# US 2013/0158263 A1 · Intermediates for the preparation of hmg coa reductase inhibitors and processes for the preparation thereof

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- Number: US 2013/0158263 A1
- Document ID: US20130158263A1
- Status: Published application
- Kind: A1
- Application number: 13/576,296
- Filed: 2011-02-23
- Published: 2013-06-20
- Earliest claimed: 2010-02-23
- Assignees: Cadila Healthcare Limited
- Inventors: Shriprakash Dhar Dwivedi; Dhimant Jasubhai Patel; Mahesh Laljibhai Rupapara
- Web page: https://patentgrep.com/patent/US20130158263A1

## CPC

- C07D 405/12: linked by a chain containing hetero atoms as chain links
- A61P 3/06: Antihyperlipidemics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- C07D 257/04: Five-membered rings
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

A compound of Formula (1), is disclosed wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group, R is selected from: wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl, Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy, Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S, Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

## Claims

### Claim 1

A compound of Formula (1),
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group,
R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

### Claim 2 (depends on 1)

The compound as claimed in claim 1, selected from:

### Claim 3

A compound of Formula (2),
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

### Claim 4 (depends on 3)

The compound as claimed in claim 3, selected from:

### Claim 5

A compound of Formula (5),
wherein R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

### Claim 6 (depends on 5)

The compound of Formula (5) as claimed in claim 5, which is represented by:

### Claim 7

A compound of Formula (6),
wherein R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms.

### Claim 8

A compound of Formula (8),
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
Ra and Rb are same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms;
R10 is a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
wherein R1 and R2 are same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano; and
X1 is CH2, O, S or NR7,
wherein R7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.

### Claim 9

A compound of Formula (8B),
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
R10 is a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
wherein R1 and R2 are same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl;
R4 is H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, or cyano; and
X1 is CH2, O, S or NR7,
wherein R7 is H, alkyl, aryl, alkanoyl, aroyl, or alkoxycarbonyl.

### Claim 10 (depends on 9)

The compound as claimed in claim 9, which is selected from:

### Claim 11

A compounds of Formula (11),
wherein R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S.

### Claim 12 (depends on 1)

A process for the preparation of a compound of Formula (1),
as claimed in claim 1, the process comprising the steps of:
(a) reacting (S)-4-chloro-3-hydroxybutyric acid ester (7),
with a thiol derivative of Formula 3, selected from
wherein R4a, Rc, Rd and X are as defined in claim 1, in a suitable organic solvent in the presence of a base to obtain a compound of Formula (11);
(b) reacting the compound of Formula (11) with a compound of Formula (7a),
wherein Ra and Rb are the same or different and each represents hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, in an inert organic solvent to obtain a compound of Formula (6);
(c) treating the compound of Formula (6) with dialkylalkoxyborane in the presence of a base to obtain a compound of Formula (5);
(d) reacting the compound of Formula (5) with a suitable reagent in the presence of a catalyst in a polar organic solvent to obtain a compound of Formula (2),
wherein R, P1, P2, Ra and Rb are as defined in claim 1; and
(e) oxidizing the compound of Formula 2 with a suitable oxidizing agent to obtain the compound of Formula 1.

### Claim 13 (depends on 12)

The process as claimed in step (a) of claim 12, wherein the suitable organic solvent comprises one or more of toluene, xylene, ethylbenzene, cyclohexane, hexane, heptane, methylene dichloride, ethylene dichloride, and ethyl acetate.

### Claim 14 (depends on 12)

The process as claimed in step (a) of claim 12, wherein the base comprises one or more inorganic bases selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, and sodium hydride, or one or more organic bases selected from the group consisting of triethylamine, diisopropylethylamine, diisopropyl amine, 1,8-diazabicycloundec-7-ene (DBU), and pyridine.

### Claim 15 (depends on 12)

The process as claimed in step (c) of claim 12, wherein the dialkylalkoxyborane is selected from group consisting of diethylmethoxyborane, diethylethoxyborane, and dimethylethoxyborane.

### Claim 16 (depends on 12)

The process as claimed in step (c) of claim 12, wherein the base comprises one or more of alkali metal hydrides selected from the group consisting of sodium hydride, potassium hydride, lithium hydride, sodium borohydride, potassium borohydride, and lithium aluminium hydride.

### Claim 17 (depends on 12)

The process as claimed in step (c) of claim 12, further comprising purifying the compound of Formula (5′) in a suitable organic solvent selected from the group consisting of one or more of C1-C4 alcohol, water, and aliphatic hydrocarbons.

### Claim 18 (depends on 12)

The process as claimed in step (d) of claim 12, wherein the suitable reagent comprises one or more of 2,2-dimethoxypropane, 2,2-dimethoxypentane, 1,1-dimethoxycyclohexane, and 2,2-dimethoxybutane.

### Claim 19 (depends on 12)

The process as claimed in step (d) of claim 12, wherein the catalyst comprises one or more of camphor sulfonic acid, methane sulphonic acid, ethane sulfonic acid, pyridinium p-toluene sulfonic acid, and p-toluene sulfonic acid.

### Claim 20 (depends on 12)

The process as claimed in step (e) of claim 12, wherein the suitable oxidizing agent comprises one or more of hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochloride, N-chlorosuccimide, N-bromosuccinimide, and oxone.

### Claim 21 (depends on 8)

A process for the preparation of a compound of Formula 8 as claimed in claim 8,
the process comprising the steps of: condensing a compound of Formula (1),
with an aldehyde compound of Formula,
wherein R10 is as defined in claim 8, in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in an inert organic solvent to obtain the compound of Formula (8).

### Claim 22

A process for the preparation of a compound of Formula (8B2),
the process comprising the steps of:
(a) reacting chiral sulfide diol of Formula (5a),
with 2,2-dimethoxypropane to obtain a compound of Formula (2a-B);
(b) oxidizing the compound of formula (2a-B) with a suitable oxidizing agent to provide a compound of the Formula (1a-B);
(c) condensing the compound of Formula (1a-B) with an aldehyde compound of Formula,
wherein R10 is, a hydrophobic anchor or a residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula,
in the presence of a base selected from the group consisting of sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain the compound of Formula (8B2).

### Claim 23 (depends on 22)

The process as claimed in claim 22, wherein the reaction of step (a) is performed in the presence of a catalyst selected from one or more of camphor sulfonic acid, methane sulphonic acid, ethane sulfonic acid, pyridinium p-toluene sulfonic acid, p-toluene and sulfonic acid.

### Claim 24 (depends on 22)

The process as claimed in claim 22, wherein the suitable oxidizing agent comprises one or more of hydrogen peroxide, m-chloroperbenzoic acid, sodium hypochloride, N-chlorosuccimide, N-bromosuccinimide, and oxone.

### Claim 25 (depends on 21)

The process as claimed in claim 21, wherein the suitable organic solvent comprises one or more of C1-C4 alcohol selected from methanol, ethanol, isopropanol, and butanol; C2-C4 ketone selected from acetone, methyl and isobutyl ketone; amides selected from dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, and dimethylsulfoxide.

### Claim 26

A process for the preparation of an HMG-CoA reductase inhibitor of Formula (9),
wherein
Y is selected from the group consisting of Na+, K+, Li+, Mg2+, Ca2+, Zn2+, Ba2+, Sr2+; and amine and
R10 is a hydrophobic anchor or residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
wherein R1 and R2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl; R4 is selected from H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, and cyano; X1 is selected from CH2, O, S and NR7, wherein R7 is selected from H, alkyl, aryl, alkanoyl, aroyl, and alkoxycarbonyl, the process comprising:
(a) condensing a compound of Formula (1)
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an aldehyde compound,
wherein R10 is as defined above, in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in an inert organic solvent to obtain a compound of Formula (8);
(b) hydrolyzing the compound of Formula (8) under acidic conditions to obtain a compound of Formula (8A);
(c) treating the compound of Formula (8A) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9),
(d) optionally treating the alkali metal salt of Formula (9) with a source of cation; and
(e) isolating the HMG-CoA reductase inhibitors of Formula (9).

### Claim 27

A process for the preparation of an HMG-CoA reductase inhibitor of general Formula (9),
wherein
Y is selected from the group consisting of Na+, K+, Li+, Mg2+, Ca2+, Zn2+, Ba2+, Sr2+; and amine and
R10 is a hydrophobic anchor or residue of an HMG-CoA reductase inhibitor and is selected from a compound of Formula (a) to (i),
wherein R1 and R2 are the same or different and are independently selected from alkyl, arylalkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, heteroaryl and cycloheteroalkyl; R4 is selected from H, halogen, CF3, hydroxy, alkyl, alkoxy, alkanoylamino, aroylamino, and cyano; X1 is selected from CH2, O, S and NR7, wherein R7 is selected from H, alkyl, aryl, alkanoyl, aroyl, and alkoxycarbonyl, the process comprising:
(a) condensing a compound of Formula (1B)
wherein P1 and P2 are alcohol protecting groups or 1,3-diol protecting group;
R is selected from:
wherein R4a is selected from alkyl, aryl, arylalkyl and cycloalkyl,
Rc is selected from H, alkyl, aryl, alkaoxy, haloalkyl, monohaloalkyloxy, and dihaloalkyloxy,
Rd is selected from alkyl, aryl, arylalkyl, CF3, halo and NO2 and X is selected from O, N—H, N-alkyl and S,
Ra and Rb are same or different and each represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an aldehyde compound,
wherein R10 is as defined above, in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in an inert organic solvent to obtain a compound of Formula (8B);
(b) hydrolyzing the compound of Formula (8B) under acidic conditions to obtain a compound of Formula (8A);
(c) treating the compound of Formula (8A) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9),
(d) optionally treating the alkali metal salt of Formula (9) with a source of cation; and
(e) isolating the HMG-CoA reductase inhibitor of Formula (9).

### Claim 28

A process for the preparation of rosuvastatin calcium of Formula (9a),
the process comprising:
(a) condensing a compound of Formula (1a-B),
with an aldehyde compound of Formula,
wherein R10 is
in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain a compound of Formula (8B2);
(b) hydrolyzing the compound of Formula (8B2) under acidic conditions to obtain a compound of Formula (8B2-b);
(c) treating the compound of Formula (8B2-b) with an alkali metal hydroxide to form the corresponding alkali metal salt of Formula (9B);
wherein, Y is selected from Na+, K+, and Li+;
(d) treating the alkali metal salt of rosuvastatin of Formula (9) with a source of calcium to obtain a calcium salt of rosuvastatin; and
(e) isolating the rosuvastatin calcium of Formula (9a).

### Claim 29 (depends on 28)

The process as claimed in claim 28, wherein the hydrolysis of compound (8B2) under acidic conditions can be done by one or more of hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

### Claim 30 (depends on 28)

The process as claimed in claim 28, wherein the alkali metal hydroxide is selected from one or more of sodium hydroxide, potassium hydroxide, and lithium hydroxide.

### Claim 31 (depends on 28)

The process as claimed in claim 28, wherein the alkali metal salt of rosuvastatin is rosuvastatin potassium.

### Claim 32 (depends on 28)

The process as claimed in claim 28, wherein the calcium source is selected from one or more of calcium chloride, calcium hydroxide, calcium acetate and hydrates thereof.

### Claim 33 (depends on 28)

The process as claimed in claim 28, wherein the rosuvastatin calcium is isolated in amorphous form.

### Claim 34

2-((4R,6S)-6-(E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide.

### Claim 35 (depends on 34)

The compound as claimed in claim 34, which is crystalline.

### Claim 36 (depends on 35)

The compound as claimed in claim 35, wherein the crystalline form is characterized by an X-ray powder diffraction pattern having characteristics peaks expressed in degrees 2θ at 5.4°, 10.0°, 12.4°, 14.8°, 16.3°, 17.4°, 18.0°, 20.7°, 23.6°, 24.1°, 25.9°, and 27.2°±0.2°.

### Claim 37 (depends on 35)

The compound as claimed in claim 35, wherein the crystalline form is characterized by an IR spectrum having peaks at about 1633, 1543, 1508, 1442, 1384, 1232, 1197, 1161, 1082, 1026, 962, 848, 777, 567, and 511 cm−1.

### Claim 38

A process for the preparation of 2-((4R,6S)-6-(E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide of Formula (8B2),
the process comprising the steps of:
(a) condensing a compound of Formula (1a-B),
with an aldehyde compound of Formula,
wherein R10 is
in the presence of a base selected from sodium hydride, potassium tert-butoxide, LiHMDS and NaHMDS in a suitable organic solvent to obtain a compound of Formula (8B2);
(b) extracting the compound of Formula (8B2) with a water immiscible organic solvent;
(c) removing the water immiscible organic solvent to obtain a residue;
(d) treating the residue with a suitable organic solvent;
(e) heating reaction mixture of step (d) at an elevated temperature;
(f) cooling the reaction mixture to ambient temperature; and
(g) isolating 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl-sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide in crystalline form.

### Claim 39 (depends on 38)

The process as claimed in claim 38, wherein in step (a) the suitable organic solvent comprises one or more of C1-C4 alcohol selected from methanol, ethanol, isopropanol, and butanol, and the like, C2-C4 ketone selected from acetone, methyl and isobutyl ketone, and amides selected from dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, and dimethylsulfoxide.

### Claim 40 (depends on 38)

The process as claimed in claim 38, wherein the water immiscible organic solvent comprises one or more of toluene, xylene, ethylbenzene, ethyl acetate, butyl acetate, and methylene dichloride.

### Claim 41 (depends on 38)

The process as claimed in claim 38, wherein in step (d) the suitable organic solvent comprises one or more of C1-C4 alcohol selected from methanol, ethanol, isopropanol, and butanol and, C2-C4 ketone selected from acetone and methyl isobutyl ketone, amides selected from dimethylformamide, dimethylacetamide, N-methyl pyrrolidone, and dimethylsulfoxide, and ethers selected from methyl tert-butyl ether, diisopropylether, cyclohexane, n-heptane, and n-hexane.

### Claim 42 (depends on 38)

The process as claimed in claim 38, wherein the elevated temperature is from about 40° C. to about 100° C.

### Claim 43 (depends on 38)

The process as claimed in claim 38, wherein the ambient temperature is from about 0° C. to about 30° C.

### Claim 44

A compound selected from:
(S)-ethyl 3-hydroxy-4-(1-phenyl-1H-tetrazol-5-ylthio)butanoate (11a);
(S)-5-hydroxy-N,N-dimethyl-3-oxo-6-(1-phenyl-1H-tetrazol-5-ylthio)hexanamide (6a);
(3R,5S)-3,5-dihydroxy-N,N-dimethyl-6-(1-phenyl-1H-tetrazol-5-ylthio)hexanamide (5a);
2-((4R,6S)-2,2-diethyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-A);
2-((4R,6S)-2,2-dimethyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-B);
N,N-dimethyl-2-((2R,4S)-4-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetamide (2a-C);
2-((4R,6S)-2-ethyl-2-methyl-6-((1-phenyl-1H-tetrazol-5-ylthio)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (2a-D);
2-((4R,6S)-2,2-diethyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-A);
2-((4R,6S)-2,2-dimethyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-B);
N,N-dimethyl-2-((2R,4S)-4-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetamide (1a-C);
2-((4R,6S)-2-ethyl-2-methyl-6-((1-phenyl-1H-tetrazol-5-ylsulfonyl)methyl)-1,3-dioxan-4-yl)-N,N-dimethylacetamide (1a-D);
2-((4R,6S)-6-(E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)-N,N-dimethylacetamide (8B2); and
2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-1,5-dioxaspiro[5.5]undecan-2-yl)-N,N-dimethylacetamide (8B3).

### Claim 45 (depends on 17)

The process as claimed in step (c) of claim 17, wherein the aliphatic hydrocarbon is selected from n-hexane, n-heptane, cyclohexane, methylene dichloride and toluene.