanyl)methylpiperidinone
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(3S,5S,6R,8S)Allyl(3-chlorophenyl)(4-chlorophenyl)isopropyl
methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium trifluoromethanesulfonate
(736 mg, 1.242 mmol) was weighed into an oven dried 50 mL pear-bottom flask and
dissolved in 20 mL dry toluene. The toluene was removed under a vacuum to remove
trace water in the solid. The process was repeated twice, and the resulting residue was
dried under a strong vacuum.
A solution of sodium isopropyl sulfide was prepared by adding potassium 2-
methylpropanolate (3.0 mL, 3.00 mmol, 1 M solution in tetrahydrofuran) to a solution
of propanethiol (331 mg, 4.35 mmol) in 8 mL dimethylformamide that had been
prepared under nitrogen and cooled to 0 °C. The sulfide solution was allowed to stir at
room temperature for five minutes and was cooled to 0°C. The dry (3S,5S,6R,8S)allyl-
6-(3-chlorophenyl)(4-chlorophenyl)isopropylmethyl-2,3,5,6,7,8-
hexahydrooxazolo[3,2-a]pyridinium trifluoromethanesulfonate (736 mg, 1.242 mmol)
was dissolved in dimethylformamide (8 mL total) and transferred (3 transfers total) via
syringe to the sulfide solution over the course of 5 minutes. After 5 minutes, the ice bath
was removed and the pale orange solution was allowed to warm to room temperature.
After stirring overnight, the mixture was partitioned between ethyl acetate and
saturated ammonium chloride solution. The aqueous phase was saturated in sodium
chloride and back-extracted three times. The combined organics were washed twice with
saturated sodium bicarbonate, twice with brine, dried over sodium sulfate, filtered, and
concentrated under a vacuum to provide a residue that was purified by silica gel column
chromatography (80 g column, gradient elution of 0% to 50 % ethyl acetate in hexanes).
Method for making
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Step A. (3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
hydroxymethylbutanyl)methylpiperidinone
Lithium hydroxide hydrate (64.6 g, 1540 mmol) was added portionwise, over a 5
minute period, to a solution of (3S,5S,6R,8S)allyl(3-chlorophenyl)(4-
chlorophenyl)isopropylmethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium
trifluoromethanesulfonate (Step F above) dissolved in tetrahydrofuran (500 ml) and water
(300 ml). The reaction mixture was stirred at room temperature for 1 hour and
concentrated under a vacuum. The residue was dissolved in ethyl acetate (ca. 1.3 L) and
the layers were separated. The organic layer was washed with 1N hydrochloric acid (ice
cooled, with enough hydrochloric acid to protonate and remove any remaining 2,6-
dimethylpyridine (300 mL x 2)), water and brine. The solvent was removed under a
vacuum to give a residue which was purified by silica gel column chromatography (1500
g column, gradient elution of 0% to 50% ethyl acetate in hexanes. The product was also
crystallized from cyclohexane.
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Step B. (3S,5S,6R,8S)Allyl(3-chlorophenyl)(4-chlorophenyl)
isopropylmethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium 4-
methylbenzenesulfonate
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)hydroxy
methylbutanyl)methylpiperidinone (49.77 g, 98 mmol) was transferred to a 1000
mL flask containing 4-methylbenzenesulfonic acid hydrate (19.27 g, 101 mmol) and a
stirring bar. The reactants were suspended in toluene (230 mL). The flask was equipped
with a Dean Stark trap and reflux condenser, and the stirred mixture was heated at reflux
in a preheated bath. After 1 hour, the solvent was carefully removed under a vacuum and
the resulting residue was further dried under high vacuum. The title compound was taken
to the next step without purification.
Step C. (3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone
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(3S,5S,6R,8S)Allyl(3-chlorophenyl)(4-chlorophenyl)isopropyl
methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium 4-methylbenzenesulfonate,
dry, powdered potassium carbonate (26.9 g, 195 mmol) and propanethiol (14 ml, 150
mmol) were added along with 200 mL freshly sparged dimethyformamide. The mixture
was heated under argon at 50 °C. After about 21 hours, a solution of meta-
chloroperbenzoic acid (68.2 g, 77% pure by weight, in 100 mL dimethylformamide) was
transferred to a dropping funnel and rapidly added to the stirred reaction mixture while
the flask was immersed in an ice bath. After 5 minutes, the resulting yellow solution was
allowed to warm to room temperature. After 10 minutes, additional meta-
chloroperbenzoic acid (12 g, 77% wt %) was added as a solid and the mixture was stirred
at room temperature. Upon completion, the mixture was poured into ethyl acetate and
washed with 1 M sodium hydroxide (500 mL) that had been poured into ice. The
aqueous phase was back-extracted three times and washed with additional 1 M NaOH
(500 mL, also poured into ice). The aqueous layer was washed once with ethyl acetate
and the organics were combined. Sodium thiosulfate (1 M in water, 250 mL) was added
to the organics in a large Erlenmeyer flask, and the mixture was stirred for twenty
minutes. The organic phase was washed again with sodium thiosulfate (1 M in water,
250 mL) and the mixture was allowed to stand over the weekend. The organics were
concentrated to ca. 500 mL, then sequentially washed with 10% aqueous citric acid, 1 M
sodium hydroxide, and brine. The organics were dried over sodium sulfate, filtered, and
concentrated to give the crude product. The residue was purified by flash column
chromatography (1.5 kg silica gel column, gradient elution of 0% to 50% ethyl acetate in
hexanes) to give the title compound as a white solid.
Synthesis of Compound A (Synthesis A)
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid
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Ruthenium(III) chloride trihydrate (22 mg, 0.084 mmol) and sodium periodate
(1.12 g, 5.24 mmol) were added to a mixture of (3S,5R,6S)allyl(3-chlorophenyl)
(4-chlorophenyl)((S)(isopropylthio)methylbutanyl)methylpiperidinone
(390 mg, 0.752 mmol) in acetonitrile (4.0 mL), carbon tetrachloride (4.0 mL),and water
(6.0 mL). The resulting dark brown mixture was vigorously stirred at ambient
temperature overnight. The mixture was filtered through a pad of diatomaceous earth,
washing with ethyl acetate. The filtrate was partitioned between 2 M HCl and ethyl
acetate. The aqueous phase was back-extracted twice with ethyl acetate, and the
combined organics were washed with brine, dried over sodium sulfate, filtered, and
concentrated under a vacuum to a residue that was purified by flash chromatography (40
g silica gel column, gradient elution of 0% to 15% isopropanol in hexanes). Fractions
containing the desired product were combined, stripped of solvent, redissolved in
minimal ACN/water, frozen, and lyophilized to give a white powder.
Subsequently, a mixture of (3S,5R,6S)allyl(3-chlorophenyl)(4-
chlorophenyl)((S)(isopropylthio)methylbutanyl)methylpiperidinone
(388 mg, 0.748 mmol), ruthenium(III) chloride trihydrate (19.56 mg, 0.075 mmol), and
sodium periodate (1.15 g, 5.38 mmol) in acetonitrile (4 mL), carbon tetrachloride (4.00
mL), and water (4.00 mL) was vigorously stirred at ambient temperature. After four
hours, the mixture was filtered through a pad of diatomaceous earth, and the filtrate was
partitioned between ethyl acetate and 2 M HCl. The aqueous phase was back-extracted
twice with ethyl acetate, and the combined organics were washed with brine, dried over
sodium sulfate, filtered, and concentrated under a vacuum to a residue. The residue was
purified by flash chromatography (40 g silica gel column, gradient elution of 0% to 15%
isopropanol in hexanes). Fractions containing the product were concentrated and
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combined with the solid obtained in the prior experiment. The combined material was
dissolved in minimal acetonitrile/water, frozen, and lyophilized overnight to give a white
solid.
The resulting XRPD pattern was consistent with the amorphous form (Figure 2) .
Synthesis of Compound A (Synthesis B)
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid
Sodium periodate (2.85 g, 13.32 mmol) and ruthenium(III) chloride trihydrate
(0.049 g, 0.189 mmol) were added to a mixture of (3S,5R,6S)allyl(3-chlorophenyl)-
6-(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methylpiperidin-
2-one (1.73 g, 3.14 mmol) in acetonitrile (18 mL), carbon tetrachloride (18 mL), and
water (27 mL). The mixture was stirred vigorously at room temperature for 25 hours. The
mixture was diluted with 2M HCl and filtered through a pad of diatomaceous earth and
rinsed with ethyl acetate. The organic layer was separated, washed with brine, dried over
sodium sulfate, filtered, and concentrated under a vacuum. The material was purified
twice by flash chromatography (120g silica gel, gradient elution of 0% to 20%
isopropanol in hexanes; 120 g column, gradient elution of 0% to 15% gradient
isopropanol in hexanes). It was purified once more by flash chromatography (220 g
silica gel; gradient elution 0% to 20% isopropanol in hexanes, 45 minutes) using a
method in which the purest fractions were concentrated and set aside and mixed fractions
were pooled and resubjected to the chromatography.
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Subsequently, a mixture of (3S,5R,6S)allyl(3-chlorophenyl)(4-
chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methylpiperidinone
(4.1 g, 7.45 mmol), ruthenium(III) chloride trihydrate (0.120 g, 0.459 mmol), and sodium
periodate (6.73 g, 31.5 mmol) in acetonitrile (40 mL), carbon tetrachloride (40 mL), and
water (60 mL) was vigorously stirred at ambient temperature for 23 hours. The reaction
was diluted by addition of 2 M aqueous HCl and filtered through a diatomaceous earth
pad, washing with copious ethyl acetate. Most of the organics were removed under a
vacuum. The crude product was extracted into ethyl acetate, washed with brine, dried
over sodium sulfate, filtered, and concentrated to a residue that was purified twice by
flash chromatography (330 g silica gel column, gradient elution of 0% to 20%
isopropanol in hexanes; 330 g silica gel column, gradient elution of 0% to 20%
isopropanol in hexanes) to give an off-white foam. The material was purified by flash
chromatography three additional times (220 g silica gel column; gradient elution 0% to
% isopropanol in hexanes, 45 minutes) using a method in which the purest fractions
were concentrated and set aside and mixed fractions were pooled and resubjected to the
chromatography.
Mixed fractions from both experiments were combined and purified by flash
chromatography twice more (220 g silica gel column; gradient elution 0% to 20%
isopropanol in hexanes, 45 minutes), and again the pure fractions were set aside.
All of the pure fractions were combined, concentrated under a vacuum, dissolved in
minimal acetonitrile/water and lyophilized.
The XRPD pattern was consistent with the amorphous form (Figure 2).
Synthesis of Compound A (Synthesis C)
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid
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(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (5.05 g, 9.17 mmol)
was weighed into a 500 mL round bottom flask containing a large stir bar and 2.04 g
sodium periodate (2.04 g). The mixture was diluted with carbon tetrachloride (52 mL),
acetonitrile, (52 mL) and water (78 mL). The flask was immersed in a room temperature
water bath and the internal temperature was monitored with a digital thermocouple.
Ruthenium chloride hydrate (approximately 50 mg) was added in a single portion.
The internal temperature rose to 22 °C, then ice was added to the bath to cool the
mixture. Additional ruthenium chloride hydrate (25 mg) was added 3 minutes later.
After stirring for a total of thirty minutes, Three portions of sodium periodate (2.08 g,
2.07 g and 2.08 g) were slowly added on 15 minute intervals. The temperature was kept
below 19 °C, and ice was quickly added to the bath if the internal temperature began to
rise. The mixture was stirred at ambient temperature overnight. The mixture was filtered
through a pad of diatomaceous earth and the filter cake was washed copiously with ethyl
acetate. The filtrate was concentrated under a vacuum and partitioned between 2 M HCl
(100 mL) and ethyl acetate (200 mL).
Two rounds of flash column chromatography (330 g silica gel, then 220 g silica
gel, gradient elution of 0% to 20% isopropanol in hexanes) provided the title compound.
A portion of this material was lyophilized from acetonitrile and water. The less pure
fractions were repurified by two additional rounds of flash column chromatography (220
g then 330 g silica gel columns, gradient elution of 0% to 20% isopropanol in hexanes).
The most pure fractions from both runs were combined, concentrated under a vacuum
and lyophilized from acetonitrile and water to give the title compound.
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The XRPD pattern was consistent with the amorphous form (Figure 2).
The three syntheses above resulted in amorphous compound A. No crystalline
form was obtained. Attempts to crystallize amorphous compound A made in the above
procedure (Synthesis C) are summarized in Table 1A below.
Table 1A
Mass of Volume Solvent composition Condition Observation
Compound solvent
A (mg) (mL)
7.5 1.0 Water/ethanol (90/10 Slurry at Amorphous
v/v)) room by XRPD
temperature after 2
months
8.0 1.0 Water/dimethyl Slurry at Amorphous
formamide (90/10 room by XRPD
(v/v)) temperature after 2
months
8.7 1.0 Heptane/toluene Slurry at Amorphous
(98/2 (v/v)) room by XRPD
temperature after 2
months
8.7 1.0 Heptane/methyl-t- Slurry at Amorphous
butylether (98/2 room by XRPD
(v/v)) temperature after 2
months
9.5 1.0 Cyclohexane/toluene Slurry at Amorphous
(98/2 (v/v)) room by XRPD
temperature after 27 days
.5 1.0 Cyclohexane/methyl-Slurry at Amorphous
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t-butylether (98/2 room by XRPD
(v/v)) temperature after 27 days
The amorphous compound made in the procedure above (Synthesis C) was used
in a high-throughput (HT) polymorph screen. The starting material was observed to be
amorphous by XRPD. In the form screening experiment, of 192 conditions tested, only 1
crystalline sample was observed representing one form shown in Figure 5 (compound A
crystalline Form 2). The form identified by the HTS screen is not consistent with
compound A crystalline anhydrous.
The compound loading amount was about 8 mg/well. Amorphous compound A
(Synthesis C) was dispensed into each well on a 96-well glass vial rack. The solid
samples in the vials were then transferred to a 96-well crystallization source plate.
Per library design, crystallization solvents were dispensed into the source plate
(960 μL/vial) (Table 1 and Table 2). After solvent addition, the source plate was
sonicated for 30 minutes, then heated at 55 C with stirring for 30 minutes and kept at 25
C without stirring for 30 minutes. Maintaining at 25 ºC, the solvents in the source plate
were aspirated and filtered into a filtration plate. The filtrate was subsequently aspirated
and dispensed into three crystallization plates (evaporation, precipitation, cooling). After
completion of 96-well filtration, the source plate was kept stirring at 25 ºC for 8 hours.
The evaporation plate (200 μL/well filtrate) was left open at ambient for 24 hours. The
sealed precipitation plate (150 μL/well filtrate injected into pre-filled 150 μL anti-
solvent; either water or heptane (Table 1)) was cooled linearly from 25 ºC to 5 ºC in 8
hours and held at 5 ºC for 8 hours. The sealed cooling plate (300 μL/well filtrate) was
started at 25 ºC, cooled to 5 ºC in 8 hours, and held at 5 ºC for additional 8 hours. At the
end of crystallization, the precipitation and cooling plates were centrifuged at 5 ºC for 10
min at 1500 rpm, and the supernatant in each well of both plates was aspirated and
discarded. Prior to dissembling each of 4 plates to collect the crystal samples on its 96-
well glass substrates, wick paper was used to dip into each well to ensure the dryness.
Table 1. Solvent Dispense Table For HT Form Screen. All Solvent Mixtures
Are (V/V).
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7 8 9 10 11 12
AntiWater Water Water Water Heptane Heptane
solv
DCE/Hepta DCE/hepta Toluene/hept MTBE/hepta THF/heptane THF.heptane
ne (5/95) ne (10/90) ane (5/95) ne (5/95) (20/80) (40/60)
THF/Hepta THF/hepta Toluene/hept MTBE DMF/heptan DMF/heptan
ne (5/95) ne (10/90 ane (10/90) (10/90) e (20/80) e (40/60)
IPAc/Hepta IPAc/hepta Acetic acid MEK/heptan Acetone/hept Acetone/hept
ne (5/95) ne (10/90) e (5/95) ane (20/80) ane (40/60)
IPA/Heptan IPA/heptanHeptane MEK/heptan Acetonitrile/ Acetonitrile/
e (5/95) e (10/90)e e (10/90) heptane heptane
(20/80) (40/60)
DCE/cyclo DCE/cyclo Toluene/cycl MTBE/cyclo Ethanol/cycl Ethanol/cycl
hexane hexane ohexane hexane ohexane ohexane
(5/95) (10/90) (5/95) (5/95) (20/80) (40/60)
THF/cyclo THF/cyclo Toluene/cycl MTBE/cyclo IPA/cyclohe IPA/cyclohe
hexane hexane ohexane hexane xane (20/80) xane (40/60)
(5/95) (10/90) 10/90) (10/90)
IPAc/cyclo IPAc/cyclo Acetic acid MEK/cycloh NMP/cycloh NMP/cycloh
hexane hexane exane (5/95) exane exane
(5/95) (10/90) (20/80) (40/60)
IPA/cycloh IPA/cycloh cyclohexane MEK/cyclohwater 0.01M
exane exane exane NaOH in
(5/95) (10/90) (10/90) water
Birefringence images were collected for each well of the four 96-well plates using
cross-polarized light optical microscopy. XRPD patterns were collected on a Bruker D8
Discover X-ray diffraction system fitted with a motorized xyz sample stage and a general
area detector diffraction system (GADDS )area detector. The screen samples on a flat
glass plate were mapped and a sample area of 1 mm was scanned in oscillating mode for
3 minutes from 5º to 48º 2 θ using CuK α radiation (40 kv, 40 mA) through a graphite
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monochromator and a collimator of 0.5 mm pinhole. In addition to the screen plates the
starting material, was also analyzed using this instrument and method.
In addition, HT crystallization experiments using bases as additives were
conducted. Stoichiometric amounts of CH OK, CH ONa, Tris and ammonium hydroxide
were added as MeOH solutions, Ca(OH) , lysine, diethanolamine, and diethylamine were
added as aqueous solutions and the solvent evaporated under a stream of blown nitrogen
prior to solvent dispensing.
Per library design, crystallization solvents were dispensed into the source plate
(960 μL/well). After solvent addition, the source plate was sonicated for 30 minutes, then
heated at 55ºC with stirring for 30 minutes and kept at 25 ºC without stirring for 30
minutes. Maintaining at 25 ºC, the solvents in the source plate were aspirated and filtered
into a filtration plate. The filtrate was subsequently aspirated and dispensed into three
crystallization plates (evaporation, precipitation, cooling). After completion of 96-well
filtration, the source plate was kept stirring at 25ºC for 8 hours. The evaporation plate
(200 μL/well filtrate) was left open at ambient for 24 hours. The sealed precipitation plate
(150 μL/well filtrate injected into pre-filled 150 μL anti-solvent) was cooled linearly
from 25ºC to 5ºC in 8 hours and held at 5ºC for 8 hours. The sealed cooling plate (300
μL/well filtrate) was started at 25ºC, cubic cooled to 5ºC in 8 hours, and held at 5ºC for
additional 8 hours. At the end of crystallization, the precipitation and cooling plates were
centrifuged at 5ºC for 10 min at 1500 rpm, and the supernatant in each well of both plates
was aspirated and discarded. Prior to dissembling each of 4 plates to collect the crystal
samples on its 96-well glass substrates, wick paper was used to dip into each well to
ensure the dryness.
None of these experiments resulted in any crystalline salts. Seven (7) samples
yielded a crystalline form consistent with the XRPD pattern of Figure 4 (compound A
crystalline form 1). All crystalline samples observed in this part of the screen were
processed by evaporation. Samples evaporated from IPA with CH OK, from MeCN with
Tris, from THF/H O (90/10) with lysine, from IPA with lysine, from THF/water (90/10)
with diethanolamine, from MeCN with diethanolamine, and from toluene/MeOH (50/50)
with diethanol amine gave crystalline samples that were consistent with Compound A
Crystalline Form 1 by XRPD.
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Table 2. Solvent Dispense Table For HT Form Screen. All Solvent Mixtures Are (V/V).
1 2 3 4 5 6
Counterion\anti- Heptane Heptane Heptane Heptane Heptane Heptane
solvent
Ammonia THF THF/H O IPA MeCN IPA Toluene/MeOH
(90/10) (50/50)
CHOK THF THF/H O IPA MeCN IPA Toluene/MeOH
B 3 2
(90/10) (50/50)
C CH3ONa THF THF/H2O IPA MeCN IPA Toluene/MeOH
(90/10) (50/50)
Ca(OH) THF THF/H O IPA MeCN IPA Toluene/MeOH
D 2 2
(90/10) (50/50)
(0.5 eq)
E Tris THF THF/H O IPA MeCN IPA Toluene/MeOH
(90/10) (50/50)
Lysine THF THF/H O EtOH/H O MeCN IPA MeCH/H O
F 2 2 2
(90/10) (90/10) (90/10)
Dienthanolamine THF THF/H O IPA MeCN IPA Toluene/MeOH
(90/10) (50/50)
Diethylamine THF THF/H O IPA MeCN IPA Toluene/MeOH
(90/10) (50/50)
Crystallization Studies
Experiment 1
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid (100 mg) was placed in a 13
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mm test tube, and 1 mL of 40% ethanol in water was added at room temperature. The
material did not dissolve, even after heating at reflux. An additional 2 mL of 40%
ethanol in water was added, and still the material did not completely dissolve after reflux.
Ethanol was added dropwise until the material went into solution. The solution was
slowly cooled. The material oiled-out before reaching room temperature.
Experiment 2
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid (100 mg) was placed in a 13
mm test tube and dissolved in 1 mL ethanol and heated to reflux. Water was added
dropwise until the cloudiness that formed upon addition took a few seconds to disappear
(1 mL water, total, was added). The solution was cooled slowly. It oiled-out before
reaching room temperature. Additional ethanol (0.2 mL) was added, and the mixture was
heated to reflux. The material oiled out upon slow cooling to room temperature.
Additional ethanol (0.2 mL) was added, and the mixture was heated at reflux. The
mixture did not oil out after cooling to room temperature, but no crystals formed. After
1.5 hours at room temperature the solution was placed in the freezer, and the material
oiled-out.
Experiment 3
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid (100 mg, white foam) was
placed in a 13 mm test tube, and 1 mL of 60% ethanol in water was added at room
temperature. The foam either completely dissolved or mostly dissolved before
precipitating out as a white solid. The solid was collected by vacuum filtration.
Analysis showed the solid was more pure than the starting material. 2-((3R,5R,6S)(3-
Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)
methyloxopiperidinyl)acetic acid (100 mg, white foam) was placed in a 13 mm test
tube, and 1 mL of 60% ethanol in water was added. The mixture was stirred at room
temperature during addition and the material briefly dissolved before precipitating as a
white solid. The mixture was heated at reflux to dissolve the material and slowly cooled
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to room temperature. After stirring overnight at room temperature, no crystals had
formed. The solution was seeded with solid prepared in the preceding experiment, and
solid formed immediately. The crystals were collected by vacuum filtration and washed
with a cold solution of 60% ethanol in water to provide a white crystalline solid.
Analysis showed further improvement to the purity, and X-ray diffraction indicated the
material was crystalline. The XRPD was consistent with Compound A ethanolate
(Figure 6).
Experiment 4
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid (100 mg, white foam) was
placed in a 13 mm test tube, and 0.75 mL of 60% ethanol in water was added. The
mixture was stirred at room temperature during addition, and after a few minutes, the
foam was replaced by a white crystalline solid. The mixture was heated to reflux, slowly
cooled to room temperature without stirring. After a few days, large crystals had formed.
They were collected by vacuum filtration to provide the title compound as colorless
needles. A single crystal X-ray structure was obtained and was consistent with
compound A ethanolate (Figure 6).
Synthesis of Compound A Ethanolate
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methyloxopiperidinyl)acetic acid
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (86.8 g, 158 mmol)
was dissolved in acetonitrile (300 mL) and ethyl acetate (300 mL) and transferred to a 2
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L 3-neck Morton flask. Water (450 mL) was added. The flask was equipped with a
thermocouple and magnetic stir bar and then submerged in a water bath. Ruthenium(III)
chloride hydrate (0.782 g, 3.47 mmol) was added followed by sodium periodate (33.75
g). The temperature rose from 17 °C to 22 °C. After 35 minutes, a second aliquot of
sodium periodate (33.75 g) was added and the temperature increased from 21 °C to 25
°C. After 38 minutes, a third aliquot of sodium periodate (33.75 g) was added, and the
temperature increased from 22 °C to 28 °C over 12 minutes. Ice was added to the water
bath and once the mixture had cooled (approximately 8 minutes) a third aliquot of sodium
periodate (35 g) was added. The temperature increased from 21 °C to 25 °C. After
stirring at room temperature overnight, sodium periodate (20g) was added, and 4 hours
later, another aliquot of sodium periodate (20g) was added. After one hour, the mixture
was stirred at room temperature with an overhead stirrer. Then the reaction mixture was
filtered through a Büchner funnel and the filter cake was rinsed with ethyl acetate. The
cake was dried overnight in the vacuum filtration apparatus.
The material was added to a large separatory funnel with water (1 L) and ethyl
acetate (500 mL). Brine was added (50 mL). After 5 hours, the phases were separated
and the organic phase was washed with 10% sodium bisulfite solution. After standing
overnight, the phases were separated and the organic phase was washed with brine (1 L).
After 30 minutes the organic phase was separated, dried over sodium sulfate, filtered and
concentrated under a vacuum. The crude material was purified by flash column
chromatography (1.5 kg silica gel column, gradient elution of 0% to 50% isopropanol in
hexanes) to provide the title compound as a white foam.
The resulting 2-((3R,5R,6S)(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methyloxopiperidinyl)acetic acid was
dissolved in ethanol and transferred to a 500 mL pear shaped flask. The solvent was
removed under a vacuum to provide a white solid. A solution of 60% ethanol in water
(360 mL) was added and the mixture was heated to 90 °C to dissolve all of the material.
The solution was slowly cooled and seeded at 50 °C, 45 °C, and 40 °C with
approximately 5 mg of crystalline product but the material dissolved. The solution was
seeded at 37 °C with approximately 5 mg crystalline product and the material did not
dissolve. The material was slowly cooled to room temperature and placed in the freezer
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overnight. Crystals were collected by vacuum filtration through a Büchner funnel and
washed with cold 60% ethanol in water (approximately 100 mL). The material was dried
by pulling air through the filter bed for 4 hours to provide a white solid (80.6 g). The
material was placed under a vacuum at room temperature for two days. Next, the
material was placed on a rotary evaporator at 50 °C at 15 Torr (2 kPa) for 4 hours. It was
then placed under a vacuum at 50 °C overnight. NMR analysis indicated 6 wt% ethanol
was present in the sample.
A small portion of the sample (100 mg) was slurried in water (0.5 mL) overnight.
The solid was collected by vacuum filtration and washed with water to provide a white
solid. NMR analysis indicated that 2.9 wt% ethanol was present. The material was re-
slurried in water (0.5 mL) overnight and collected by vacuum filtration to provide a white
solid. NMR analysis indicated that 0.5 wt% ethanol was present. X-ray diffraction
indicated that the material had become amorphous.
The remainder of the material was heated at 55 °C under a vacuum overnight.
After cooling to room temperature, it was slurried in water (250 mL) and stirred
mechanically. Aliquots were periodically removed and the solid was measured for
ethanol content. After 40 hours, additional water (100 mL) was added and the material
was stirred at room temperature for an additional 4.5 days. The material was collected by
vacuum filtration to provide a white granular solid which was resuspended in water (350
mL) and mechanically stirred at room temperature for about 8 hours. The material was
collected by vacuum filtration through a Büchner funnel to provide a white solid. The
solid was dried by pulling air through the filter bed for 6 hours and then it was allowed sit
open to the atmosphere in the hood overnight to provide a white solid containing 3.5 wt%
ethanol.
Manual Polymorph Screening
Samples were prepared according to the following general procedure.
Approximately 20 mg of compound A ethanolate were weighted and added to a 1 dram
vial. Solvent, 1 mL, was added to the vial. The samples were allowed to slurry.
Solvents tested were water/ethanol (80/20, v/v), water/ethanol (70/30, v/v), water/ethanol
(60/40, v/v), water/1-propanol (90/10, v/v), water/1-propanol (80/20, v/v), water/1-
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propanol (70/30, v/v), water/acetonitrile (95/5, v/v), water/acetonitrile (90/10, v/v),
water/acetone (95/5, v/v), water/acetone (90/10, v/v), heptane, heptane/isopropyl acetate
(99/1, v/v), cyclohexane, cyclohexane/isopropyl acetate (99/1, v/v). Observations were
noted at the start of the experiment and on days 3, 7, 10, 13 and 19. Samples were
analyzed by XRPD on days 7 and 10, 13, or 19. Results are given in Table 3. The XRPD
was consistent with Compound A ethanolate (Figure 6), Compound A Propanol Solvate
(Figure 7), Compound A Crystalline Anhydrous (Figure 1) or Compound A Amorphous
(Figure 2).
Table 3
Sample Solvent Crystalline Form
1 water/ethanol (80/20, v/v) Yes Ethanolate
2 water/ethanol (70/30, v/v) Yes Ethanolate
3 water/ethanol (60/40, v/v) Yes Ethanolate
4 water/1-propanol (90/10, Yes Propanol
v/v) Solvate
water/1-propanol (80/20, Yes Propanol
v/v) Solvate
6 water/1-propanol (70/30, Yes Propanol
v/v) Solvate
7 water/acetonitrile (95/5, Yes Crystalline
v/v) Anhydrous
8 water/acetonitrile (90/10, Yes Crystalline
v/v) Anhydrous
9 water/acetone (95/5, v/v) Yes Crystalline
Anhydrous
water/acetone (90/10, v/v) No Amorphous
11 heptane Yes Crystalline
Anhydrous
12 heptane/isopropyl acetate Yes Crystalline
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(99/1, v/v) Anhydrous
13 cyclohexane Yes Crystalline
Anhydrous
14 cyclohexane/isopropyl Yes Crystalline
acetate (99/1, v/v) Anhydrous
Synthesis of Compound A Ethanolate
2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)
methylbutanyl)methyloxopiperidinyl)acetic acid
A number of batches were processed in series and combined for the final purification.
Batch 1:
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (80.6 g, 146 mmol)
was dissolved in acetonitrile (280 mL) and ethyl acetate (280 mL) and transferred to a 2
L 3-neck Morton flask. Water (418 mL) was added. The flask was equipped with a
thermocouple and submerged in a water bath. Ruthenium(III) chloride hydrate (0.726 g,
3.22 mmol) was added followed by sodium periodate (31.25 g). The temperature rose
from 17 °C to 24 °C, and ice was added to a water bath to control the temperature. After
minutes, a second aliquot of sodium periodate (31.25 g) was added and the
temperature increased from 18 °C to 20 °C. After 15 minutes a third aliquot of sodium
periodate (31.25 g) was added and the temperature increased from 18 °C to 25.6 °C.
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Additional ice was added to the water bath. After 10 minutes, a fourth aliquot of sodium
periodate (31.25 g) was added. After stirring for two hours sodium periodate was added
(15g) and after 90 minutes sodium periodate (6 g) was added again. After one hour, the
liquid was decanted into a large separatory funnel. The solid material was rinsed with
ethyl acetate (1.5 L), added to the separatory funnel, and washed with 10% sodium
bisulfite (1 L). The organic layer was washed with brine and the phases were allowed to
separate overnight. The solid material was re-slurried with ethyl acetate (300 mL) and
filtered. The filtrate was washed with 10% sodium bisulfite and brine. The combined
organic layers were dried over sodium sulfate, filtered, and concentrated. The crude
material was purified by flash column chromatography (1.5 kg silica gel column, gradient
elution of 0% to 50% isopropanol in hexanes) to provide the title compound.
Batch 2:
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (90.4 g, 162 mmol)
was dissolved in acetonitrile (308 mL) and ethyl acetate (308 mL) and transferred to a 2
L 3-neck Morton flask. Water (463 mL) was added. The flask was equipped with a
thermocouple and a mechanical stirrer. Ruthenium(III) chloride hydrate (0.803 g, 3.56
mmol) was added and the reaction vessel was submerged in a cool water bath. Sodium
periodate was added in portions (first portion: 34.0 g), and the temperature was
monitored to keep the reaction mixture below 25 °C. Ice was periodically added to the
water bath to assist in temperature control.
After stirring for 12 minutes, a second portion was added (39.7 g), followed 28
minutes later by a third portion (36.6 g), and after 13 minutes, a forth portion (35.6 g).
The mixture was stirred overnight at room temperature, and a fifth portion was added (15
g), and after 25 minutes, a sixth portion (16.5 g) was added. After about 15 minutes, the
reaction mixture was decanted into a separatory funnel and the remaining solid was
rinsed with ethyl acetate (2 x 1 L). The organics were collected and washed with 10%
sodium bisulfite (1 L). The organic layer was washed with brine (1 L) and dried over
sodium sulfate, filtered and concentrated. The crude material was purified by flash
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column chromatography (1.5 kg silica gel column, gradient elution of 0% to 20%
isopropanol in hexanes) to provide the title compound.
Batch 3:
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (131.8 g, 239 mmol)
was dissolved in acetonitrile (402 mL) and ethyl acetate (402 mL) and transferred to a 2
L 3-neck Morton flask. Water (603 mL) was added. The flask was equipped with a
thermocouple and a mechanical stirrer. Ruthenium(III) chloride hydrate (1.079 g, 4.79
mmol) was added and the reaction vessel was submerged in a cool water bath. Sodium
periodate was added in portions (first portion: 59 g), and the temperature was monitored
to keep the reaction mixture below 25 °C. Ice was periodically added to the water bath to
assist in temperature control.
After stirring for 45 minutes, a second portion was added (50 g), followed 30
minutes later by a third portion (22 g), after 20 minutes by a forth portion (30 g), and
after 20 minutes by a fifth portion (50 g). After stirring for two hours a sixth portion (20
g) was added, followed 20 minutes later by a seventh portion (10 g) and 20 minutes after
that by an eighth portion (10 g). After 15 minutes, the reaction mixture was decanted into
a separatory funnel and the remaining solid was rinsed with ethyl acetate (2 x 1 L). The
organics were collected and washed with 10% sodium bisulfite (1 L). The organic layer
was washed with brine (1 L) and dried over sodium sulfate, filtered and concentrated. To
remove particulates, the material was dissolved in dichloromethane, filtered and
concentrated. The crude material was divided into two portions and each was purified by
flash column chromatography (1.5 kg silica gel column, gradient elution of 0% to 20%
isopropanol in hexanes) to provide the title compound.
Batch 4:
(3S,5R,6S)Allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (87.3 g, 159 mmol)
was dissolved in acetonitrile (302 mL) and ethyl acetate (302 mL) and transferred to a 2
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L 3-neck Morton flask. Water (453 mL) was added. The flask was equipped with a
thermocouple and a mechanical stirrer. Ruthenium(III) chloride hydrate (0.786 g, 3.49
mmol) was added and the reaction vessel was submerged in a cool water bath. Sodium
periodate was added in portions (first portion: 34.5 g), and the temperature was
monitored to keep the reaction mixture below 25 °C. Ice was periodically added to the
water bath to assist in temperature control.
After stirring for 1 hour, a second portion was added (34.4 g), followed 30
minutes later by a third portion (34.5 g), and after 30 minutes by a forth portion (34.5 g).
The maximum temperature was 27 °C. After stirring for 3.5 hours a fifth portion (20 g)
was added, followed 1 hour later by a sixth portion (5 g). After 15 minutes, the reaction
mixture was decanted into a separatory funnel and the remaining solid was rinsed with
ethyl acetate (2 x 1 L). The organics were collected and washed with 10% sodium
bisulfite (1 L). The organic layer was washed with brine (0.5 L) and dried over sodium
sulfate, filtered and concentrated. The crude material was purified by flash column
chromatography (Biotage SNAP cart, 1.5 kg silica gel column, gradient elution of 0% to
50% isopropanol in hexanes) to provide the title compound. Impure fractions were
repurified by flash column chromatography (1.5 kg silica gel column, gradient elution of
0% to 20% isopropanol in hexanes) to provide the title compound.
Batch 5:
Impure fractions from Batches 1 through 4 were repurified by multiple iterations
of flash column chromatography (amount of silica gel varied from 330 g to 1.5 kg,
gradient elution of 0% to 20% isopropanol in hexanes) to provide the title compound.
Final Purification:
Material from Batches 1 through 5 were combined with a portion of the material
from another synthesis, 18 g. 2-((3R,5R,6S)(3-Chlorophenyl)(4-chlorophenyl)
((S)(isopropylsulfonyl)methylbutanyl)methyloxopiperidinyl)acetic acid
(400 g) was dissolved in ethanol and concentrated under a vacuum to provide a white
crystalline solid. A solution of 60% ethanol in water (1900 mL) was added and the
mixture was heated to 80 °C while rotating on a rotary evaporator at atmospheric
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pressure. After the material had dissolved, the solution was slowly cooled while
mechanically stirring the flask. After 3 hours, the temperature had cooled to 50 °C and
the material was seeded with crystalline 2-((3R,5R,6S)(3-chlorophenyl)(4-
chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methyl
oxopiperidinyl)acetic acid. The solid completely dissolved. After 30 minutes, the
solution was re-seeded (45 °C) and the material began to slowly crystallize. Once the
mixture had cooled to room temperature, it was placed in the freezer overnight. The
crystals were collected by vacuum filtration through a Büchner funnel. The filter cake
was washed with ice-cold 60% ethanol in water and dried under a vacuum on the
Büchner funnel to provide a white solid. NMR analysis indicated that 7.8 wt% ethanol
was present (1 molar equivalent). Water (deionized and filtered (Milli-Q filtration
system, EMD Millipore, Billerica, MA)) was added to the solid and the mixture was
mechanically stirred at room temperature overnight. Aliquots were periodically removed
to monitor the ethanol content of the solid. After three days, the material was vacuum
filtered through a Büchner funnel, washed with water (deionized and filtered as described
above) and dried by pulling a vacuum through the filter cake for 3 hours. The filter cake
was air-dried for two days in the funnel, then, it was transferred to a 2 L flask as a white
solid and dried under a vacuum overnight. NMR analysis indicated that 6.2 wt% ethanol
was present.
The XRPD pattern was consistent with Compound A ethanolate (Figure 6).
H NMR (500 MHz, DMSO-d , δ ppm): 12.43 (br s, 1H), 7.72 (br, 1H), 7.37 (br, 2H),
7.23 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.02 (t, J = 1.9, 1.9 Hz, 1H), 6.99 (br,
1H), 6.98 (dt, J = 7.7, 1.4, 1.4 Hz, 1H), 5.01 (d, J = 11.2 Hz, 1H), 3.84 (dd, J = 14.0, 10.1
Hz, 1H), 3.59 (ddd, J = 13.7, 11.3, 2.9 Hz, 1H), 3.39 (m, 1H), 3.18 (dd, J = 13.9, 1.3 Hz,
1H), 3.06 (ddd, J = 10.6, 8.1, 1.6 Hz, 1H), 2.95 (d, J = 13.7 Hz, 1H), 2.50 (d, J = 13.8 Hz,
1H), 2.12 (t, J = 13.5 Hz, 1H), 2.10 (m, 1H), 2.03 (dd, J = 13.3, 3.0 Hz, 1H), 1.29 (d, J =
6.8 Hz, 3H), 1.29 (d, J = 6.8 Hz, 3H), 1.23 (s, 3H), 0.55 (d, J = 6.6 Hz, 3H), 0.37 (d, J =
6.9 Hz, 3H); MS (ESI) = 568.2 [M + H] .
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Synthetic procedures for making 2-((3R,5R,6S)(3-chlorophenyl)(4-
chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)methyl
oxopiperidinyl)acetic acid (Compound A)
Scheme 1-Procedure 1
Preparation of PropaneSulfinic Acid:
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Tetrahydrofuran (20 L) was added to a reaction vessel and the temperature of the
vessel was cooled to –50 °C. Sulfur dioxide (3.5 kg, 54.6 mol) was condensed in the
reaction vessel at –50 °C. Isopropyl magnesium chloride (2M in tetrahydrofuran, 21 L,
42 mol) was added to the solution. The reaction mixture was agitated for 30 min at –
10 °C and aqueous 2.5 N hydrochloric acid (18.5 l, 46.2 mol) was added. The reaction
mixture was warmed to 20 °C and t-butylmethyl ether (10 L) was added. The phases
were separated and the aqueous phase was extracted twice with t-butylmethyl ether (10
L). The combined organic extracts were washed with aqueous sodium chloride (12 wt%,
mL) and concentrated under reduced pressure to afford the desired sulfinic acid in
82% yield (3.7 Kg).
Preparation of (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone:
To a solution of propanesulfinic acid (912 g, 8.4 mol) in toluene (7.5 L) was
added tetrahydrofuran (3.6 L). Sodium t-butoxide (2M in tetrahydrofuran, 3.6 L, 7.2
mol) was added while maintaining the temperature of the mixture below 20 °C. The pH
of the mixture was measured to be approximately 6. The mixture was distilled under
atmospheric pressure to produce a distillate mass of 6.6 Kg. (3S,5S,6R,8S)Allyl(3-
chlorophenyl)(4-chlorophenyl)isopropylmethyl-2,3,5,6,7,8-
hexahydrooxazolo[3,2-a]pyridinium naphthalenesulfonate, hemi-toluene solvate
(also called the “oxoiminium salt, hemi-toluene solvate” herein) (3.62 Kg, 5.2 mol) and
toluene (7.8 L) were added, maintaining the temperature of the mixture below 30 °C.
The mixture was distilled under atmospheric pressure to produce a distillate mass of 7.2
Kg while simultaneously adding dimethylacetamide (10.9 L). The mixture was agitated
at approximately 120 °C for 14 h and cooled to 25 °C. t-Butylmethyl ether (9.1 L) and
water (14.5 L) were added to the mixture and the biphasic mixture was agitated until no
solids were visible. The phases were separated. The organic phase was washed with
water (7.3 L) and aqueous saturated sodium bicarbonate (7.1 L). The organic phase was
filtered and distilled under reduced pressure to produce a distillate mass of 15 Kg while
simultaneously adding acetonitrile (21.3 L). Water (2 L) was added and the solution was
seeded with (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)
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(isopropylsulfonyl)methylbutanyl)methylpiperidinone (160 g, 0.29 mol) at 25
°C (The seed material was prepared via the same process in a previously conducted
smaller scale experiment). The mixture was agitated at 25 °C for 25 min and cooled to
°C over approximately 45 min. A mixture of acetonitrile (3.0 L) and water (7.0 L)
was added to the reaction mixture over 1.5 h. The resultant mixture was agitated for 1 h
and filtered. The product was washed with a mixture of acetonitrile (3.6 L) and water
(2.4 L). The product was dried under nitrogen to afford (3S,5R,6S)allyl(3-
chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)
methylpiperidinone (2.9 Kg) in 86% yield.
Preparation of Compound A Ethanolate:
To a solution of (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)-
1-(isopropylsulfonyl)methylbutanyl)methylpiperidinone (2.4 Kg, 4.4 mol) in
ethyl acetate (8.4 L), acetonitrile (8.6 L), and water (6.5 L) was added ruthenium chloride
hydrate (20.5 g, 0.09 mol). Sodium periodate (5.0 kg, 23.2 mol) was added in four 4
equal portions over the course of 1.5 h, maintaining the temperature of the mixture
between 20 °C and 28 °C. The mixture was agitated for 2.5 h and filtered through a layer
of diatomaceous earth (3.33 Kg). The resulting diatomaceous earth cake was washed
with isopropyl acetate (10.4 L) and water (3 L). The filtrate was phase separated. The
organic phase was washed twice with an aqueous sodium chloride solution (25 wt%, 5.5
L), washed twice with an aqueous sodium chloride and sodium bisulfite solution (25 wt%
sodium chloride and 20 wt% sodium bisulfite, 7.8 L), and once with an aqueous sodium
chloride solution (25 wt%, 6.5 L). The organic phase was distilled under reduced
pressure while simultaneously adding isopropyl acetate (12.4 L). The batch was filtered.
Charcoal (680 g) was added and the mixture was agitated for 13 h. The mixture was
filtered through a layer of diatomaceous earth (1.5 Kg) and the diatomaceous earth cake
was washed with isopropyl acetate (8 L). The solution was distilled under reduced
pressure to produce a distillate mass of 24.5 Kg while simultaneously adding ethanol (16
L). Heptane (8.5L) was added and the solution was seeded with Compound A Ethanolate
(The seed material was prepared via the same process in a previously conducted smaller
scale experiment) (95 g). The mixture was agitated at 20 °C for 40 min and distilled
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under reduced pressure to produce a distillate mass of 10.9 Kg while simultaneously
adding heptane (8.8 L). The mixture was agitated for 12 h and filtered. The product was
washed with a mixture ethanol (0.4 L) and heptane (1.6 L). The product was dried under
nitrogen to afford Compound A Ethanolate (1.99 Kg) in 70% yield.
Preparation of Compound A Crystalline Anhydrous:
Compound A Ethanolate (1.0 Kg, 1.62 mol) was dissolved in methanol (8.5 L)
and the resultant solution was filtered. The solution was warmed to 35 °C and water (2.5
L) was added. The solution was seeded with Compound A Crystalline Anhydrous (50 g,
0.074 mol) and cooled to 20 °C over the course of 4 h (The seed material was prepared
via the same process in a previously conducted smaller scale experiment). Water (2 L)
was added over the course of 30 min. The mixture was agitated for 30 min and filtered.
The product was dried under nitrogen to afford Compound A Crystalline Anhydrous
(0.86 Kg) in 93% yield.
H NMR (400 MHz, DMSO-d ) δ 12.37 (s, 1H), 7.36 (bs, 4H), 7.23 (t, 1H, J = 7.9 Hz),
7.16 (ddd, 1H, J = 7.9, 1.9, 1.0 Hz), 7.02 (t, 1H, J = 1.9 Hz), 6.98 (bd, 1H, J = 7.9 Hz),
.02 (d, 1H, J = 7.9 Hz), 3.84 (dd, 1H, J = 13.4, 10.2 Hz), 3.58 (ddd, 1H, J = 13.5, 11.3,
3.0 Hz), 3.39 (spt, 1H, J = 6.8 Hz), 3.17 (bd, 1H, J = 13.4 Hz), 3.07 (bt, 1H, J = 8.6 Hz),
2.95 (d, 1H, J = 13.9 Hz), 2.51 (d, 1H, J = 13.9 Hz), 2.13 (bt, 1H, J = 13.5 Hz), 2.11 (spt,
1H, J = 6.8 Hz), 2.04 (dd, 1H, J = 13.5,3.0 Hz), 1.30 (2x d, 6H, J = 6.8 Hz), 1.24 (s, 3H),
0.56 (d, 3H, J = 6.8 Hz), 0.38 (d, 3H, J = 6.8 Hz); Exact Mass [C H Cl NO S] :
28 36 2 5
calculated = 568.1691, measured M/Z [M+1] = 568.1686.
It is noted that when seed crystals are used in the procedures set forth in this
application, the seed crystals can be obtained by following the procedures set forth
herein, typically on a smaller scale, to obtain seed crystals for the larger scale syntheses.
Scheme 2- Procedure 2
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Preparation of Calcium PropaneSulfinate Dihydrate:
Tetrahydrofuran (20 L) was added to a reaction vessel and the temperature of the
vessel was cooled to –50 °C. Sulfur dioxide (3.5 kg, 54.6 mol) was condensed in the
reaction vessel at –50 °C. Isopropyl magnesium chloride (2M in tetrahydrofuran, 21 L,
42 mol) was added to the solution. The reaction mixture was agitated for 30 min at –
°C and aqueous 2.5 N hydrochloric acid (18.5 l, 46.2 mol) was added. The reaction
mixture was warmed to 20 °C and t-butylmethyl ether (10 L) was added. The phases
were separated and the aqueous phase was extracted twice with t-butylmethyl ether (10
L). The combined organic extracts were washed with aqueous sodium chloride (12 wt%,
mL) and concentrated under reduced pressure to afford the desired propanesulfinic
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acid in 82% yield (3.7 Kg). The propanesulfinic acid was dissolved in ethanol (37 L)
and a solution of calcium acetate monohydrate (3.0 Kg, 17.1 mol) in water (7.2 L) was
added. The resultant mixture was agitated for 1 h and filtered. The product was washed
with a mixture of ethanol (10.8 L) and water (1.1 L). The product was dried under
nitrogen to afford calcium propanesulfinate dihydrate in 86% yield (4.26 Kg). H
NMR (400 MHz, DMSO-d6) δ 3.37 (s, 4H), 1.88 (spt, 2H, J = 7.0 Hz), 0.92 (d, 12H, J =
7.0 Hz).
Preparation of (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone:
Calcium propanesulfinate dihydrate (2943616) (2.7 Kg, 9.36 mol) and toluene
(22 L) were added to a 60 L vessel. The reaction mixture was warmed to 110 °C and
distilled under reduced pressure to produce a distillate mass of 50 Kg while
simultaneously adding toluene (43 L). The reaction mixture was cooled to 40 ° C and
(3S,5S,6R,8S)Allyl(3-chlorophenyl)(4-chlorophenyl)isopropylmethyl-
2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium naphthalenesulfonate, hemi toluene
solvate (3.6 Kg, 5.2 mol) and toluene (9.0 L) were added. The reaction mixture was
warmed to 110 °C and distilled under atmospheric pressure to produce a distillate mass of
.8 Kg while simultaneously adding dimethylacetamide (10.9 L). The mixture was
agitated at approximately 120 °C for 14 h and cooled to 40 °C. t-Butylmethyl ether (9.1
L) and water (14.5 L) were added to the mixture and the biphasic mixture was agitated
until no solids were visible. The phases were separated. The organic phase was washed
twice with water (2x 7.3 L), once with aqueous saturated sodium bicarbonate (7.1 L), and
once with an aqueous sodium chloride (12 wt%, 7.1 L). The organic phase was cooled to
20 °C, filtered, and distilled under reduced pressure to produce a distillate mass of 15 Kg
while simultaneously adding acetonitrile (21.3 L). Water (2 L) was added. The solution
was seeded with (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (160 g, 0.29 mol) at 25
°C. The mixture was agitated at 25 °C for 25 min and cooled to 20 °C over
approximately 45 min (The seed material was prepared via the same process in a
previously conducted smaller scale experiment). A mixture of acetonitrile (3.0 L) and
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water (7.0 L) was added to the reaction mixture over 1.5 h. The resultant mixture was
agitated for 1 h and filtered. The product was washed with a mixture of acetonitrile (3.6
L) and water (2.4 L). The product was dried under nitrogen to afford (3S,5R,6S)allyl-
-(3-chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)-
3-methylpiperidinone (2.8 Kg) in 83% yield.
Preparation of Compound A Ethanolate:
A solution of (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)
(isopropylsulfonyl)methylbutanyl)methylpiperidinone (1.6 Kg, 2.9 mol) in a
mixture of water (2.4 L) and acetonitrile (21.6 L) was allowed to flow through the
continuous stirred-tank reactor ozone vessel (1 L vessel) at a flow rate of 60 mL/min at
°C (alternatively, the ozonolysis was performed in a reaction vessel using an ozone
sparger). The reaction mixture was added to a solution of sodium chlorite (80 wt%, 1.0
Kg, 11.6 mol) in water (5.6 L) over the course of 6 h (alternatively, the aqueous solution
of sodium chlorite was added to the reaction mixture). The reaction mixture was agitated
for 16 h and a solution of sodium bisulfite (1.2 Kg, 11.6 mol) in water (5.6 L) was added
over the course of 2 h. The mixture was agitated for 1 h and the phases were separated.
To the organic phases were added isopropyl acetate (8 L) and water (8 L). The mixture
was agitated for 30 min and the phases were separated. The organic phase was washed
once with aqueous sodium chloride (6 wt%, 8 L), three times with aqueous 1M sodium
phosphate (pH 6, 8 L), and once with aqueous sodium chloride (6 wt%, 8 L). The
organic phase was filtered. The mixture was distilled under reduced pressure to produce
a distillate mass of 35 Kg while simultaneously adding isopropyl acetate (32 L). The
mixture was distilled under reduced pressure to produce a distillate mass of 36 Kg while
simultaneously adding ethanol (32 L). Heptane was added (9.6 L) and the mixture was
distilled under reduced pressure to produce a distillate mass of 5 Kg. The mixture was
seeded with Compound A Ethanolate (80 g, 0.13 mol) (The seed material was prepared
via the same process in a previously conducted smaller scale experiment). Heptane (6.4
L) was added over the course of 1 h, the mixture was agitated for 12 h, cooled to 15 °C,
and filtered. The product was washed with a mixture of ethanol (90 mL) and heptane
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(4.8 L). The product was dried under nitrogen to afford Compound A Ethanolate (1.33
Kg) in 81% yield.
Preparation of Compound A Crystalline Anhydrous:
Compound A Ethanolate (1.0 Kg, 1.62 mol) was dissolved in methanol (8.5 L)
and the resultant solution was filtered. The solution was warmed to 35 °C and water (2.5
L) was added. The solution was seeded with Compound A Crystalline Anhydrous (50 g,
0.074 mol) and cooled to 20 °C over the course of 4 h (The seed material was prepared
via the same process in a previously conducted smaller scale experiment). Water (2 L)
was added over the course of 30 min. The mixture was agitated for 30 min and filtered.
The product was dried under nitrogen to afford Compound A Crystalline Anhydrous
(0.86 Kg) in 93% yield.
H NMR (400 MHz, DMSO-d ) δ 12.37 (s, 1H), 7.36 (bs, 4H), 7.23 (t, 1H, J =
7.9 Hz), 7.16 (ddd, 1H, J = 7.9, 1.9, 1.0 Hz), 7.02 (t, 1H, J = 1.9 Hz), 6.98 (bd, 1H, J =
7.9 Hz), 5.02 (d, 1H, J = 7.9 Hz), 3.84 (dd, 1H, J = 13.4, 10.2 Hz), 3.58 (ddd, 1H, J =
13.5, 11.3, 3.0 Hz), 3.39 (spt, 1H, J = 6.8 Hz), 3.17 (bd, 1H, J = 13.4 Hz), 3.07 (bt, 1H, J
= 8.6 Hz), 2.95 (d, 1H, J = 13.9 Hz), 2.51 (d, 1H, J = 13.9 Hz), 2.13 (bt, 1H, J = 13.5
Hz), 2.11 (spt, 1H, J = 6.8 Hz), 2.04 (dd, 1H, J = 13.5,3.0 Hz), 1.30 (2x d, 6H, J = 6.8
Hz), 1.24 (s, 3H), 0.56 (d, 3H, J = 6.8 Hz), 0.38 (d, 3H, J = 6.8 Hz); Exact Mass [C H
28 36
Cl NO S] : calculated = 568.1691, measured M/Z [M+1] = 568.1686. An XRPD pattern
representative of compound A crystalline anhydrous is shown in Figure 1.
An alternative route to a make compound A crystalline anhydrous is to make a
DABCO salt instead of the ethanolate as shown in Scheme 3.
Scheme 3-DABCO Salt Process
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Preparation of Compound A DABCO Salt:
Ozone was delivered to an agitated solution of (3S,5R,6S)allyl(3-
chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)
methylpiperidinone (4.0 Kg, 7.27 mol) in a mixture of water (6 L) and acetonitrile (54
L) using a subsurface C22 Hastelloy sparger at 20 °C over the course of ten hours. An
aqueous solution of sodium chlorite (80 wt%, 2.5 Kg, 29 mol) in water (14 L) was added
over the course of 1 h, maintaining the temperature of the mixture below 40 °C. The
reaction mixture was agitated for 12 h and a solution of sodium bisulfite (3.0 Kg, 29
mol) in water (14 L) was added over the course of 2 h, maintaining the temperature of the
reaction mixture below 40 °C. The mixture was agitated for 1 h and the phases were
separated. To the organic phases were added isopropyl acetate (IPAC) (20 L) and 1M
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aqueous sodium phosphate pH 6 (8 L). The mixture was agitated for 30 min and the
phases were separated. The organic phase was washed with 1M aqueous sodium
phosphate pH 6 (20 L) and with 1M aqueous sodium chloride (20 L). The mixture was
distilled under reduced pressure to produce a distillate mass of 75 Kg while
simultaneously adding isopropyl acetate (80 L). The water content of the solution by
Karl Fisher was less than one percent. The organic phase was filtered. The solution was
further distilled to a volume of approximately 16 L. The solution was heated to 55 °C
and 1,4-diazabicyclo[2.2.2]octane (DABCO, 424 g, 3.65 mol) was added. (3S,5R,6S)
allyl(3-chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutan-
2-yl)methylpiperidinone 1,4-diazabicyclo[2.2.2]octane (DABCO) salt seeds (136 g,
0.18 mol) were added as a slurry in isopropyl acetate and heptane (1/1, 800 mL). The
mixture was agitated at 55 °C for 20 minutes and cooled to 20 °C over the course of 2 h.
Heptane was added (16.8 L) over the course of 1 h and the mixture was agitated at 20 °C
for 12 h. The product was filtered and the filter cake was washed once with a mixture of
isopropyl acetate and heptane (2/3, 21 L) and once with a mixture of isopropyl acetate
and heptane (1/4, 21 L). The product was dried under nitrogen to afford Compound A
DABCO Salt (4.64 Kg) in 87% yield (100% liquid chromatography area percent
(LCAP), 78.9 wt% Compound A). The compound A DABCO salt is a solvate of
isopropyl acetate (IPAC) in accordance with Scheme 3. The Compound A DABCO Salt
is the better performing purification control point to enhance the purity of the drug
substance (Compound A). Typically, the purity of crude reaction mixtures of 97 to 99
liquid chromatography area percent purity can be improved to 100 liquid chromatography
area percent purity (no impurity at greater level than 0.05 liquid chromatography area
percent) using the crystallization of the DABCO salt. For comparison, enhancement of
purity of the drug substance (Compound A) using Compound A Ethanolate as a control
point allows for crude reaction mixtures of 97 to 99 liquid chromatography area percent
purity to be improved to 99.5 to 99.6 liquid chromatography area percent purity (and
multiple impurities are present in the filtered material at greater levels than 0.05 liquid
chromatography area percent).
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H NMR (400 MHz, CDCl ): δ ppm 0.49 ( d, J = 6.8 Hz, 6H), 0.64 (d, J = 6.4 Hz, 6H),
1.23 (d, J = 6.0 Hz, 12H), 1.41 (s, 6H), 1.43 (d, J = 7.6 Hz, 12H), 2.02 (s, 6H), 2.05-2.00
(m, 2H), 2.30-2.15 (m, 4H), 2.71 (d, J = 13.2, 2H), 2.84 (dd, J = 2.0, 13.6, 2H), 2.90 (d, J
= 13.6 Hz, 2H), 2.96 (s, 12H), 3.11 (pent, J = 6.8 Hz, 2H), 3.67-3.22 (m, 2H), 3.55-3.48
(m, 2H), 4.07 (dd, J = 10.4, 13.2 Hz, 2H), 4.99 (sept, J = 6.4 Hz, 2H), 5.13 (d, J = 11.2
Hz, 2H), 7.10-6.98 (m, 8H), 7.35-7.10 (m, 8H), 13.2 (br, 2H). C NMR (101 MHz,
CDCl ) δ ppm 15.3, 15.7, 20.3, 21.0, 21.4, 21.8, 25.6, 32.6, 39.6, 41.5, 44.5, 44.6, 44.8,
47.0, 54.8, 58.4, 67.6, 69.2, 76.7, 77.0, 77.4, 125.7, 126.9, 128.2, 128.5, 129.8, 133.9,
134.0, 137.5, 143.8, 170.7, 174.6, 176.3. m.p. 103 °C.
Preparation of Compound A Crystalline Anhydrous
To (3S,5R,6S)allyl(3-chlorophenyl)(4-chlorophenyl)((S)(isopropyl
sulfonyl)methylbutanyl)methylpiperidinone 1,4-diazabicyclo[2.2.2]octane
(DABCO) salt (8.28 Kg, 5.79 mol) were added isopropyl acetate (41.4 L) and water (41.4
L). To the mixture was added 4M aqueous hydrochloric acid (3 L, 12.1 mol) and the
biphasic mixture was agitated for 30 minutes. The phases were separated and the organic
phases was washed twice with 1M aqueous sodium phosphate pH 6 (25 L) and once with
aqueous sodium chloride (7 wt%, 33 L). The mixture was distilled under reduced
pressure to produce a distillate mass of 56 Kg while simultaneously adding isopropyl
acetate (42 L). The isopropyl acetate content and the water content by Karl Fisher were
both measured to be less than one percent in the solution. The organic phase was filtered.
The organic phase was distilled under reduced pressure to generate a distillate mass of 20
kg while simultaneously adding acetic acid (45 L). The solution was heated to 60 °C and
deionized water (29 L) was added over the course of 30 minutes. (3S,5R,6S)allyl
(3-chlorophenyl)(4-chlorophenyl)((S)(isopropylsulfonyl)methylbutanyl)
methylpiperidinone seeds (320 g, 0.56 mol) were added as a slurry in acetic acid and
deionized water (3/2, 1 L). The mixture was agitated at 60 °C for 3 h, and cooled to 20
°C over the course of 6 h. The mixture was agitated at 20 °C for 12 h. Deionized water
(7 mL) was added over the course of 1 h and the mixture was agitated for one additional
hour. The product was filtered and the filter cake was washed once with a mixture of
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acetic acid and deionized water (1/1, 13 L) and three times with deionized water (3 x 65
L). The product was dried under nitrogen to afford (3S,5R,6S)allyl(3-
chlorophenyl)(4-chlorophenyl)((S)(isopropyl sulfonyl)methylbutanyl)
methylpiperidinone (6.3 Kg) in 92% yield (100% LCAP, 100.3 wt%, 320 ppm acetic
acid, <100 ppm water).
A synthesis of Compound A is shown in Scheme A. An important intermediate in
the synthesis is the compound (3S,5S,6R,8S)Allyl(3-chlorophenyl)(4-
chlorophenyl)isopropylmethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridinium
naphthalenesulfonate (also called the “oxoiminium salt” or “oxazolinium salt” herein).
Due to difficulties crystallizing the TfO or TsO salts of (3S,5S,6R,8S)Allyl(3-
chlorophenyl)(4-chlorophenyl)isopropylmethyl-2,3,5,6,7,8-
hexahydrooxazolo[3,2-a]pyridinium naphthalenesulfonate, they were not isolated.
Crystallization is useful because it can be used to remove impurities generated in the
process or found in the starting materials. Hence, a hydrolysis to a crystalline lactam
followed by a re-formation of the oxoiminium salt can be used.
Scheme A
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The present disclosure describes a process to make an oxoiminium
naphthalenesulfonate salt, and particularly an oxoiminium naphthalenesulfonate salt,
hemi toluene solvate, that is crystalline. Using the oxoiminium naphthalenesulfonate salt,
hemi-toluene solvate provides for an improved method of making Compound A (See,
Scheme B below).
Scheme B
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The oxoiminium salt, hemi-toluene hydrate was made by heating (3S,5R,6S)
allyl(3-chlorophenyl)(4-chlorophenyl)((S)hydroxymethylbutanyl)
methylpiperidinone and 1-naphthalene sulfonic acid in toluene under dehydrative
conditions. The crystalline material is characterized as a hemi-toluene solvate by NMR,
DSC, and XRPD. This crystalline form is a shelf-stable substance, which is, therefore,
well suited as a reagent to make Compound A. One way of making the oxoiminium salt
is by ion exchange using 1-naphthalene-sulfonate, followed by crystallization from
toluene. It was found that the advantages of using 1-naphthalene sulfonate over other
counterions included rapid crystallization kinetics, predictable crystal habit and size, low
room-temperature solubility in toluene (<10 mg/ml), high melting point (207–209 °C),
and most importantly, high impurity purging capability. All process impurities including
stereoisomers were routinely purged to less than 0.5 liquid chromatography area percent
(LCAP) with a single crystallization. (See Scheme C below)
Scheme C
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Formation of the oxoiminium salt as shown in Scheme D below could be
accomplished by double dehydrative cyclization using Tf O under cryogenic conditions
(conditions a) or using Ts O at elevated temperatures (conditions b).
Scheme D
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The advantages of Conditions a is that the reaction could be performed in a single
step. However, these conditions can have side reactions (such as undesirable elimination
leading to stilbene-type byproducts) and undesirable cryogenic processing. The latter
(conditions b) is a step-wise process, with well characterized formation of intermediates
on route to the oxoiminium naphthalenesulfonate salt. Since Ts O is a milder reagent,
undesirable double cyclizations are significantly reduced and higher yields (>75% vs
<60% yield) can be obtained. In addition, the process is more desirable for scale-up
under heating conditions.
Scheme E
Step-wise conversion of valinol adduct (labeled “amide” in Scheme E) to oxoiminium
naphthalenesulfonate salt under Ts O conditions is shown in Scheme E.
Below is the a description of the process that enabled multiple kilogram delivery
of the oxoiminium salt. The first step of the process is reacting (3S,5R,6R)allyl(3-
chlorophenyl)(4-chlorophenyl)methyltetrahydro-2H-pyranone with L-valinol at
an elevated temperature. The low optical purity (80% ee) and general purity (85%) of the
starting lactones is acceptable. The valinol adduct is formed as a diastereomeric mixture,
which is telescoped into subsequent synthetic steps.
In the presence of 2,6-lutidine, the reaction of the valinol adduct (amide in
Scheme E) with tosic anhydride is essentially instantaneous at 15 to 25 °C, providing
hydroxy oxazoline as a stable intermediate. In the presence of additional tosic anhydride
and 2,6-lutidine, a second observable reaction intermediate, tosyl oxazoline, forms.
Finally, after prolonged heating of the reaction mixture at its reflux temperature (55 °C
for 1 day), the reaction proceeds to completion to provide oxoiminium tosylate.
The reaction mixture is quenched with sulfuric acid and washed multiple times
with a sodium 1-naphthylsulfonate solution to facilitate counter ion exchange. After a
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distillation step in which the reaction solvent is switched from dichloromethane to
toluene, oxoiminium salt crystallizes as a rod-like hemi-toluene solvate.
In summary, crystalline oxoiminium salt is an isolatable, stable intermediate that
is good for purging various impurities such as diastereomers and stilbene using
crystallization. As a material to make compound A, the oxoiminium salt, hemi-toluene
solvate has desirable features, including isolability in high chemical and stereoisomeric
purity, bulk properties suitable for standard manufacturing techniques, and stability to
storage.
Scheme F
Preparation of oxoiminium salt, hemi-toluene solvate:
In accordance with Scheme F, L-Valinol (2.6 Kg, 25.2 mol) was melted at 50 °C
and (3S,5R,6R)allyl(3-chlorophenyl)(4-chlorophenyl)methyltetrahydro-2H-
pyranone (3.6 Kg, 84.0 wt%, 80.8% ee, 7.9 mol) was added. The mixture was heated
to 110 °C and agitated at that temperature for 5 h. The mixture was cooled to 20 °C and
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dichloromethane (17.9 L) was added. Aqueous 1N hydrochloric acid (18.5 L) was added
and the biphasic mixture was agitated for 10 min. The phases were separated and the
organic phase was washed with an aqueous sodium chloride solution (20 wt%, 7 L). The
organic phase was distilled under atmospheric pressure to produce a distillate mass of
13.7 Kg while simultaneously adding dichloromethane (3.3 L). The organic phase was
added over the course of 10 min to a solution of p-toluene sulfonic anhydride (5.9 Kg, 18
mol) in dichloromethane (23.0 L). 2,6-Lutidine (3.56 Kg, 33.2 mol) was added over the
course of 1 h, maintaining the temperature of the mixture below 25 °C. The mixture was
agitated at 20 °C for 40 min. The mixture was distilled under atmospheric pressure and
at 40 °C to produce a distillate mass of 13.0 Kg. The mixture was added to aqueous 2N
sulfuric acid (19.5 Kg) over the course of 15 min, maintaining the temperature below 20
°C. The mixture was agitated for 15 min and the phases were separated. The organic
phase was washed twice with an aqueous sodium 1-naphthylsulfonate solution (10 wt%,
19.4 Kg), and once with an aqueous sodium bicarbonate solution (5 wt%, 19.5 Kg). 1-
naphthylsulfonic acid dihydrate (64 g, 0.26 mol) was added.
The organic phase was distilled under reduced pressure and maintaining a
temperature of 50 °C to produce a distillate mass of 39.9 Kg while simultaneously adding
toluene (27.0 L). The mixture was seeded with oxoiminium salt, hemi-toluene solvate
(40 g, 0.06 mol) and agitated for 20 min (The seed material was prepared via the same
process in a previously conducted smaller scale experiment). The mixture was cooled to
°C and agitated for 20 h. The mixture was filtered. The product cake was washed
with toluene (7.9 L) and dried under nitrogen to afford oxoiminium salt, hemi-toluene
solvate (3.7 Kg, 63.6 wt%, 99.7% ee, 99/1 DR) in 76% yield.
H NMR (400 MHz, DMSO-d6) d 8.03-8.00 (m, 1H), 7.93-7.90 (m, 3H), 7.56-7.42 (m,
6.5 H), 7.33 (s, 1H), 7.27-7.13 (m, 6H), 5.85 (m, 1H), 5.35 (m, 3H), 5.02 (m, 1H), 4.93 (t,
1H, J = 9.98 Hz), 4.3 (m, 1H), 4.09 (m, 1H), 2.79 (m, 2H), 2.39 (t, 1H, J = 13.3 Hz), 2.3
(s, 1.5 H), 2.01 (dd, 1H, J = 13.69, 3.13 Hz), 1.34 (s, 3H), 0.61 (d, 3H, J = 6.46 Hz), 0.53
(d, 3H, J = 6.85 Hz), 0.41 (m, 1H)
Anhydrous Oxoiminium Salt
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The oxoiminium salt, hemi-toluene solvate (1g) was dissolved in chloroform (10
mL) and the solution was concentrated under reduced pressure. To the residue obtained
was added chloroform (10 mL) and the solution was concentrated under reduced pressure
again. Finally, to the residue obtained was added chloroform (10 mL) and the solution
was concentrated under reduced pressure.
H NMR (400 MHz, CDCl ) d 9.13 (d, 1H, J = 8.61 Hz), 8.35 (d, 1H, J = 7.24 Hz), 7.86
(t, 2H, J = 9.0 Hz), 7.57 (m, 1H), 7.48 (m, 2H), 7.28 (m, 5H), 7.09 (m, 3H), 6.11 (d, 1H,
J = 11.15 Hz), 5.81 (m, 1H), 5.54 (m, 1H), 5.32 (m, 2H), 4.79 (m, 1H), 4.64 (dd, 1H, J =
9.00, 4.89 Hz), 3.56 (m, 1H), 2.89 (t, 1H, J = 13.69 Hz), 2.65 (m, 2H), 1.97 (dd, 1H, J =
14.08, 3.33 Hz), 1.54 (s, 3H), 0.66 (s, 3H), 0.36 (m, 1H), 0.59 (s, 3H)
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Claims (5)
1. The compound 10
2. The compound
3. The compound of claim 2, which is in crystalline form. 15 4. The compound of claim 3, characterized by a powder X-ray diffraction pattern comprising peaks at diffraction angle 2 theta degrees at approximately 8.7, 18.5, 22.6 and
26.6.
5. The compound of claim 4, having the X-ray diffraction pattern substantially as shown 20 in
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